Aziridination of γ,δ-dibromoethyl-2-pentenoate with primary amines: Extension of the Gabriel-Cromwell reaction

Article abstract of DOI:10.1016/j.tetlet.2004.06.005

Ethyl (E)-4,5-dibromo-2-pentenoate readily reacts with an assortment of primary amines in the presence of DBU to afford the corresponding conjugated aziridines in good to moderate yields. That the reaction is compatible with a nucleoside-derived amine suggests a broad scope of application.

Full text of DOI:10.1016/j.tetlet.2004.06.005

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5807–5810
Aziridination of c,d-dibromoethyl-2-pentenoate with primary
amines: extension of the Gabriel–Cromwell reactionq
Rachel L. Wellerb and Scott R. Rajskia,*
aThe School of Pharmacy, University of Wisconsin, Madison, WI 53705-2222, USA
bDepartment of Chemistry, University of Wisconsin, Madison, WI 53706-1396, USA
Received 31 May 2004; revised 3 June 2004; accepted 3 June 2004
Abstract—Ethyl (E)-4,5-dibromo-2-pentenoate readily reacts with an assortment of primary amines in the presence of DBU to
afford the corresponding conjugated aziridines in good to moderate yields. That the reaction is compatible with a nucleoside-derived
amine suggests a broad scope of application.
Ó 2004 Elsevier Ltd. All rights reserved.
Aziridines figure prominently in a variety of biologically
active substances and more often than not are integral to
the useful bioactivities of the substances which contain
them. Natural and synthetic materials belonging to the
FR-900482,1–3 mitomycin,4–6 and azinomycin7;8 classes
to name just a few, are the focus of chemists and biol-
ogists alike by virtue of complex molecular architecture
and potent biological/medicinal utility. Aziridines also
serve as important synthetic intermediates en route to a
wide array of interesting compounds including unnatu-
ral a and b-amino acids,9 ligands for asymmetric catal-
ysis,10 peptido-mimetics11 and b-lactams.12 The ability
of aziridines to undergo highly predictable regio- and
stereoselective ring opening reactions makes them
powerful synthetic tools.13
manipulations or result in differentially masked sec-
ondary aziridines. An exception to this involves a novel
electrochemical aziridination that converges primary
amines and olefinic substrates.15
Since its inception in 1952 many variations on the
Gabriel–Cromwell reaction have sought to broaden its
scope. These include adaptation to solid phase,16
development of asymmetric induction methods,17 and
the use of cyclic halides or triflates allowing access to
bicyclic aziridines.18 These efforts and many others have,
however, been restricted to the use of a,b-dihalo and
vinyl triflate carbonyl compounds or nitriles as the
electrophilic component of such condensations. Our
interests in generating aziridine modified nucleosides
mandated an investigation of the Gabriel–Cromwell
reaction with more elaborate dihalides.
Of several existing aziridination strategies, the Gabriel–
Cromwell reaction14 is one of the most convenient and
useful. The reaction involves direct aziridination of an
a,b-dibromo ester or ketone following treatment with a
primary amine and a nitrogenous base, typically triethyl-
amine. One useful feature of the Gabriel–Cromwell
reaction is that the aziridination is a single convergent
step resulting in a tertiary aziridine nitrogen. Many
classical aziridine-forming reactions involve multiple
Aziridine-containing compound
intended to serve as a precursor to cofactor mimics of
S-adenosyl-
-methionine; such 50 aziridino adenylates
1
(Scheme 1) is
L
are well known methyltransferase-dependent DNA
alkylating agents.19 Our interest in 1 in this capacity
prompted investigation into an extended version of the
Gabriel–Cromwell aziridination as a key step in the
synthesis of this, and more structurally elaborate
cofactor mimics. It was envisioned that a 4,5-dibromo-
c,d-unsaturated ester would allow for aziridination at
the nucleoside 50 position while also providing an
opportunity for meaningful structure elaboration of the
aziridine sidechain. That dihalides such as 2 appeared to
have not been utilized in aziridinations gave some cause
Keywords: Nucleoside; Aziridination; Cofactor; Gabriel–Cromwell.
q Supplementary data associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2004.06.005
* Corresponding author. Tel.: +1-608-262-7582; fax: +1-608-262-5345;
e-mail: srrajski@pharmacy.wisc.edu
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.06.005

5808
R. L. Weller, S. R. Rajski / Tetrahedron Letters 45 (2004) 5807–5810
Scheme 1. Nucleoside aziridination via isomerization of vinyl bromide 4.
for concern. Pleasantly, these concerns were unfounded
as revealed by reactions of 2 with a small array of rep-
resentative amines, inclusive of 50-amino adenylate 3.
amines resulted in mixtures of vinyl bromides analogous
to 4, and the desired aziridines. The fact that aziridin-
ation occurred in one step, presumably by the expected
pathway, combined with the success of the DBU-medi-
ated isomerization of 4, suggested that reaction condi-
tions could be found that would allow one to avoid vinyl
bromide formation altogether.
Dibromide 2 was synthesized from commercially avail-
able ethyl (S)-(E)-4,5-isopropylidenedioxy-2-penteno-
ate. It is interesting to note that this isopropylidene had
been used previously by Mohr and co-workers to gen-
erate the corresponding a,b-dibromoester, from which
was derived a mixture of cis and trans aziridines for the
study of new oxazoline-forming reactions.20 We found
that 2 was readily generated from the corresponding diol
following treatment with carbon tetrabromide and tri-
phenylphosphine, a variation of monobromination
conditions reported by Padwa and colleagues, in 70%
yield.21 Initial attempts to couple 2 with the 50-amino-
adenosine under standard Gabriel–Cromwell conditions
failed to afford the desired aziridine; affording instead
vinyl bromide 4 with reasonable efficiency.22 NOESY
experiments reveal spatial proximity of the vinyl proton
and the amino linked allylic methylene protons consis-
tent with Z olefin 4.
Three model amines were used to identify reaction
conditions capable of effecting aziridination in one step.
Benzylamine (5a), tetrahydrofurfurylamine (5b), and
neopentylamine (5c) were reacted with 2 in THF.
Optimum conditions were identified using benzylamine
and tetrahydrofurfurylamine; trials were run with
two different bases, triethylamine and DBU, at room
temperature and reflux. The results are summarized in
Table 1.
In all cases examined, the use of triethylamine led to
formation of significant amounts of vinyl bromide which
could not be converted to aziridine over extended peri-
ods of time. When run at room temperature, reactions
failed to reach completion even after 2 days. Conversely,
reactions performed at reflux reached completion within
7 h, but typically afforded lower ratios of aziridine to
vinyl bromide than those conducted at ambient tem-
perature.
It was unclear to us whether 4 was an intermediate
en route to the desired product and these reaction con-
ditions were not favorable for subsequent progression to
the aziridine, or if formation of 4 is divergent from the
path to aziridination. In an attempt to either prevent
formation of 4 or force its conversion to 1, THF was
substituted with DMF. Disappointingly, reactions run
at 90 °C or reflux in DMF for up to 2 days showed only
formation of 4, in addition to some predictable
decomposition.
Importantly, the use of DBU instead of triethylamine
makes this reaction viable. In all cases examined, the
yield of aziridine either approached or exceeded 70%
with no evidence of vinyl bromide formation. It is also
interesting to note that refluxing conditions gave rou-
tinely higher yields and are amenable to shorter reaction
times, however milder ambient conditions are clearly
a viable option for sensitive substrates, still resulting in
good yields.
Confronted with 4, we envisioned that aziridination
might still be accomplished, albeit in two steps as opposed
to one, via isomerization to an a,b-unsaturated ester, so
as to intersect the pathway ordinarily followed in the
Gabriel–Cromwell reaction. Indeed, treatment of 4 with
DBU in CH2Cl2 afforded 1 in very respectable yield.23
Having realized the importance of our selection of DBU
for this variation of the Gabriel–Cromwell reaction, we
returned our attention to nucleoside 1 (Scheme 2).
Gratifyingly, 50-aminoadenosine 3 condensed with 2 in
the presence of two equivalents DBU over the course of
Interestingly, model reactions run under standard
Gabriel–Cromwell conditions with simplified primary

R. L. Weller, S. R. Rajski / Tetrahedron Letters 45 (2004) 5807–5810
5809
Table 1. Reaction of ethyl (E)-4,5-dibromo-2-pentenoate with model primary amines; product partitioning between aziridines and vinyl bromides
Entry
Amine
Base
T (°C)
6:7
Yield 6 (%)
1
2
3
4
5
6
7
8
9
5a
5a
5a
5a
5b
5b
5b
5b
5c
TEA
TEA
DBU
DBU
TEA
TEA
DBU
DBU
DBU
25
67
25
67
25
67
25
67
67
1:1.9
1:2.5
n/a
31
24
68
75
22
30
63
80
74
n/a
1:1.6
1:1.9
n/a
n/a
n/a
Scheme 2. Nucleoside aziridination via extended Gabriel–Cromwell reaction.
8 h to afford 1 in yields ranging from 69% to 74%.24 As
with the simplified amines, the use of DBU completely
eliminated vinyl bromide formation while affording
yields very comparable to those obtained with simpler
a,b-dibromoesters.22 Not insignificantly, the use of
3 equiv of DBU allowed the reaction to reach comple-
tion after only 5 h at reflux. Just as model studies with
5a–c demonstrated the usefulness of this new aziridin-
ation reaction with simple amines, the effective conver-
gence of 2 with 3 demonstrates the compatibility of
DBU-mediated aziridination with nucleosides and per-
haps significantly more complex molecules.
Acknowledgements
We are grateful to the American Foundation for Phar-
maceutical Education (AFPE) and Burroughs-Well-
come Trust Fund for a New Investigator in Pharmacy
Award (administered by American Association of Col-
leges of Pharmacy), and University of Wisconsin
Graduate School and School of Pharmacy for generous
startup funding.
References and notes
This extension of the Gabriel–Cromwell reaction
broadens the number of avenues by which aziridines can
be constructed in a one step process. That the resulting
aziridine is in conjugation with a,b-unsaturated systems
suggests the possibility of significantly greater synthetic
flexibility and diversification options than is ordinarily
associated with aziridine-2-carboxylates resulting from
classical Gabriel–Cromwell reactions. Such chemistries
and the continued pursuit of cofactor mimics derived
from 1 will be reported in due course.
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