Indium mediated efficient conversion of 2-iodomethyl aziridines to chiral allylic amines

Article abstract of DOI:10.1055/s-2001-17441

Chiral allylic amines are synthesized in high yields by treatment of 2-iodomethyl N-tosyl aziridines with metallic indium in methanol at reflux.

Full text of DOI:10.1055/s-2001-17441

1608
LETTER
Indium Mediated Efficient Conversion of 2-Iodomethyl Aziridines to Chiral
Allylic Amines
Indium
M
.
ediated Conv
S
ersion of 2-Io
.
domethyl
A
z
Y
iridine to Chiral
A
a
llylic Amin
d
es av,* A. Bandyopadhyay, B. V. S. Reddy
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad-500 007, India
Fax +091(40)7170512; E-mail: yadav@iict.ap.nic.in
Received 14 August 2001
allylic amines using indium metal. The treatment of 2-io-
Abstract: Chiral allylic amines are synthesized in high yields by
treatment of 2-iodomethyl N-tosyl aziridines with metallic indium
in methanol at reflux.
domethyl N-tosyl aziridines with indium metal in reflux-
ing methanol afforded the corresponding chiral allylic
amines (Table, entries a–e) in excellent yields. Addition-
ally, reaction of aziridines bearing iodine at an allylic po-
sition (entries f and g) with indium metal in refluxing
methanol resulted in the formation of chiral 5-amino-1,3-
dienes.
Key words: indium, N-tosyl aziridine, chiral allylic amine
Chiral allylic amines are versatile building blocks1 for the
synthesis of - and - amino acids, alkaloids and carbohy-
drate derivatives. The allylic amines are transformed to a
range of products by functionalization, reduction or oxi-
dation of the double bond.2 In addition, the allylic amine
core unit is found in many bioactive molecules,3 for exam-
ple (S)-Vigabatrin,3j an anti-convulsive drug, and they are
also structural components of peptide isoteres, and act as
-turn promoters.4 Thus, the synthesis of chiral allylic
amines is an important industrial and synthetic goal. Con-
sequently several procedures have been developed for the
synthesis of chiral allylic amines, which include: asym-
metric allylic amination,5 asymmetric nucleophilic addi-
tion to carbon-nitrogen double bonds,6 asymmetric
addition to alkynes,7 and modification of enantiomerically
pure -amino aldehydes.8 However most previous syn-
thetic transformations involve Wittig olefination on N-
protected -amino aldehydes, which are often susceptible
to racemization of the stereogenic centers.8a,9 Recently
chiral allylic amines have also been synthesized from azir-
idinemethanol sulfonate esters10a as well as 5-hydroxym-
ethyl-2-oxazolidinone tosylates using Te(II).10b However,
many of these procedures have limitations in terms of
yields, reaction times, selectivity, stability and availability
of the reagents. Therefore there is a need to develop a con-
venient and potentially practical method for the synthesis
of chiral allylic amines.
Scheme 1 illustrates the synthesis of 2-iodomethyl aziri-
dine from allylic alcohol 1. Allylic alcohol 1 was subject-
ed to Sharpless asymmetric epoxidation13 to afford epoxy
alcohol 2. The chiral epoxy alcohol 2 was transformed in
excellent overall yield to the “inverted” aziridino alcohol
5 by a straightforward series of operations.14,15 The amino
function was then protected as the p-toluenesulfonamide
to give 6. The TBDMS ether was then deprotected by
TBAF in HOAc at 0 °C to give 2-hydroxymethyl aziridine
7 which on treatment with triphenylphosphine, iodine and
imidazole in a mixture of ether and acetonitrile16 gave 2-
iodomethyl aziridine 8. Treatment of 8 with indium metal
in refluxing methanol for 4-5 h gave the corresponding
chiral allylic amine 9 in excellent yield (Scheme 2).
N3
OH
a
b
R
OH
R
OH
OH
R
+
R
OH
O
1
OH
d
N3
2
3
R = alkyl
H
N
N3
OH
c
OTBDMS
R
f
OTBDMS
N-Ts
R
+
R
OTBDMS
OH
N-Ts
6
N3
5
4
N-Ts
e
g
R
I
R
OH
R
OTBDMS
Indium mediated transformations11 have attracted much
interest because of certain unique properties possessed by
indium. Indium is stable in water or air and does not re-
quire any activation or anhydrous reaction conditions.
Furthermore, the first ionization potential of indium is
much lower than that of zinc or tin, hence it could be a po-
tential reducing agent.
8
7
Scheme 1 Reagents: a) L-(+)-DIPT, Ti(OiPr)4, TBHP, DCM, –
20 °C. b) NaN3, MeO(CH2)2OH, H2O, reflux. c) TBDMSCl, imida-
zole, DCM, 0 °C. d) PPh3, toluene, reflux. e) TsCl, pyridine, –20 °C.
f) TBAF, HOAc, 0 °C. g) PPh3, I2, imidazole, ether:CH3CN (3:1), r.t.
In continuation of our interest in the use of indium metal
for various transformations,12 we herein describe a novel
and highly efficient procedure for the synthesis of chiral
NHTs
N-Ts
Indium
R
I
, Methanol
R
8
9
Synlett 2001, No. 10, 28 09 2001. Article Identifier:
1437-2096,E;2001,0,10,1608,1610,ftx,en;D14801ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214
Scheme 2

LETTER
Indium Mediated Conversion of 2-Iodomethyl Aziridine to Chiral Allylic Amines
1609
Table Indium Mediated Efficient Conversion of 2-Iodomethyl N-Tosyl Aziridines to Chiral Allylic Aminesa
Entry
a
2-Iodomethyl N-tosyl aziridine
Allylic amines
% Yieldb
(time, h)
[ ]20
D
(c, CHCl3)
95 (4)
–15.0 (0.55)
b
96 (4)
–22.6 (0.5)
c
d
e
f
92 (4.5)
90 (5)
–14.6 (0.75)
–15.8 (1.0)
–
82 (4)
91 (4.5)
–4.7 (0.7)
g
93 (5)
+3.3 (1.1)
a All products are characterized by 1H, 13C NMR, mass spectra, and also by the comparison with authentic samples.
b Isolated and unoptimized yields.
Several examples illustrating this novel and efficient pro-
tocol for the synthesis of chiral allylic amines are listed in
the Table.17 This method is very simple, more convenient
and does not require any promotors or additives. Methanol
appears to be the solvent of choice for this reaction. No ra-
cemization or side products are observed under the reac-
tion conditions. Indium was found to be more effective
than other metals such as zinc, samarium and yttrium for
this transformation.
b
a
N-Ts
N-Ts
CHO
N-Ts
CHO
R
R
R
OH
11
7
10
c
d
N-Ts
N-Ts
OH
R
I
R
12
13
Scheme 3 Reagents: a) SO3 Py, Et3N, DCM–DMSO, 0 °C. b)
Ph3P=CHCHO, benzene, r.t. c) NaBH4, MeOH, 0 °C. d) PPh3, I2, imi-
dazole, ether–CH3CN, (3:1), r.t.
In summary we have demonstrated a novel and efficient
protocol for the synthesis of chiral allylic amines using in-
dium metal. In addition to its simplicity and milder reac-
tion conditions, the method provides high yields of
products with greater selectivity, which makes it a very
useful and attractive process for the synthesis of chiral al-
lylic amines.
Scheme 3 illustrates the synthesis of compound 13 from
2-hydroxymethyl aziridine 7. Compound 7 on oxidation
with SO3 Py gave the aldehyde 10, which without purifi-
cation, was treated with formylmethylenetriphenylphos-
phorane to give , -unsaturated aldehyde 11. Reduction
of aldehyde group with NaBH4 in methanol gave 12,
which on treatment with triphenylphosphine, iodine and
imidazole in a mixture of ether and acetonitrile gave 13.
Treatment of 13 with indium metal in refluxing methanol
for 4-5 h gave the corresponding chiral amino diene 14 in
excellent yield (Scheme 4).
Acknowledgement
Two of the authors (AB/BVSR) are thankful to UGC/CSIR, New
Delhi respectively for financial support.
NHTs
Indium
N-Ts
, Methanol
I
R
R
13
14
Scheme 4
Synlett 2001, No. 10, 1608–1610 ISSN 0936-5214 © Thieme Stuttgart · New York

1610
J. S. Yadav et al.
LETTER
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(10 mL) was heated under reflux for an appropriate time
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the solvent was removed in vacuo, diluted with water and
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acetate-hexane, 1:9) to afford pure chiral allylic amine.
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CDCl3) 0.89 (t, J = 7.0 Hz, 3 H), 1.19 (m, 12 H), 1.47 (m,
2 H), 2.42 (s, 3 H), 3.73 (m, 1 H), 4.56 (d, J = 8.0 Hz, 1 H),
4.92 (dd, J = 10.0, 1.0 Hz, 1 H), 4.99 (dd, J = 16.0, 1.0 Hz, 1
H), 5.51 (m, 1 H), 7.24 (d, J = 8.0 Hz, 2 H), 7.73 (d, J = 8.0
Hz, 2 H). 13C NMR (50 MHz, CDCl3) 142.98, 138.11,
137.87, 129.36, 127.13, 115.59, 56.27, 35.44, 31.76, 29.31,
29.10, 25.15, 22.56, 21.41, 14.03. EIMS (m/z) 210 [M+-
C8H17]. 2f: 1H NMR (400 MHz, CDCl3) 0.87 (t, J = 6.8 Hz,
3 H), 1.17 (m, 6 H), 1.45 (m, 2 H), 2.43 (s, 3 H), 3.81 (m, 1
H), 4.48 (d, J = 8.0 Hz, 1 H), 5.03 (dd, J = 10.0, 1.5 Hz, 1 H),
5.09 (dd, J = 17.5, 1.5 Hz, 1 H), 5.38 (dd, J = 16.0, 7.5 Hz, 1
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10.0, 12.0 Hz, 1 H), 7.29 (d, J = 7.8 Hz, 2 H), 7.77 (d, J = 7.8
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24.98, 22.38, 21.39, 13.86. EIMS (m/z) 236 [M+-C5H11].
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Synlett 2001, No. 10, 1608–1610 ISSN 0936-5214 © Thieme Stuttgart · New York