Intramolecular aziridination: Decomposition of diazoamides with tethered imino bonds

Article abstract of DOI:10.1021/ol990750h

(Matrix presented) Of three possible mechanistic pathways, tethered oximino ethers react intramolecularly with diazoamides to produce a diazabicyclo[5.1.0]-hexane aziridine containing skeleton. Several acyclic and cyclic templates were synthesized and reacted with rhodium catalysts to prepare their corresponding annulated aziridines. Anomalous behavior was discovered with the piperidine template, resulting in an aziridination occurring during the attempted diazo-transfer reaction, rather than the catalyzed carbenoid reaction.

Full text of DOI:10.1021/ol990750h

ORGANIC
LETTERS
1999
Vol. 1, No. 4
667-670
Intramolecular Aziridination:
Decomposition of Diazoamides with
Tethered Imino Bonds
Dennis L. Wright† and Mark C. McMills*
Department of Chemistry and Biochemistry and The Program in Molecular and
Cellular Biology, Ohio UniVersity, Athens, Ohio 45701
mmcmills1@ohiou.edu
Received June 21, 1999
ABSTRACT
Of three possible mechanistic pathways, tethered oximino ethers react intramolecularly with diazoamides to produce a diazabicyclo[5.1.0]-
hexane aziridine containing skeleton. Several acyclic and cyclic templates were synthesized and reacted with rhodium catalysts to prepare
their corresponding annulated aziridines. Anomalous behavior was discovered with the piperidine template, resulting in an aziridination occurring
during the attempted diazo-transfer reaction, rather than the catalyzed carbenoid reaction.
We recently reported one of the first examples of a novel
intramolecular [2 + 1] cyclization pathway utilizing a
rhodium-mediated metallocarbenoid intermediate to generate
a cyclic substrate containing an aziridine.1-3 It could be
envisioned that the presence of a metallocarbenoid interme-
diate in proximity to an imino CdN moiety could lead to
several reaction pathways resulting in the formation of
medicinally relevant heterocycles. A [2 + 1] insertion/
annulation of the putative ylide intermediate with the CdN
bond of the imino group could be envisioned for Path A.
Similarly, an aziridine might be available through a direct
carbenoid insertion process, analogous to a carbene-alkene
cyclopropanation reaction.4 These similar pathways could
lead to the formation of substituted diazabicyclo[3.1.0]-
† Current address: Department of Chemistry, University of Florida,
Gainesville, FL 32606.
(1) (a) McMills, M. C.; Wright, D. L.; Zubkowski, J.; Valente, E.
Tetrahedron Lett. 1996, 37, 7205-7208. (b) Aziridine substrates derived
from diazoketones have been reported as minor reaction products. Padwa,
A.; Dean, D. C. J. Org. Chem. 1990, 55, 405. (c) Padwa, A.; Dean, D. C.;
Osterhout, M. H.; Precedo, L.; Semones, M. A. J. Org. Chem. 1994, 59,
5347.
137-ORGN. (m) Mahy, J. P.; Bedi, G.; Battioni, P.; Mansuy, D. J. Chem.
Soc., Perkin Trans. 2 1988, 1517-1524. (n) Vedejs, E.; Sano, H.
Tetrahedron Lett. 1992, 33, 3261-3264. (o) Wipf, P.; Henninger, T. C. J.
Org. Chem. 1997, 62, 1586-1587.
(2) For alternative approaches to aziridination from alkene substrates,
see: (a) Evans, D. A.; Faul, M. M.; Bilodeau, M. T. J. Org. Chem. 1991,
56, 6744-6 (b) Evans, D. A.; Faul, M. M.; Bilodeau, M. T.; Anderson, B.
A.; Barnes, D. M. J. Am. Chem. Soc. 1993, 115, 5328-9 (c) Evans, D. A.;
Faul, M. M.; Bilodeau, M. T. J. Am. Chem. Soc. 1994, 116, 2742. (d)
Bergmeier, S. C.; Seth, P. P. J. Org. Chem. 1997, 62, 2671-2674. (e)
Dubois, J.; Tomooka, C. S.; Hong, J.; Carreira, E. M. Acc. Chem. Res.
1997, 30, 364-372. (f) Evans, D. A.; Faul, M. M.; Bilodeau, M. T. J. Org.
Chem. 1991, 56, 6744-6746. (g) Ando, T.; Minakata, S.; Ryu, I.; Komatsu,
M. Tetrahedron Lett. 1998, 39, 309-312. (h) Atkinson, R. S.; Fawcett, J.;
Russell, D. R.; Tughan, G. J. Chem. Commun. 1986, 832-834. (i) Atkinson,
R. S.; Gattrell, W. T.; Ayscough, A. P.; Raynham, T. M. Chem. Commun.
1996, 1935-1936. (j) Harm, A. M.; Knight, J. G.; Stemp, G. Synlett 1996,
677. (k) Hogale, M. B.; Shelar, A. R.; Chavan, P. B. Indian J. Chem., Sect.
B 1992, 31, 456-458. (l) Jacobsen, E. N.; Li, Z.; Protopopova, M. Abstracts
of Papers, 205th National Meeting of the American Chemical Society,
Denver, CO; American Chemical Society: Washington, DC, 1993; Abstract
(3) For approaches to aziridination of imines, see: (a) Hansen, K. B.;
Finney, N. S.; Jacobsen, E. N. Angew. Chem., Int. Ed Engl. 1995, 34, 676.
(b) Li, Z.; Conser, K. R.; Jacobsen, E. N. J. Am. Chem. Soc. 1993, 115,
5326-7 (c) Li, Z.; Quan, R. W.; Jacobsen, E. N. J. Am. Chem. Soc. 1995,
117, 5889-10. (d) Aggarwal, V. K.; Thompson, A.; Jones, R. V. H.;
Standen, M. C. H. Phosphorus, Sulfur Silicon Relat. Elem. 1997, 120, 361.
(e) Dekimpe, N.; Desmaele, D. Tetrahedron Lett. 1994, 35, 8023. (f) Mohan,
J. M.; Uphade, B. S.; Choudhary, V. R.; Ravindranathan, T.; Sudalai, A.
Chem. Commun. 1997, 1429. (g) Rasmussen, K. G.; Jorgensen, K. A. J.
Chem. Soc., Perkin Trans. 1 1997, 1287. (h) Wang, D. K.; Dai, L. X.;
Hou, X. L. Chem. Commun. 1997, 1231. (i) Wipf, P.; Miller C. P.
Tetrahedron Lett. 1992, 33, 6267. (j) Osborn, H. M. I.; Sweeney, J.
Tetrahedron: Asymmetry 1997, 8, 1693.
(4) Moran, M.; Bernardinelli, G.; Muller, P. HelV. Chim. Acta 1995, 78,
2048.
10.1021/ol990750h CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/28/1999

hexane-containing natural products, a critical structural
feature of the mitomycin class of antineoplastic agents.
Alternatively, Path B can be viewed operationally as forma-
tion of an azomethine ylide intermediate, followed by [1,3]-
dipolar cycloaddition of a suitable dipolarophile leading to
the formation of the 3,8-diazabicyclo[3.1.0]octane core, a
substructure found in the potent antitumor, antibiotic com-
pounds such as quinocarcin and naphthyridinomycin.
Herein, we wish to report our efforts directed toward the
formation of aziridine-containing natural products utilizing
Path A as a method for preparation of these highly bioactive
natural products. Structural variation and process parameters
will be the initial focus of this study. Toward that end, several
structurally diverse substrates were examined, including
acyclic, cyclic, and bicyclic diazoamides.
With the successful completion of a simple acyclic
analogue assured, attention turned to the synthesis of systems
containing more complex cyclic ring systems such as those
found in the mitomycins and higher homologues. To study
the role of conformational effects on the diazodecomposition
process, three additional substrates were prepared and
examined for metal-mediated conversion to the aziridine-
containing cyclic substrate. The cycloaddition precursors
were prepared from commercially available amino acid or
alcohol starting materials (Scheme 2).
Scheme 2. Preparation of Cyclic DiazoAmides
To facilitate this investigation, N-methylethanolamine (1)
was protected as its trifluoromethyl amide (CF3CO2Et)5 then
oxidized (buffered PCC) to generate the corresponding
aminoaldehyde (Scheme 1). The aldehyde was converted to
Scheme 1. Acyclic DiazoAmide Precursor
The same synthetic sequence, successful in preparing the
acyclic diazoamide (3), was used to synthesize the diazo-
pyrrolidine oxime, commencing with proline methanol.
Pipecolic acid and isoquinoline-2-carboxylic acid were
protected as the corresponding tert-butyl carbamates (BOC2O),
reduced with borane-THF complex, and then oxidized under
Swern conditions to prepare the protected aminoaldehydes
in excellent yield. All aldehydes were converted to a mixture
of oxime ether isomers (6a-c) by exposure to methoxyl-
amine hydrochloride in an alcoholic solvent (3-9:1, E/Z
ratio). Deprotection of the tert-butyl carbamate occurred
readily through brief exposure to TFA. The crude amines
were acetoacetylated in high yield by treatment with diketene.
Conversion to diazoketoamides (7a-c) was best accom-
plished utilizing Davies protocol under conditions determined
for the formation of the acyclic diazoamide.
With the formation of pyrrolidine diazoamide (7a) secure,
attention turned to a determination and optimization of
conditions necessary for the aziridination process to occur.
Addition of 2 mol % of rhodium acetate to a refluxing
solution of diazoamide (7a) in chloroform resulted in the
formation of the aziridine-containing pyrrolizidine (8) in good
yield (aziridination of proline derivative, eq 2). The catalytic
a mixture of oxime ether isomers (2) by exposure to
methoxylamine hydrochloride in an alcoholic solvent
(3.5:1, E/Z ratio). Deprotection occurred readily utilizing
basic conditions for hydrolysis of the trifluoromethyl amide.
The crude amine was then acetoacetylated in high yield by
treatment with diketene. Conversion to diazoketoamide (3)
was best accomplished by reaction with p-acetamido-
benzenesulfonylazide6 and DBU followed by rapid chro-
matographic purification.
Allowing acyclic diazoamide (3) to react in the presence
of rhodium acetate (2 mol %, rt) effected clean conversion
to diazabicyclo[3.1.0]hexane (4) in excellent chemical yield
(86%) as a 3.5:1 mixture, in favor of the exo-containing
N-methoxyl group, in less than 3 h (acyclic diazodecompo-
sition, eq 1). It was observed that this reaction could be
catalyzed by copper (acac)2 as well. Both catalytic reactions
resulted in the formation of the same easily separable pair
of bicyclic aziridine conformers.
diazodecomposition reaction was found to be much slower
than that of the acyclic diazoamide (3), while a number of
668
Org. Lett., Vol. 1, No. 4, 1999

undetermined side products accompanied formation of the
aziridinopyrrolizidine (8).
The reactivity profile of the isoquinoline series was similar
to that found with the acyclic substrate, only one pair of
N-O isomers being formed cleanly during the reaction.
Reaction time is slower than that of the acyclic system but
much faster than that of the pyrrolidine diazoamide. These
results prompted us to investigate the thermal stability of
the diazoamides of the acyclic, pyrrolidine, and isoquinoline
series.
To probe the subtle conformational effects that give rise
to the surprising lack of reactivity found in the catalytic
aziridination of pyrrolidine diazoamide 7a (Scheme 1), a
ring-expanded analogue was prepared from pipecolic acid.
Surprisingly, it was found that exposure of ketoamide (9) to
standard diazo-transfer conditions failed to produce the
expected diazoamide (7b), rather it directly deliVered the
aziridinoindolizidine (10) in 88% isolated yield, also as a
separable mixture of inVertomers (aziridination of piperidine
derivative, eq 3).7 The intermediate diazo oxime (7b) could
The acyclic analogue differs from all of the other examples
in that the two reacting appendages are not constrained in a
reactive conformation imposed by the rigid piperidine or
isoquinoline template. Accordingly, this derivative showed
a much greater thermal stability than either the isoquinoline
or pipecolinic system. The acyclic diazoamide (7a) displayed
a half-life of >10 days (as monitored by 1H NMR).
Surprisingly, pyrrolidine diazoamide (7c) was found to be
remarkably resistant to any noncatalyzed cyclization condi-
tions and showed no conversion to aziridine after 1 month
at room temperature. Clean conversion was realized under
thermal conditions by refluxing the diazoamide for 24-48
h in polar solvents. For comparison, it was found that the
piperidine diazoamide could not be isolated at room tem-
perature and was so reactive that at -78 °C it still formed
an aziridine in 1-2 h. The isoquinoline diazoamide had a
thermal half-life of about 4-6 h at room temperature. The
speed of formation may suggest that the two reactive ends
of the tether, the diazoamide and the oxime, are placed in
close proximity in a highly reactive conformation, hastening
aziridine formation.
A possible mechanistic interpretation of this proposed
reaction sequence could involve several different pathways
from one initial intermediate. Formation of a fleeting or stable
diazoamide is followed by (1) the intramolecular cyclization
to the azomethine ylide (12) formed after addition of catalytic
metal or (2) a direct carbenoid CdN insertion process
analogous to intramolecular cyclopropanation. A plausible
mechanism for the noncatalyzed process could involve the
intermediacy of a [2 + 3]-dipolar cycloadduct between the
diazo group and the pendant oxime to produce a triazole
intermediate (13) which spontaneously collapses with con-
comitant loss of nitrogen to form the aziridines 4, 8, or 1111
(Scheme 3). Support for the triazole intermediate with
diazoamide (7c) is provided through the observation of a
pyrazole intermediate in a related olefin-containing sub-
be observed in the crude NMR and IR spectra, but complete
cyclization occurred prior to isolation.8 This result is in direct
contrast to the results seen previously, where rhodium
catalysis was required to generate the aziridine, from the
proposed metallocarbenoid intermediate. An attempt to
prepare a similar diazoamide by an alternative route utilizing
Padwa’s diazomalonylchloride produced identical results.9
With the large disparate reactivity discovered between the
acyclic and two cyclic substrates, a third derivative was
prepared with two additional sp2 centers. Isoquinoline
carboxylic acid provided the additional rigidifying sp2 centers
through the facility of an aromatic ring at C4-C5 of the
piperidine moiety. The addition of a benzene ring serves to
restrict the conformational mobility of the two reactive
moieties of isoquinoline (7c).
It was found that addition of a catalytic amount of rhodium
acetate (2 mol %, room temperature, dichloromethane)
resulted in the formation of the aziridinoisoquinoline (11)
in excellent yield in approximately 20 min (aziridination of
isoquinoline derivative, eq 4). Starting with a single diazo
(5) Curphey, T. J. J. Org. Chem. 1979, 44, 2805.
(6) Davies, H. M. L.; Cantrell, W. R.; Romines, K. R.; Baum, J. S. In
Organic Synthesis; Meyers, A. I., Ed.; 1991; Vol. 70, p 93.
(7) Aziridine nitrogen bearing electronegative heteroatoms possess high
barriers to inversion, see: (a) Schurig, V., Leyrer, U. Tetrahedron:
Asymmetry 1990, 1, 865. (b) Atkinson, R. S., Williams, P. J. J. Chem. Soc.,
Perkin Trans. 2 1996, 205. (c) Kost D., Raban, M. J. Am. Chem. Soc. 1982,
104, 2960. The products of systems in this study show no tendency to
interconvert N-O stereochemistry.
(8) The trans relationship at the bridgeheads was assigned by the small
coupling constant between the two bridgehead protons and with analogy to
compound 10.
(9) Marino, J. P.; Osterhout, M. H.; Price, A. T.; Sheehan, S. M.; Padwa,
A. Tetrahedron Lett. 1994, 35, 849.
(10) The structure was confirmed by X-ray crystallographic analysis. The
coordinates have been deposited with the Cambridge Crystallographic
Database.
(11) A similar pathway has been suggested for the spontaneous formation
of triazoles. Hunig, S.; Kraft, P. Heterocycles 1995, 40, 639.
oxime isomer (E) provided by chromatographic isolation of
the diazotization products, the reaction produced a single
N-O isomer. The cyclization adduct was unambiguously
assigned through the facility of a single-crystal X-ray
analysis.10
Org. Lett., Vol. 1, No. 4, 1999
669

aziridine moiety as a departure point for further elaboration.
Current investigations are aimed at further functionalization
of the aziridine-containing substrates as well as the applica-
tion of asymmetric catalysis to provide a route to chiral
aziridines.
Scheme 3. Proposed Aziridination Mechanism
Acknowledgment. We thank the donors of the Petroleum
Research Fund, administered by the American Chemical
Society, and the OURC for financial support. One of us
(M.C.M.) thanks Professor Paul Wender for his kindness
during a recent sabbatical at Stanford.
Supporting Information Available: Full characterization
for compounds 1-11. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL990750H
strate.12 Experiments designed to determine the overall steric
and electronic requirements for these cyclization reactions
are ongoing in this lab.
Conclusions. The utilization of carbenoid intermediates
for the intermolecular aziridination of CdN bonds has
recently matured into a valuable synthetic method. This study
demonstrates for the first time that intramolecular metallo-
carbenoid addition can be accomplished, thus providing
efficient access to novel heterocyclic systems.13 Many of
these types of products can serve as advanced intermediates
for synthesis utilizing the potential reactive nature of the
(12) We have observed an analogous cycloaddition with a similarly
disposed olefin to produce a simple pyrazole. This structure was confirmed
by X-ray crystallography. Weekly, R. M. Masters Thesis, Ohio University,
1997. See also: Doyle, M. P.; Kalinin, A. V. J. Org. Chem. 1996, 61, 2179.
Doyle, M. P.; Dorow, R. L.; Tamblyn, W. H. J. Org. Chem. 1982, 47,
4059.
(13) For a related approach to the mitomycins, see (a) Jones, G. B.;
Moody, C. J. Chem. Commun.. 1988, 1009. (b) Jones, G. B.; Moody, C. J.;
Padwa, A.; Kassir, J. M. J. Chem. Soc., Perkin Trans. 1 1991, 1, 1721.
670
Org. Lett., Vol. 1, No. 4, 1999