Stable aziridinium salts as versatile intermediates: Isolation and regio- and stereoselective ring-opening and rearrangement

Article abstract of DOI:10.1002/anie.200805244

Rock trapping and exploration: Aziridinium bromide salts were discovered serendipitously during bromination of N,N-dicarboxymethylated β-amino alcohols. Regiospecific ring-opening and rearrangement of the isolated, surprisingly stable aziridinium salts produces useful molecules including C-functionalized oxomorpholines and α,β-unsaturated amines. 2009 Wiley-VCH Verleg GmbH & Co. KGaA, Weinheim.

Full text of DOI:10.1002/anie.200805244

Angewandte
Chemie
Retraction
*
The following article from Angewandte Chemie International Edition, “Stable Aziridinium Stable Aziridinium Salts as Versatile
Salts as Versatile Intermediates: Isolation and Regio- and Stereoselective Ring-Opening Intermediates: Isolation and Regio- and
and Rearrangement”, published online on January 13, 2009 in Wiley Online Library
(www.onlinelibrary.wiley.com, DOI: 10.1002/anie.200805244) and in print (Angew.
Chem. Int. Ed. 2009, 48, 1328–1330), has been retracted by agreement between the
corresponding author, the journal Editor, Dr. Peter Gçlitz, and Wiley-VCH. The
Stereoselective Ring-Opening and
Rearrangement
H. A. Song, M. Dadwal, Y. Lee, E. Mick,
retraction has been agreed upon because by performing additional NMR analyses and H.-S. Chong*
preparing authentic reference compounds, the authors discovered that the structures of
1328–1330
the aziridinium ions 3 were incorrectly assigned.
Angew. Chem. Int. Ed. 2009, 48
DOI 10.1002/anie.200805244
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DOI: 10.1002/anie.200805244
Aziridinium Salts
Stable Aziridinium Salts as Versatile Intermediates: Isolation and
Regio- and Stereoselective Ring-Opening and Rearrangement**
Hyun A. Song, Mamta Dadwal, Yeseul Lee, Emily Mick, and Hyun-Soon Chong*
Table 1: Formation of aziridinium cations 3 and ring-opened compounds
4 and 5.
Avariety of aziridinium cations have been generated in situ as
precursors of enantiomerically pure organic compounds and
biological active agents. Several aziridinium cations have
been proposed as intermediates in the reaction of nitrogen
mustards with interstrand cross-linked DNA.[1] The ring-
opening of substituted aziridinium cations has been recog-
nized as an efficient synthetic route to chiral 1,2- and 1,3-
diamines, 3,4-diamino nitriles, nitrogen-containing hetero-
cycles, and a,b-diamino esters.[2] The synthetic methods to
generate quaternary aziridinium cations as reactive inter-
mediates involve N-alkylation of aziridines,[3] intramolecular
substitution of b-amino halides,[4] and mesylation of b-amino
alcohols.[5] Research efforts have been made to characterize
Entry Substrate
R
R’ Product Yield [%]
aziridinium salts, and formation of several aziridinium salts
was induced by using heavy counter anions such as fluorobo-
rate or perchlorate.[6]
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2 f
H
H
tBu
Bn
tBu
tBu
tBu
tBu
4a
4b
3c
3d
3e
3 f
86
85
44
51
55
67
66
23
(S)-methyl
rac-benzyl
(S)-4-nitrobenzyl
rac-4-nitrobenzyl
3-(4-nitrophenyl)propyl tBu
(S)-CO2CH3 tBu
Herein, we describe the synthesis and characterization of
a series of aziridinium salts obtained from the bromination of
N,N-dicarboxymethylated b-amino alcohols. To our knowl-
edge, this is the first report on the isolation of a series of stable
aziridinium cations prepared directly from b-amino alcohols
under mild conditions. We also report regioselective and
stereoselective ring-opening and unprecedented regiospecific
rearrangement of aziridinium cations to generate useful
organic molecules such as a,b-unsaturated amino esters, and
C-functionalized oxomorpholine in excellent yield.
Table 1 shows the aziridinium cations 3 that have been
isolated by reaction of N,N-dicarboxymethylated b-amino
alcohols 2 with N-bromosuccinimide (NBS) and triphenyl-
phosphine (PPh3). We initially wanted to prepare N,N-
dicarboxymethylated b-amino ethyl bromide 4 as a precursor
molecule of a macrocyclic ligand. In a typical bromination
reaction, b-amino ethanol 2 (1 equiv) in CH2Cl2 was treated
with a mixture of NBS (1.2 equiv) and PPh3 (1.2 equiv) at
08C. However, instead of providing the desired SN2 product 4,
the reaction led to the aziridinium bromide salt 3 from an
intramolecular rearrangement as evidenced by 1H and
13C NMR spectroscopic and high-resolution mass spectral
data. As a potential mechanism shown in Table 1, the reaction
2g
2h
3g
5h
of 2 with phosphonium salt formed by reaction of NBS and
PPh3 affords the substitution product, which then rearranges
to form the aziridinium cations 3 by attack of the nucleophilic
nitrogen atom followed by removal of triphenylphosphine
oxide.
This unexpected result prompted us to explore the scope
of the reaction using various backbone-substituted N,N-
dicarboxymethylated b-amino alcohols. In particular, we
wanted to understand the effect that substituents in 2 have
on the formation of the strained aziridinium cation. It appears
that the steric hindrance of any R substituent on the b-amino
alcohol backbone prevents SN2 attack of bromide at the less
hindered methylene carbon. All backbone-substituted
b-amino ethanols 2 including 2c, which has the sterically
less demanding methyl group, were transformed to aziridi-
nium salts by intramolecular rearrangement (Table 1,
entry 3). It should be noted that the reaction of 2a (R’ =
tBu) and 2b (R’ = Bn), which contain no backbone substitu-
tion, led to the intermolecular substitution products 4a and
4b, respectively, and no aziridinium salts were formed
(Table 1, entries 1 and 2). This experimental result proves
that steric hindrance caused by substitution of the backbone
in 2 resulted in the formation of the aziridinium salts. All
aziridinium salts were readily purified by flash silica gel
chromatography and fully characterized by 1H and 13C NMR,
HRMS, and/or CHN analysis (see the Supporting Informa-
tion). No peak corresponding to the CH2Br unit in the normal
[*] H. A. Song, M. Dadwal, Y. Lee, E. Mick, H.-S. Chong
Chemistry Division
Biological, Chemical, and Physical Sciences Department
Illinois Institute of Technology, Chicago, IL (USA)
E-mail: chong@iit.edu
[**] This work was supported in part by a research grant from the U.S.
National Institutes of Health (R01A112503-01A2). H.A.S. is the
recipient of the Kilpatrick fellowship 2007–2008.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200805244.
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substitution product 4 was present in 1H and
13C NMR spectra of the aziridinium salts. Inter-
estingly, no aziridinium cation was obtained
from the substrate 3, which has a methyl ester
group, and bromination of 3 produced the
secondary aminoethyl bromide 5h (Table 1,
entry 8). It appears that the attack of the counter
anion bromide at the electron-deficient methine
carbon in the aziridinium cation generated in
situ led to the formation of 5h.
Bromination of amino alcohol 2d using
different reagents was attempted (Table 2).
Among the brominating reagents studied,
CBr4/PPh3 was found to be the best and it
smoothly converted 2d to the desired product
3d in 89% yield (Table 2, entry 4). Reaction of
2d with SOBr2 proceeded very slowly, providing
3d in poor yield (12%; Table 2, entry 2). No
reaction was observed between 2d and PBr3 in
CH2Cl2 (Table 2, entry 3).
Scheme 1. Reactions of aziridinium salts. TFA=trifluoroacetic acid.
Table 3: Regioselective ring-opening and rearrangement of aziridinium
cations.
Table 2: Formation of aziridinium bromide salt 3d by bromination using
various reagents.
Entry Reagents
Solvent
T
Reaction time
Yield [%]
1
2
3
4
NBS, PPh3 CH2Cl2 08C–RT
4 h
5 h
51%
8%
no reaction
89%
SOBr2
CHCl3
CH2Cl2 RT
CHCl3 RT
RT
PBr3
CBr4, PPh3
3 h
Entry Substrate Nu
Base
T
Product (Yield)
Ring-opening of aziridinium cations has been recognized
1
2
3
3c
3e
3e
NaCN
NaCN
NaN3
DIPEA RT
DIPEA RT
DIPEA RT
6a (100%)
6b (84%)
6c (45%)
7c (29%)
8c (7%)
as a useful synthetic route for the generation of 1,2- or 1,3-
diamine analogues.[2a,5] Encouraged by the efficient prepara-
tion of the aziridinium salts, we wanted to investigate their
ring-opening by various nucleophiles (Scheme 1 and Table 3).
First, the stability of the aziridinium cation was investigated.
The aziridinium cations are stable at room temperature and
inert to nucleophilic attack of the counteranion bromide; they
can be stored at À208C for years. When a solutions of the
aziridinium salt 3g in CH3CN was stirred at room temper-
ature for 14 days, no transformation and no ring-opening by
the counteranion bromide was observed (Table 3, entry 5).
Aziridinium salt 3g was stable in acidic media, and the tert-
butyl groups in 3g were removed to produce 10 in good yield
(Scheme 1). However, when refluxed in CH3CN in the
presence of diisopropylethylamine (DIPEA), 3g was trans-
formed into the oxomorpholine analogue 9g by regiospecific
opening of the cation at the methine carbon (Table 3, entry 6).
The carbonyl oxygen of the tert-butyl carboxylate group in 3g
is proposed to attack the more substituted carbon to afford
intramolecular cyclization product 9g (77%). It is interesting
to note that the reaction of 3 f with DBU (diaza(1,3)bicyclo-
4
5
6
7
8
3 f
3g
3g
3g
3g
–
–
–
DBU
–
08C
RT
8 f (100%)
3g (100%)
DIPEA 828C 9g (77%)
DIPEA RT
DIPEA RT
NaCN
NaN3
6d (99%)
6e (41%)
7e (30%)
6 f (52%)
9
3g
CH3(CH2)2SH DIPEA RT
[5.4.0]undecane, 3 equiv) produced the a,b-unsaturated
amino diacetate 8 f with exclusive stereospecificity in quanti-
tative yield (Table 3, entry 4). Only the trans isomer was
isolated from elimination of the methylene proton and
opening of the aziridinium cation at the less hindered
carbon. When the aziridinium cations 3c, 3e, and 3g
(Table 3, entries 1, 2, and 7) were treated with the strong
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nucleophile cyanide, opening of the aziridinium cations
Experimental Section
occurred at the less hindered methylene carbon in an SN2
manner to afford the respective regiospecific ring-opening
products 6a, 6b, and 6d as the exclusive regioisomers.
Products 6a and 6d were obtained from 3c and 3g,
respectively, in almost quantitative yield, while 6b arose in
slightly lower yield (84%) from the reaction of more hindered
3e. The reaction of the aziridinium cations 3e and 3g with the
less nucleophilic azide provided a mixture of the regioisomers
6 and 7 resulting from opening of the cation at both the
methine and methylene carbons (Table 3, entries 3 and 8).
The regioisomers 6c (45%) and 6e (41%) were obtained as
the major products from attack of azide at methylene carbon
of 3e and 3g, respectively. Formation of the regioisomers 7c
(29%) and 7e (30%) as the minor products from the
regioselective opening of the aziridinium cations at the
more hindered methine carbon can be explained by the
thermodynamic control of the reaction with the more weakly
nucleophilic azide.[3a] The reaction of 3e with azide also
provided the elimination product trans-8c (7%). The ring-
opening of 3g by propanethiol took place at the less
substituted carbon, exclusively providing 6 f in 52% yield
(Table 3, entry 9).
We also investigated the stereochemistry of the nucleo-
philic opening of the enantiomerically pure aziridinium
cations (Table 3, entries 1—3). The stereospecific ring-open-
ing of optically pure 3c and 3e by cyanide at the less
substituted methylene carbon provided optically pure 6a and
6b, respectively. The reaction of 3e ([a]2D6 = + 11.878) with
azide afforded optically pure 6c ([a]2D6 = + 6.228) and 7c
([a]2D6 = À4.918) as the regioselective isomers. The optical
rotation data suggest that the ring-opening of the aziridinium
cation by cyanide and azide proceeds by a SN2 displacement.
In summary, the present report describes the potential of
aziridinium cations as isolable intermediates to generate
various useful organic molecules for asymmetric synthesis and
biological applications. We have shown that the stable
aziridinium salts can be prepared directly from bromination
of b-amino alcohols and purified by flash column chromatog-
raphy. Regioselective and stereoselective ring-opening and
rearrangement of the aziridinium cations produced useful
organic compounds including a,b-unsaturated amines and
C-functionalized oxomorpholine. We are currently studying
the scope of these reactions by using a series of N- and
C-substituted b-amino alcohols.
Typical procedure for the synthesis of 3g: Portions of NBS (1.2 mmol)
were added over 30 min to a solution of 2g (1 mmol) and PPh3
(1.2 mmol) in CH2Cl2 at 08C. The resulting mixture was stirred for
3 h at 08C. The ice bath was removed, and the reaction mixture was
warmed to room temperature, stirred for 1 h, and concentrated to
dryness. The residue was purified by column chromatography on silica
gel (60–230 mesh) eluting with 10% EtOAc in hexanes to provide 3g
as yellowish oil (4.8 g, 66%). The aziridinium salt 3g was fully
characterized by 1H and 13C NMR, HRMS, and CHN analysis.
Received: October 27, 2008
Published online: January 13, 2009
Keywords: aziridinium ions · rearrangement · regioselectivity ·
.
strained molecules
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