Diastereoselective one-step synthesis of functionalized cis-aziridinyl alcohols from oxiranyl carbaldimines

Article abstract of DOI:10.1021/ol051090l

(Chemical Equation Presented) Upon treatment with lithiumorganic nucleophiles, trans-configured oxiranyl carbaldimines are transformed into anti-configured cis-aziridinyl alcohols with excellent diastereoselectivity. This conversion may be explained by a new type of the aza-Payne rearrangement, including first a nucleophilic attack on the imine carbon atom with diastereofacial differentiation followed by an intramolecular nucleophilic opening of the oxiranyl ring with simultaneous formation of the aziridine ring.

Full text of DOI:10.1021/ol051090l

ORGANIC
LETTERS
2005
Vol. 7, No. 15
3267-3270
Diastereoselective One-Step Synthesis
of Functionalized cis-Aziridinyl Alcohols
from Oxiranyl Carbaldimines
Julia Luzia Bilke, Monika Dzuganova, Roland Fro
1hlich, and
Ernst-Ulrich Wurthwein*
1
Organisch-Chemisches Institut der Westfa¨lischen Wilhelms-UniVersita¨t Mu¨nster,
D-48149 Mu¨nster, Germany
wurthwe@uni-muenster.de
Received May 11, 2005
ABSTRACT
Upon treatment with lithiumorganic nucleophiles, trans-configured oxiranyl carbaldimines are transformed into anti-configured cis-aziridinyl
alcohols with excellent diastereoselectivity. This conversion may be explained by a new type of the aza-Payne rearrangement, including first
a nucleophilic attack on the imine carbon atom with diastereofacial differentiation followed by an intramolecular nucleophilic opening of the
oxiranyl ring with simultaneous formation of the aziridine ring.
Similar to oxiranes, aziridines are valuable building blocks
in modern synthetic organic chemistry. Besides the applica-
tion of aziridines in the stereoselective synthesis of important,
biologically active compounds such as alkaloids, â-lactam
antibiotics, and amino acids, they have found use as chiral
auxiliaries or ligands in transition-metal-catalyzed re-
actions.1,2
carbon centers in one step, which is described best as an
aza-Darzens reaction (Scheme 1).5
Scheme 1
Among several synthetic routes starting from 1,2-amino
alcohols, hydroxycarboxylic acids, epoxides, alkenes, dioles,
azirines, and imines, the aza-Payne reaction provides an
attractive but rarely used access to the heterocycle.3,4
In this report, we present a new type of the aza-Payne
reaction, in which oxiranyl carbaldimines 1 are transformed
into aziridinyl alcohols 2 with excellent regio- and diaste-
reoselectivity upon treatment with lithiumorganic nucleo-
philes. This work is based on our earlier discovery that
oxiranyl carbaldimines 1 dimerize in a highly diastereo-
selective process to yield aziridine derivatives 3 with up to
four stereogenic centers and up to seven functionalized
Thus, dropwise addition of a THF solution of oxiranyl
carbaldimines 1a-k to a solution of the lithium reagent in
dry THF at -78 °C, warming to room temperature, and
subsequent aqueous workup gave the aziridinyl alcohols
2aa-kc in good yields and excellent diastereoselectivity6,7
(Scheme 2, Table 1, see Figure 1 for the X-ray structure of
2hc).8
(1) McCoull, W.; Davis, F. A. Synthesis 2000, 1347-1365.
(2) Sweeney, J. B. Chem. Soc. ReV. 2002, 31, 247-258.
(3) Tanner, D. Angew. Chem. 1994, 106, 625-646; Angew. Chem., Int.
Ed. Engl. 1994, 33, 599-616.
(5) Alickmann, D.; Fro¨hlich, R.; Wu¨rthwein, E.-U. Org. Lett. 2001, 10,
1527-1530.
(6) Compare: Evans, D. A.; Williams, J. M. Tetrahedron Lett. 1988,
29, 5065-5068.
(4) Coutrot, P.; El Gadi, A. J. Organomet. Chem. 1985, 280, C-11.
10.1021/ol051090l CCC: $30.25
© 2005 American Chemical Society
Published on Web 06/29/2005

Scheme 2
Table 1. Synthesis of Oxiranyl Carbaldimines 1 and Formation
of Aziridinyl Alcohols 2 by Nucleophilic Attack
1
R1
R2
Nu
2
yield [%]
1a
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
Pr
i-Pr
MeLi
BuLi
PhLi
MeLi
BuLi
PhLi
PhCCLi
MeLi
BuLi
PhLi
2aa
2ab
2ac
2ba
2bb
2bc
2bd
2ca
2cb
2cd
2d
42
60
63
35
47
65
33
54
47
70
69
35
67
65
60
53
59
74
56
76
92
41
60
49
59
64
32
56
65
i-Pr
i-Pr
t-Bu
t-Bu
t-Bu
t-Bu
Pr
1b
1c
Pr
Pr
The corresponding starting materials 1a-k were synthe-
sized in a straightforward manner starting from R,â-unsatur-
ated aldehydes by epoxidation with hydrogen peroxide in
buffered aqueous solution as an oxidant (30% yield),
followed by condensation with aliphatic amines (75% yield)
as cis/trans mixtures (average cis/trans ratio of 8:92).9,10 The
corresponding diastereomeric ratio of the cis-aziridinyl
alcohols 2aa-kc was determined to be 92:8 (anti/syn). The
diastereomers can be separated by flash chromatography.11,12
The transformation of aminomethyloxiranes into aziridinyl
alcohols is known as the aza-Payne rearrangement.13 How-
ever, in most cases, external nucleophiles are used for the
ring opening of the oxirane. Vaultier et al.14 have induced
this rearrangement by deprotonation of aminomethyloxiranes,
thus generating an internal nucleophile for ring conversion.
Here, we report on the first case wherein an amine anion is
generated as an intermediate by attack of a nucleophile on
an imine functionality. This approach broadens the scope of
the reaction considerably.
1d
1e
c-Hex
c-Pr
c-Pr
1-Adama
1-Adama
i-Pr
i-Pr
i-Pr
t-Bu
t-Bu
t-Bu
Pr
PhLi
BuLi
PhLi
2ea
2eb
2fa
1f
PhLi
2-furanyl-Li
MeLi
BuLi
PhLi
MeLi
BuLi
PhLi
BuLi
PhLi
PhCCLi
BuLi
PhLi
2fb
2ga
2gb
2gc
2ha
2hb
2hc
2ia
1g
1h
1i
Pr
Pr
2ib
2ic
2ja
1j
i-Pr
i-Pr
t-Bu
t-Bu
t-Bu
Pr
Pr
Pr
Pr
2jb
1k
MeLi
BuLi
PhLi
2ka
2kb
2kc
a 1-Adam: 1-adamantyl.
(7) Kim, S.-W.; Noh, H.-Y.; Paek, S. I.; Ha, H.-J.; Lee, W. K. Bull.
Korean Chem. Soc. 2004, 25, 1617-1618.
To explain this unprecedented transformation we suggest
a highly diastereoselective aza-Payne rearrangement reaction,
(8) Typical Experimental Procedure for the Preparation of 2hc. Under
an argon atmosphere, phenyllithium (1.10 mL, 2.20 mmol, 2.0 M in dibutyl
ether) was dissolved in anhydrous THF (15 mL) at -78 °C. A solution of
1h (339 mg, 2.00 mmol) in dry THF was added dropwise over 30 min, and
the mixture was allowed to warm to room temperature over 16 h. After
addition of water (20 mL), the aqueous phase was extracted with
dichloromethane (4 × 20 mL), and the combined organic layers were dried
over magnesium sulfate. The solvent was evaporated, and the organic residue
was purified by flash chromatography to give anti,cis-2hc (0.469 g, 1.86
mmol, 93.0%) as a colorless solid. Mp: 56 °C. 1H NMR (300 MHz,
3
3
CDCl3): δ ) 0.92 (d, J ) 6.8 Hz, 3H, (CH3)2CHCH), 0.95 (d, J ) 6.8
3
Hz, 3H, (CH3)2CHCH), 1.07 (s, 9H, (CH3)3C), 1.74 (dsept, J1 ) 6.8 Hz,
3J2 ) 4.0 Hz, 1H, (CH3)2CHCH), 2.15 (dd, 3J1 ) 7.6 Hz, 3J2 ) 6.4 Hz, 1H,
3
3
3
CHCHPh), 2.93 (d, J ) 6.4 Hz, 1H, CHPh), 3.24 (dd, J1 ) 7.6 Hz, J2
3
) 4.0 Hz, 1H, CHCH(OH)), 7.20 (br t, J ) 7.1 Hz, 1H, CHarom), 7.27-
7.31 (m, 2H, CHarom), 7.40-7.42 ppm (m, 2H, CHarom). 13C NMR (75 MHz,
CDCl3): δ ) 16.1, 19.5 ((CH3)2CHCH(OH)), 26.9 ((CH3)3C), 31.2
((CH3)2CH), 37.0 (CHPh), 42.1 (PhCHCH), 53.1 (CH3)3C), 74.0 (CH(OH)),
126.7, 127.7, 128.1 (CHarom), 138.2 ppm (Cipso). MS (EI, m/z) ) 247 [M+],
232, 230, 216, 190, 160, 148, 118, 106, 91, 70, 57. IR (KBr): ν˜ ) 3350
cm-1 (s, OH), 3086 (m, CHarom), 3062 (m, CHarom), 3028 (m, CHarom), 2968
(vs, CHaliph), 2929 (vs, CHaliph), 2906 (s, CHaliph), 2873 (s, CHaliph), 1952
(w), 1878 (w), 1815 (w), 1604 (m), 1495 (m), 1468 (s, CHaliph). Anal. Calcd
for C16H25NO (247.38): C, 77.68; H, 10.19; N, 5.66. Found: C, 77.70; H,
10.15; N, 5.49.
Figure 1. Molecular structure of 2hc in the crystalline state.
which is fully supported by quantum chemical calculations
of structural and electronical properties of the lithiated
intermediates and transition states on the SCS-MP2/6-
31+G*//RHF/6-31+G* level (Figure 2).15,16 As a first step,
we postulate the formation of a five-membered chelate ring
with the lithium cation being coordinated by nitrogen and
oxygen of the oxiranyl carbaldimine 1-Li (Erel ) 0.00 kcal
(9) Ceroni, M.; Se´quin, U. HelV. Chim. Acta 1982, 65, 302-316.
(10) Taguchi, K.; Westheimer, F. H. J. Org. Chem. 1971, 36, 1579-
1572.
(11) Schaer, C. HelV. Chim. Acta 1958, 41, 619-623.
(12) Tishenko, I. G.; Revinskii, I. F.; Grinkevich, V. G.; Suboch, V. P.
USSR Vestn. Beloruss. Un-ta, Ser. 2 1978, 1, 28-32; CAN 90:71968 (1979).
(13) For a review, see: Ibuka, T. Chem. Soc. ReV. 1998, 27, 145-154.
(14) Najime, R.; Pilard, S.; Vaultier, M. Tetrahedron Lett. 1992, 37,
5351-5354.
3268
Org. Lett., Vol. 7, No. 15, 2005

activation barrier (27.1 kcal mol-1) for this gas-phase process
due to coordinational unsaturation of the lithium ion. For
the reaction in solution, however, one can assume that other
metal ions, stemming from the reaction mixture, coordinate
to the developing oxygen anion and will contribute to lower
the barrier.
The final intermediate, the aziridinyl alcoholate 6, is by
far the energetically most stable isomer within this set of
structures (-43.1 kcal mol-1) and demonstrates the exother-
micity of the proposed reaction mechanism. In 6, the five-
membered lithium chelate ring is regenerated, now with an
sp3 instead of an sp2 carbon center next to the three-
membered ring. The higher stability of the aziridine moiety
6 compared to the oxirane structure 1-Li is obvious.
Experimentally, hydrolysis of the O-Li bond with water
yields the observed anti,cis-configured aziridinyl alcohol 2.
Even tris-substituted aliphatic R,â-unsaturated aldehydes
such as 2-methyl-2-pentenal and 3-methylcrotonaldehyde can
be transformed by the same reaction sequence via oxidation
with hydrogen peroxide17 and condensation with primary
aliphatic amines18 to give 7a-d (7a, E:Z ) 3:2), which yield
the three-membered N-heterocycles 8 after nucleophilic
attack. Depending on the position of the substituents at C2
or C3 of the epoxide moiety, either aziridinyl alcohols with
three substituents at the aziridine ring 8a or tertiary alcohols
8b-g are the reaction products (Scheme 3, Table 2).
Figure 2. Calculated energies for the interconversion of 1-Li to 6
(methyllithium as a nucleophile) (SCS-MP2/6-31+G*) [kcal/mol].
mol-1, trans diastereomer). This fixed conformation of the
electrophile offers the diastereotopic faces of the imine
double bond. The attack of the negatively charged carbon
nucleophile proceeds from the sterically less hindered,
oxirane ring remote face, forming an amine anion 4. 4 Is
predicted to be more than 19 kcal mol-1 lower in energy
compared to the starting structure with the lithium ion still
being coordinated to the nitrogen and oxygen atoms. The
calculated activation barrier amounts to ca. 13.5 kcal mol-1.
As the aziridine ring-forming step, we assume an SN2-type
attack of the negatively charged nitrogen atom on carbon
atom C2 of the oxirane ring. This attack requires a 180° turn
of the oxirane moiety to form 5, enabling a proper SN2
trajectory with inversion at the stereogenic carbon C2. This
is accompanied by the breakdown of the lithium chelate, with
the lithium counterion still being coordinated to the nitrogen
atom. Due to the incomplete coordination sphere of the metal
center, we calculate a relatively high energy of about 15.5
kcal mol-1, compared to the first intermediate 4, for this
second intermediate 5 in the gas phase. Since solvent-
stabilizing effects will be active in solution, this value is
probably too large.
Scheme 3
In the third reaction step the aziridine ring 6 is formed
after an SN2-type attack at the C2 of the epoxide, ac-
companied by simultaneous ring opening of the oxirane to
form an anti-alcoholate with respect to the cis-configured
heterocycle. In this step, the configuration at carbon atom
C2 is inverted, while that of carbon atom C3 remains
predefined by the epoxide configuration. We calculate a high
A slightly different reaction sequence and conditions are
required for the synthesis of and nucleophilic attack on
oxiranyl carbaldimines with an aromatic substitution pattern.
Because of the insufficient nucleophilicity of aniline, 4-meth-
(15) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A., Jr.;
Stratmann, R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels, A.
D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.; Cossi,
M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.;
Ochterski, J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.; Malick,
D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Cioslowski, J.;
Ortiz, J. V.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi,
I.; Gomperts, R.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.;
Peng, C. Y.; Nanayakkara, A.; Gonzalez, C.; Challacombe, M.; Gill, P. M.
W.; Johnson, B. G.; Chen, W.; Wong, M. W.; Andres, J. L.; Head-Gordon,
M.; Replogle, E. S.; Pople, J. A. Gaussian 98, revision A.11.3; Gaussian,
Inc.: Pittsburgh, PA, 1998. Details of the quantum chemical calculations
(Gaussian archive entries) are available from E.-U.W. upon request.
(16) Grimme, S. J. Chem. Phys. 2003, 118, 9095-9102.
Table 2. Synthesis of cis-Aziridines 8a-g From the Oxiranyl
Carbaldimines 7a-d
R1
R2
R3
R4
Nu
yield [%]
7a, 8a
7b, 8b
7b, 8c
7c, 8d
7c, 8e
7c, 8f
7d, 8g
Et
H
Me
H
H
H
H
t-Bu
i-Pr
i-Pr
t-Bu
t-Bu
t-Bu
c-Hex
PhLi
BuLi
PhLi
BuLi
PhLi
PhCCLi
PhLi
36
25
52
38
37
37
43
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
H
Org. Lett., Vol. 7, No. 15, 2005
3269

oxyaniline was reacted instead with 2,3-epoxybutanal to
demonstrate the chemistry of an N-aromatic-substituted
oxiranyl carbaldimine 9a.
Scheme 5
Competing reactions such as oxidation giving the corre-
sponding acid limit the direct epoxidation of cinnamaldehyde.
A two-step reaction pathway starting with the epoxidation
of cinnamyl alcohol by MCPBA followed by selective
oxidation of the alcohol functionality using the Dess-Martin
periodinane provides a good alternative strategy, yielding
the phenyl-substituted oxiranyl carbaldehyde.19,20 Condensa-
tion reaction with tert-butylamine (30% yield) gives com-
pound 9b, which decomposes upon standing within a few
days.6
These results indicate that the attack of the lithium
nucleophile and the oxirane-aziridine rearrangement proceed
rapidly, as the process is complete within less than 2 h.
Considering the smooth synthesis of different oxiranyl
carbaldimines, the easy access to functionalized lithium
organics via deprotonation with lithium bases (including
carbonyl compounds), or the possibility of transmetalation
of appropriate organo halides or tin compounds, an even
wider scope of this reaction is to be expected.
Scheme 4
In conclusion, we have developed a new and experimen-
tally easy synthesis of cis-aziridinyl alcohols and their
corresponding esters by nucleophilic attack on oxiranyl
carbaldimines. The chelate-controlled SN2-type ring opening
of the epoxides results in the formation of cis-configured
aziridines. The anti/syn ratio of the alcohol moieties depends
on the trans/cis ratio of the epoxides. The starting materials
are simply accessible via epoxidation of R,â-unsaturated
aldehydes and subsequent condensation with primary amines.
The postulated reaction mechanism, which is supported by
ab initio calculations, is described best as a variant of the
aza-Payne reaction, proceeding with excellent diastereofacial
differentiation. It includes the nucleophilic attack of an
organolithium reagent on an aldimine from the sterically less
hindered face, an SN2-type ring opening of the oxirane by
the intermediately formed amine anion with simultaneous
formation of a cis-aziridine ring, and trapping of the
aziridinyl alcoholate with water or various acid chlorides.
To prevent possible lithiation of the aromatic rings, the
lithium nucleophiles were dissolved in dry THF and cooled
to -100 °C. Very slow dropwise addition of the aryl-
substituted oxiranyl carbaldimines 9a,b as a very dilute THF
solution (2-3 mmol/10-15 mL of THF), warming to room
temperature, and aqueous workup gave the aziridinyl alcohols
10a,b in similar yield and diastereoselectivity compared to
compounds 2 and 8 with an aliphatic substitution pattern
(Scheme 4).
Trapping of the lithium alcoholates with acid chlorides as
a third reaction component is also possible in a one-pot
procedure. After formation of the aziridinyl intermediates
within a reaction time of 1 h at -78 °C and another 30 min
at -20 °C to complete the conversion, addition of a solution
of the acid chlorides and slow warming to room temperature
gave the corresponding aziridinyl esters 11a-h in good
yields. Even the formation of a bis-aziridine 11i by reaction
with phthaloyl chloride is possible (Scheme 5).
Acknowledgment. Support by the Deutsche Forschungs-
gemeinschaft (DFG, SFB 424) and by the Fonds der
Chemischen Industrie is gratefully acknowledged.
Supporting Information Available: Summary of theo-
retical data (total energies, relative energies) and crystal-
lographic data (CIF) for compounds 2hc, 8e, and 10b, as
well as NMR spectroscopic data of selected compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(17) Marshall, H.; Penninger, J.; Weyerstahl, P. Liebigs Ann. Chem. 1982,
1, 49-67.
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OL051090L
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