Efficient synthesis of functionalized aziridinium salts

Article abstract of DOI:10.1021/jo901893n

(Chemical Equation Presented) Various aziridinium salts were efficiently prepared from bromination of a series of backbone substituted N,N-bisubstituted β-amino alcohols and isolated via flash column chromatography. The effect of C-substitution, N-substitution, solvent, leaving group, and counter-anions on formation of the isolable aziridinium salts was investigated. 2009 American Chemical Society.

Full text of DOI:10.1021/jo901893n

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(CMB), mechlorethamine, and phosphamide mustards stems
Efficient Synthesis of Functionalized Aziridinium
Salts
from reaction of aziridinium cation intermediate derived from
the mustards with guanine residues in DNA to form inter-
strand cross-link.2 N-alkylation of aziridines,3 intramolecular
substitution reaction of β-amino halides,4 and mesylation or
triflation of β-amino alcohols5 were reported to produce
quaternary aziridinium cations as reactive intermediates in situ
or isolable salts6 containing a non-nucleophilic counteranion
such as fluoroborate, perchlorate, or triflate.
Hyun-Soon Chong,* Hyun A. Song, Mamta Dadwal,
Xiang Sun, Inseok Sin, and Yunwei Chen
Chemistry Division, Biological, Chemical, and Physical
Sciences Department, Illinois Institute of Technology,
Chicago, Illinois 60616
Recently, we reported the isolation of a series of stable
aziridinium salts containing bromide as a counteranion
directly from bromination of β-amino alcohols using various
brominating agents under mild conditions.7 The aziridinium
salts reported therein are stable at room temperature and can
be stored at -20 °C over years and preserved in an acidic
medium during removal of a protecting group. We also
demonstrated that the regiospecific ring-opening and intra-
molecular rearrangement of the aziridinium salts can gene-
rate the functionalized organic molecules such as β-amino
nitriles, allyl amines, and C-functionalized oxomorpholine.
In this paper, we sought to broaden the scope of formation
of aziridinium salts using various β-amino alcohols. First, we
were interested in exploring the effect of solvent on the
formation of aziridinium salts.
Bromination of N-(benzyl) and N-(tert-butoxycarbonyl-
methyl)-derived β-amino alcohol 1a was carried out in four
different solvents, CHCl3, CH2Cl2, CH3CN, and THF
(Scheme 1). Treatment of β-amino alcohol 1a in a solvent
with PPh3 and NBS at 0 °C for 4 h and warming the solution
to room temperature for 1 h resulted in the conversion of 1a
to the desired aziridinium salt 2a. Among the solvents
studied, polar aprotic CH3CN was found to be the most
efficient solvent for the formation of 2a (76%). The lowest
isolated yield of 2a was obtained from the reaction in THF,
possibly due to low solubility of the amino alcohol 1a in the
solvent.
chong@iit.edu
Received September 2, 2009
Various aziridinium salts were efficiently prepared from
bromination of a series of backbone substituted N,N-
bisubstituted β-amino alcohols and isolated via flash
column chromatography. The effect of C-substitution,
N-substitution, solvent, leaving group, and counter-
anions on formation of the isolable aziridinium salts
was investigated.
Aziridinium salts have been utilized as reactive intermediates
in asymmetric synthesis of 1,2- and 1,3-diamines, 3,4-diamino
nitriles, R,β-diaminoesters, and complex natural products.1 In
addition, they are involved in the biological activity of nitrogen
mustards as cancer drugs. Anticancer activity of chlorambucil
We extended our investigation to the effect of leaving
group and counteranion on the formation of aziridinium
salts. N,N-Bisubstituted β-amino alcohol 1b was reacted
with various reagents (Table 1). As expected, azridinium
cation 2b was produced from bromination of 1b with NBS/
PPh3 in excellent yield (89%, Table 1). Reaction of 1b with
thionyl chloride (SOCl2, Table 1) at room temperature
provided an inseparable 1:1 mixture of aziridinium salt
(3b) and the normal substitution product (4b). When the
same reaction of 1b with SOCl2 was carried out under reflux,
aziridinium cation 3b was obtained as the exclusive product
(Table 1). Interestingly, the reaction of 1b with methanesul-
fonyl chloride (MsCl) provided a mixture of 3b and 4b
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DOI: 10.1021/jo901893n
r
Published on Web 12/02/2009
J. Org. Chem. 2010, 75, 219–221 219
2009 American Chemical Society

Chong et al.
JOCNote
SCHEME 1. Solvent Effect on the Formation of Aziridinium
Cation
TABLE 2. Synthesis of N-Substituted Aziridinium Cations
product
(yield)a
entry substrate
R1
R2
R3
n
1
2
3
4
5
6
7
8
1c
1d
1e
1f
1g
1h
1i
CH2CO2t-Bu CH2CO2t-Bu NO2
1
3
1
1
1
1
1
1
2c (75%)b
2d (84%)
8e (47%)
2f (87%)
2g (92%)
2h (78%)
2i (87%)
2j (25%)b
CH2CO2Bn
H
allyl
p-NO2-Bn
allyl
Bn
CH2CO2Bn
BOC
CH2CO2t-Bu
CH2CO2t-Bu
allyl
NO2
H
H
H
H
TABLE 1. Effect of Leaving Group and Counter Anion on the Forma-
tion and Ring-Opening of Aziridinium Cations
Bn
DMB
H
1j
allyl
H
aIsolated yield. bReaction was carried out at 0 °C for 4 h and
continuous stirring at room temperature overnight.
into 3b, which was inert to intramolecular ring-opening by less
nucleophilic chloride. Iodination of β-amino alcohol 1b was
carried out with different iodinating reagents (NIS/PPh3,
I2/PPh3, or I2/PPh3/imidazole). Surprisingly, none of the iodina-
tion reactions studied provided aziridinium salt 5b, and the
secondary amino ethyl iodide 7b was isolated as the exclusive
product (Table 1). The formation of 7b suggests that the reaction
initially produced the aziridinium salt 5b, which was converted
to 7b by subsitition reaction with iodide at the electron deficient
methine carbon. The best synthetic yield of 7b (90%) was
obtained from the reaction with I2/PPh3/imidazole.
The stereochemistry of ring-opening of 5b was investi-
gated by using enantiomerically rich substrate (R)-1b
and (S)-1b, which were prepared starting from (R)-phenyl-
alanine and (S)-phenylalanine, respectively (Supporting
Information). Iodination of (R)-1b and (S)-1b provided
(R)-7b and (S)-7b resulting from double inversion in excel-
lent ee, respectively (Table 1). The result demonstrates that
ring-opening of (R)-5b and (S)-5b occurred by nucleophilic
attack of the neighboring aryl group at the methine carbon to
produce the phenonium ion intermediates (R)-6b and (S)-6b.
Opening of the three-membered ring at the methine carbon
of (R)-6b and (S)-6b by nucleophilic iodide provided (R)-7b
and (S)-7b, respectively.
Next, we turned to examining the effect of N-substitution
on the formation of aziridinium salts (Table 2). β-Amino
alcohols substituted with various functional groups inclu-
ding benzyl, allyl, p-nitrobenzyl, 2,4-dimethoxylbenzyl
(DMB), and carboxylate ester (CO2R) were reacted with
NBS/PPh3 in CHCl3. N,N-Bisubsituted β-amino alcohols
1 were prepared from the reaction of the corresponding
β-amino alcohols with alkylating agents (Supporting
Information). Aziridinium salts shown in Table 2 were
obtained from reaction of 1 with NBS/PPh3 in CHCl3 in
good to excellent isloated yield, and no attempt was made to
optimize the synthetic yield of the new aziridinium salts
reported. Azridinium cation 2c substituted with N,N-tert-
butyl acetate was prepared from 1c by a modification of the
procedure as previously reported by our group (entry 1).7 We
noted that the isolated yield of 2c can be improved when 1c
in the reaction mixture was continuously stirred for 1 day
at room temperature or kept in the freezer for several
days (75-95% vs. 54%). N,N-Bis(benzyl acetate)-derived
reaction
time
producta
substrate
reagents
solvent
CHCl3
X
(yield, eeb)
1b
NBS,
PPh3
SOCl2
4 h (0 °C),
1 h (rt)
1d (rt)
Br
2b (89%)
1b
CHCl3
CHCl3
THF
Cl
Cl
Cl
I
3b þ 4b
(43%)
3b (32%)
1b
SOCl2
MsCl
0.5 h
(reflux)
3d (rt)
1b
3b þ 4b
(51%)
7b (32%)
1b
I2, PPh3
CH2Cl2
CH2Cl2
CH2Cl2
4 h (0 °C),
1 h (rt)
4 h (0 °C),
1 h (rt)
4 h (0 °C),
1 h (rt)
1b
I2, PPh3,
Imi
I2, PPh3,
Imi
I
7b (90%)
(R)-1b
I
(R)-7b
(97%,
95%)
(S)-7b
(88%,
100%)
7b (75%)
(S)-1b
I2, PPh3,
Imi
CH2Cl2
CH2Cl2
4 h (0 °C),
1 h (rt)
I
I
1b
NIS, PPh3
4 h (0 °C),
1 h (rt)
aIsolated yield. bDetermined by chiral-HPLC.
containing chloride, not mesylate as a counteranion
1
(Table 1). H and 13C NMR data of the mixture indicate
that the inseparable mixture does not contain the peak
corresponding to the mesylate group. It was reasonably
concluded that once formed, β-amino mesylate was con-
verted to a mixture of 3b and 4b as a result of nucleophilic
attack by counteranion chloride. When continuously stirred
in CHCl3 for 10 days at room temperature, a mixture of 3b
and 4b was converted slowly but completely to aziridinium
salt 3b as evidenced by 1H and 13C NMR analysis
(Supporting Information). This experimental result suggests
that β-amino chloride 4b containing a poorer leaving group
compared to bromide or iodide was slowly transformed
220 J. Org. Chem. Vol. 75, No. 1, 2010

Chong et al.
JOCNote
TABLE 3. Synthesis of C-Substituted Chiral Aziridinium Cations
Aziridinium salts 10d (thiobenzyl), 10e (indole), and 10f
(benzyloxy tert-butyl acetate) possessing a functional group
were obtained from amino alcohols 9d-f. The functionality
was well tolerated during the reaction, and all desired
aziridinium salts with structural variation were readily iso-
lated via flash column chromatography.
In summary, we developed an efficient synthetic method
to stable aziridinium salts as potential building blocks in
asymmetric synthesis and for biological applications. We
investigated the scope of the new synthetic method and
demonstrated that various aziridinium salts can be pre-
pared from bromination of C-substituted or N-substituted
β-amino alcohols and isolated via purification with use of
flash column chromatography in good yields. We also
studied that solvent, leaving group, and counteranion
play an important role on the formation of the stable
aziridinium salts. We noted that the isolated yield of the
aziridinium salts can be optimized by varying reaction
conditions. Our new synthetic route can be applied to
the preparation of numerous aziridinium salts that can
be extensively employed in the asymmetric synthesis of
various organic molecules including functionalized 1,2 or
1,3 diamines, amino alcohols, β-alkoxy amines, β-amino
acids, and β-amino esters as chiral ligands or backbone
units of naturally occurring and biologically active
compounds.
Experimental Section
General Procedure for the Preparation of Aziridinium Salts via
Bromination. To a solution of N,N-bisubstituted alcohol 1 or 9
(1.0 equiv) and triphenylphosphine (1.2 equiv) in CH2Cl2 or
CHCl3 was portionwise added N-bromosuccinimide (1.2 equiv)
at 0 °C over 20 min. The resulting mixture was continuously
stirred for 4 h at 0 °C. The ice bath was removed, and the
reaction mixture was warmed to room temperature and stirred
for 1 h and evaporated to dryness. The residue was purified via
column chromatography on silica gel (60-230 mesh) eluting
with 5-10% EtOAc in hexanes.
Sample Procedure and Data of 10b. To a solution of 9b (166
mg, 0.50 mmol) and PPh3 (157 mg, 0.60 mmol) in CHCl3 (3 mL)
at 0 °C was added NBS (107 mg, 0.60 mmol). The residue was
purified by silica gel column chromatography eluted with 5%
EtOAc in hexanes to afford colorless oil 10b (147 mg, 75%). 1H
NMR (CDCl3, 300 MHz) δ 0.88 (d, J = 6.6 Hz, 3H), 0.98 (d,
J = 6.6 Hz, 3H), 1.41 (s, 18H), 2.03 (septet further split into d,
J = 6.6, 2.8 Hz, 1H), 3.00 (dd, J = 14.4, 7.1 Hz, 1H), 3.14 (dd,
J = 14.4, 7.1 Hz, 1H), 3.35-3.48 (m, 4H), 4.10 (td, J = 7.1, 2.8
Hz, 1H); 13C NMR (CDCl3, 300 MHz) δ 16.99 (q), 21.57 (q),
28.11 (q), 30.67 (d), 56.92 (t), 60.16 (t), 63.95 (d), 81.05 (s), 170.54
(s). HRMS (positive ion FAB) calcd for C17H32BrNO4 [M -
Br]þ m/z 314.2331, found [M - Br]þ m/z 314.2315.
aIsolated yield.
β-amino alcohol 1d was converted to 2d in 73% isolated
yield. It was observed that the carboxyl protection groups
(tert-butyl or benzyl) had no effect on the formation of
aziridinium salts (entries 1 and 2). However, when the amino
group in 1e was protected by BOC, the reaction led to the
formation of the normal substitution reaction product 8e
(entry 3). β-Amino alcohol 1 containing an N-tert-butyl
acetate group was reacted with allyl bromide or p-nitroben-
zyl bromide to provide 1f and 1g (entries 4 and 5). Bromina-
tion of 1f and 1g to afford the expected aziridinium cations 2f
and 2g was accomplished in 87% and 92% isolated yields,
respectively. N,N-Bis(benzyl)- and N,N-bis(allyl)-derived
amino alcohols 1h and 1i were converted to aziridinium
cation 2h and 2i, respectively (entries 6 and 7). Amino
alcohol 1j substituted with N-DMB and N-allyl groups
provided aziridinium cation 2j (entry 8). It should be noted
that the aziridinium cations 2h-j can be converted to diverse
organic compounds including vicinal diamines and amino
nitriles upon nucleophilic ring-opening followed by removal
of the protecting groups.
Acknowledgment. Hyun A. Song is the recipient of the
2008-9 IIT Kilpatrick fellowship. We thank Willam Sawyer
and Yeseul Lee for preparation of 2c and 9c, respectively.
Finally, asymmetric C-substituted aziridinium salts were
prepared from bromination of different β-amino alcohols in
CHCl3 as shown in Table 3. Amino alcohols 9a (n-propyl), 9b
(isopropyl), and 9c (phenyl) containing alkyl and aryl groups
provided the expected aziridinium salts 10a-c in good yield.
Supporting Information Available: Complete experimental
details and characterization of the new compounds. This ma-
terial is available free of charge via the Internet at http://pubs.
acs.org.
J. Org. Chem. Vol. 75, No. 1, 2010 221