A new and facile route for the synthesis of chiral 1,2-diamines and 2,3-diamino acids

Article abstract of DOI:10.1016/j.tetlet.2004.11.088

The synthesis of chiral diamines and diamino acids has been achieved from the corresponding N-arylsulfonyl aziridines through reaction with a chiral isocyanate and subsequent hydrolysis of 2-imidazolidinones. The method appears to be general and of wide applicability.

Full text of DOI:10.1016/j.tetlet.2004.11.088

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 479–482
A new and facile route for the synthesis of chiral 1,2-diamines
and 2,3-diamino acids
Upender K. Nadir,* R. Vijaya Krishna and Anamika Singh
Department of Chemistry, Indian Institute of Technology, Delhi, Hauz Khas, New Delhi 110 016, India
Received 19 September 2004; revised 10 November 2004; accepted 15 November 2004
Available online 7 December 2004
Abstract—The synthesis of chiral diamines and diamino acids has been achieved from the corresponding N-arylsulfonyl aziridines
through reaction with a chiral isocyanate and subsequent hydrolysis of 2-imidazolidinones. The method appears to be general and of
wide applicability.
Ó 2004 Elsevier Ltd. All rights reserved.
1,2-Diamines are important1 since they are constituents
of several natural products of biological significance and
are key materials in the preparation of compounds,
which are of value in the field of diagnostic nuclear med-
icine. They are also useful precursors of azamacrocycles
and heterocyclic compounds and are being used increas-
ingly in asymmetric synthesis as chiral auxiliaries and
as ligands for catalysts.1,2 Chiral ethylenediamine
derivatives are of interest in the preparation of cis-platin
analogues, which have been employed in cancer therapy.
imines6p are also known. Syntheses in which the
chirality originates from the catalyst have also been
reported.7a,b
Although several methods for preparing chiral diamines
and diamino acids are known, most of them suffer from
one or more drawbacks including lack of generality,
inaccessibility of starting materials and cumbersome
procedures.8 There is thus a need for developing im-
proved and more general procedures.
2,3-Diaminocarboxylic acids are constituents of several
antibiotics, natural products and biologically active
molecules.1,3 They are also used as building blocks for
peptidomimetics in medicinal chemistry due to their pro-
tease resistance and potential conformational con-
straints. Their metal complexing abilities have been
well documented.
In our ongoing programme of studying the ring opening
reactions of N-arylsulfonylaziridines,9 we have investi-
gated their reaction with isocyanates in the presence of
iodide ions to give 2-imidazolidinones.10a The regio-
and stereochemical course of these reactions has been
clearly delineated.10b In the present communication we
report the use of this reaction for obtaining chiral di-
amines and diamino acids. The synthetic rationale is
depicted in Scheme 1.
Chiral diamines can be obtained by resolution of race-
mates using optically active dicarboxylic acids such as
mandelic4a or tartaric4b or the recently reported dehy-
droabietic acid.4c Chiral diamines and diamino acids
have been prepared by a variety of other methods. Most
are based on the chirality of amino acids and related
amino alcohols.5a–d Procedures based on chiral di-
ols,6a–c mandelic6d and tartaric acids,6e cyanohydrins,6f
amines,6g hydrazones,6h,i imines6j and bisimines,6k,l azir-
idines,6m oxazolines6n and oxazolidinones6o and sulfil-
It was proposed that the reaction of aziridines with com-
mercially available R-(+)-a-methylbenzyl isocyanate 2
would give a mixture of diastereomeric 2-imidazolid-
inones, which on subsequent reduction and treatment
with acid would yield both enantiomers of the diamines.
The question of regiochemistry had already been settled
since 2-alkylaziridines have been shown to undergo
iodide attack at the unsubstituted carbon whereas
with 2-phenylaziridines the nucleophile opened the ring
at C-2.10b
Keywords: Diamines; Diamino acids; 2-Imidazolidinones.
*
Accordingly, aziridines 1a,b were prepared as previously
reported11 and reacted with isocyanate 2. The two
Corresponding author. Tel.: +91 11 26591518; fax: +91 11
26582037; e-mail: ukn@netearth.iitd.ac.in
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.11.088

480
U. K. Nadir et al. / Tetrahedron Letters 46 (2005) 479–482
H
N
Ts
N
NH2
R
Mg-MeOH
R
conc. HCl
O
R
O
.2HCl
N
H
H
N
H
NH2
H3C
Ph
5
H3C
Ph
Ts
N
CH3
NCO
-
I
Ph
4
+
+
H
2
H
N
R
Ts
1a-b
N
Mg-MeOH
NH2
conc. HCl
R-(+)-α−methylbenzyl
isocyanate
O
R
H
R
R
O
a) R = Ph
N
.2HCl
N
b) R = Me
NH2
H3C
Ph
6
H3C
Ph
H
H
3
Scheme 1. Synthesis of diamines via hydrolysis of 2-imidazolidinones.
Ts
N
H
N
R
NH2
.HCl
NH2
Mg-MeOH
conc. HCl
R
O
R
O
HO2C
N
H
N
MeO2C
H3C
MeO C
Ts
N
2H3C
Ph
Ph
CH3
NCO
-
I
10
H
8
Ph
+
R
H
+
Ts
H
N
COOMe
2
7a-b
conc. HCl
N
Mg-MeOH
NH2
R-(+)-α-methylbenzyl
R
HO2C
MeO2C
O
O
isocyanate
MeO2C
.HCl
NH2
a) R = H
b) R = Me
N
H
N
R
R
H3C
Ph
H3C
Ph
11
H
9
Scheme 2. Synthesis of diamino acids via hydrolysis of 2-imidazolidinones.
Table 1. Synthesis of diastereomeric 2-imidazolidinones from
N-arylsulfonylaziridines
Entry Aziridines Diastereomeric Yield (%)
Diastereo-
meric ratioa
mixture of
2-imidazol-
idinones
mixture
of diastereo-
mers
1
2
3
4
1a
1b
7a
7b
3a, 4a
3b, 4b
8a, 9a
8b, 9b
90
88
85
87
60:40
50:50
65:35
54:46
a The diastereomeric ratios were not always 50:50. This aspect is being
investigated.
diastereoisomers 3 and 412a,b were obtained in excellent
yields (ratio of 3:4 with R = Ph was 60:40 and with
R = Me; 50:50 as determined by H NMR), see Table
1
1. Only one regioisomer was obtained in both cases;
with 1a, the phenyl group was found to be adjacent to
the N-methylbenzyl group whereas for 1b, the methyl
group was adjacent to the N–Ts group. The regio-and
stereochemistry was further confirmed by single crystal
X-ray diffraction data of compound 3a (Fig. 1). The dia-
stereomers could be separated by crystallization and/or
column chromatography and on treatment individually
with Mg–MeOH13 followed by conc. HCl furnished
both enantiomers 5a,b and 6a,b.12c,e The dihydrochlo-
ride salts of 5a and 6a were converted into their ditosyl
Figure 1. X-ray structure of compound 3a.
derivatives to compare their optical rotations12c with
those already reported.12d
The same protocol was used to synthesize diamino acids
(Scheme 2). Aziridine 7a was prepared using our
recently reported14 method and on treatment with 2

U. K. Nadir et al. / Tetrahedron Letters 46 (2005) 479–482
481
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4. (a) Zhang, W.; Jacobsen, E. N. Tetrahedron Lett. 1991, 32,
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metry 2001, 12, 2961; (b) Kolb, H. C.; VanNieuwenhze,
M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483; (c)
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W. Tetrahedron: Asymmetry 1999, 10, 3559; (f) Effenber-
ger, F.; Kremser, A.; Stelzer, U. Tetrahedron: Asymmetry
1996, 7, 607; (g) Bruni, E.; Cardillo, G.; Orena, M.;
Sandri, S.; Tomasini, C. Tetrahedron Lett. 1989, 30, 1679;
(h) Enders, D.; Schiffers, R. Synthesis 1996, 1, 53; (i)
Enders, D.; Chelain, E.; Raabe, G. Bull. Soc. Chim. Fr.
1997, 134, 299; (j) Taniguchi, N.; Uemure, M. Synlett
1997, 51; (k) Martelli, G.; Savoia, D. Collect. Czech.
Chem. Commun. 2003, 68, 1531; (l) Roland, S.; Mangeney,
P. Eur. J. Org. Chem. 2000, 611; (m) Concellon, J. M.;
Riego, E.; Suarez, J. R. J. Org. Chem. 2003, 68, 9242; (n)
Cutri, S.; Bonin, M.; Micouin, L.; Husson, H. P.;
Chiaroni, A. J. Org. Chem. 2003, 68, 2645; (o) Cook, G.
R.; Shanker, P. S.; Pararajasingham, K. Angew. Chem.,
Int. Ed. 1999, 38, 110; (p) Viso, A.; Pradilla, de la F.;
Garcia, A.; Guerrero-Strachan, C.; Alonso, M.; Tortosa,
M.; Aida, F.; Martinez-Ripoll, M.; Fonseca, I.; Andre, I.;
Rodriguez, A. Chem. Eur. J. 2003, 9, 2867.
Figure 2. X-ray structure of compound 8a.
furnished the diastereomeric 2-imidazolidinones 8a15a
and 9a15b (65:35 diastereomeric ratio as determined by
1H NMR), Table 1. These were separated by column
chromatography and characterized. In this case also
only one regioisomer was obtained. The regio- and
stereochemistry was further confirmed by single crystal
X-ray diffraction data of compound 8a16 (Fig. 2). Suc-
cessive treatment with Mg–MeOH and conc. HCl then
furnished the corresponding diamino acids 10a and
11a15c,d in 85% overall yield. In the case of 7b, the
imidazolidinones 8b and 9b could not be separated.
However, after reduction with Mg–MeOH, the detosy-
lated imidazolidinones could be separated by column
chromatography and these, on hydrolysis with conc.
HCl, give the dihydrochloride salts of amino acids 10b
and 11b. The resulting dihydrochlorides were heated
with propene oxide to give pure monohydrochlorides
10b and 11b and their optical rotations were then
compared.15c,e
7. (a) Pach, Y. S.; Boys, M. I.; Beah, P. J. Am. Chem. Soc.
1996, 61, 428; (b) Trost, B. M.; Fandrick, D. R. J. Am.
Chem. Soc. 2003, 125, 1183.
8. Lucet, D.; Gall, T. L.; Mioskowski, C. Angew. Chem., Int.
Ed. 1998, 37, 2622.
9. Tanner, D. Angew. Chem., Int. Ed. Engl. 1994, 33, 599.
10. (a) Nadir, U. K.; Basu, N. Tetrahedron Lett. 1992, 7949;
(b) Nadir, U. K.; Basu, N. Tetrahedron 1993, 49, 7787.
11. Koul, V. K. Ph.D. Thesis, Indian Institute of Technology,
Delhi, 1982.
In conclusion we have developed a new methodology for
the synthesis of 1,2-diamines and diamino acids, which
is general and has potential for wide structural
variation.
12. (a) Spectral data for compound 3a: colourless crystalline
solid: mp 155–157 °C; IR mmax (KBr) 1716, 1350,
1
1150 cmꢀ1; H NMR (300 MHz, CDCl3) d 7.96–6.98 (m,
14H), 4.46 (m, 2H), 4.10 (t, 1H, J = 9.36 Hz), 3.59 (dd, 1H,
J = 9.49, 6.87 Hz), 2.48 (s, 3H), 1.63 (d, 3H, J = 7.23 Hz);
13C NMR (75 MHz, CDCl3) d 153.82, 144.69, 140.35,
138.30, 134.82, 129.63–126.97 (aromatic), 56.74, 53.68,
50.66, 21.67, 17.85; FAB MS (m/z) 422 (M++2, 100%).
Anal. Calcd for C24H24N2O3S: C, 68.57; H, 5.71; N, 6.66.
Found: C, 68.36; H, 5.60; N, 6.48; (b) Spectral data for
compound 4a: colourless crystalline solid: mp 135–137 °C;
Acknowledgements
We thank the Council of Scientific and Industrial Re-
search (CSIR), New Delhi for financial support of this
work and fellowships to R.V.K. and A.S. Thanks are
also due to Dr. A. Ramanan and Shailesh Upreti for
X-ray crystal data.
IR mmax (KBr) 1716, 1350, 1150 cmꢀ1
;
1H NMR
(300 MHz, CDCl3) d 8.16–7.01 (m, 14H), 5.23 (q, 1H,
J = 7.2 Hz), 4.12 (dd, 1H, J = 9.12, 5.18 Hz), 3.99 (t, 1H,
J = 9.3 Hz), 3.61 (dd, 1H, J = 9.4, 5.2 Hz), 2.49 (s, 3H),
1.04 (d, 3H, J = 7.26 Hz); 13C NMR (75 MHz, CDCl3) d
153.87, 144.63, 140.18, 138.63, 134.68, 129.47–126.72
(aromatic), 54.58, 52.16, 50.77, 21.48, 17.50; FAB MS
(m/z) 421 (M++1, 100%). Anal. Calcd for C24H24N2O3S:
C, 68.57; H, 5.71; N, 6.66. Found: C, 68.23; H, 5.94; N,
References and notes
1. Lucet, D.; Gall, T. L.; Mioskowski, C. Angew. Chem., Int.
Ed. 1998, 37, 2580.
2. Bennani, Y.; Hanessian, S. Chem. Rev. 1997, 97, 3161, and
references cited therein.

482
U. K. Nadir et al. / Tetrahedron Letters 46 (2005) 479–482
25
6.52; (c) Optical rotation ½aꢁD of the ditosyl derivative of
compound 5a: S-(+)-ditoluene-p-sulfonyl-phenylethyl-
enediamine: +19.48 (c, 0.77 in DMF) [lit.12d +19.8 (c,
(c 0.5 in 1 N HCl) [lit.15d ꢀ25.0 (c 0.5 in 1 N HCl)]; optical
25
rotation ½aꢁD of R-(ꢀ)-2,3-diamino-2-methylpropanoic
25
acid monohydrochloride 10b: ꢀ3.2 (c 0.7 in H2O) [lit.15e
25
0.77 in DMF)]; optical rotation ½aꢁD of the ditosyl
ꢀ3.5 (c 0.7 in H2O)]; optical rotation ½aꢁD of S-(+)-2,3-
derivative of compound 6a: R-(ꢀ)-ditoluene-p-sulfonyl-
phenylethylenediamine: ꢀ19.56 (c, 0.77 in DMF) [lit.12d
diamino-2-methylpropanoic acid monohydrochloride 11b:
+3.0 (c 0.7 in H2O) [lit.15e +3.5 (c 0.7 in H2O)]; (d)
Cardillo, G.; Orena, M.; Penna, M.; Sandri, S.; Tomasini,
C. Tetrahedron 1991, 47, 2263; (e) Hartwig, W.; Mitten-
dorf, J. Synthesis 1991, 939.
25
ꢀ19.8 (c, 0.77 in DMF)]; optical rotation ½aꢁD of S-(+)-
25
1,2-propanediamine 5b: +35 (c, 0.97 in benzene) [lit.12e
+34.8 (c, 0.97 in benzene)]; optical rotation ½aꢁD of R-(ꢀ)-
1,2-propanediamine 6b: ꢀ34.7 (c, 0.97 in benzene) [lit.12e
ꢀ34.8 (c, 0.97 in benzene)]; (d) Douglas, G. N.; David, F.
E. J. Chem. Soc. (C) 1966, 396; (e) Dwyer, F. P.; Garvan,
F. L.; Shulman, A. J. Am. Chem. Soc. 1959, 81, 290.
16. X-ray data for compounds 3a and 8a were collected on a
Bruker AXS SMART apex diffractometer, with a CCD
area detector (MoKa radiation, graphite monochromator,
˚
k = 0.71073 A). Cell parameters were retrieved using
13. Nadir, U. K.; Krishna, R. V. J. Heterocycl. Chem. 2004,
41, 737.
SMART software and refined using SAINTPLUS soft-
ware. Absorption correction was applied using SADABS.
Structures were solved by direct methods and refined by
least square methods as F2, using the SHEXTL pro-
gramme package. The non-hydrogen atoms were refined
anisotropically. Data for 3a: C24H24N2O3S, MW = 422,
colourless crystal, crystal system: triclinic, space group: P
14. Nadir, U. K.; Singh, A. Synth. Commun. 2004, 34, 1337.
15. (a) Spectral data for compound 8a: colourless crystalline
solid: mp 134–136 °C; IR mmax (KBr) 1750, 1720, 1350,
1160 cmꢀ1 1H NMR (300 MHz, CDCl3) d 7.93 (d, 2H,
;
J = 8.4), 7.4–7.2 (m, 7H), 5.1 (q, 1H, J = 7.0 Hz), 4.1 (dd,
1H, J = 3.7, 2.5 Hz), 3.85 (m, 2H), 3.18 (s, 3H), 2.45 (s,
3H), 1.57 (d, 3H, J = 7.07 Hz); 13C NMR (75 MHz,
CDCl3) d 169.74, 144.82, 138.51, 134.79, 129.57, 128.70,
127.99, 127.74, 53.28, 52.29, 52.07, 45.46, 21.57, 16.66;
FAB MS (m/z) 403 (M++1, 100%). Anal. Calcd for
C20H22N2O5S: C, 59.69; H, 5.51; N, 6.96. Found: C, 59.67;
H, 5.65; N, 6.91; (b) Spectral data for compound 9a:
colourless crystalline solid: mp 108–109 °C; IR mmax
˚
˚
1, cell parameters: a = 6.1897(6) A, b = 10.4578(10) A,
˚
3
˚
c = 16.6567(17) A, V = 1064.85(18) A , Z = 2, Dc =
1.312 g cmꢀ3, F(000) = 444, total number of 1s parame-
ters = 545, final
wR2 = 0.0950,
R
indices [I > 2r(I)] R1 = 0.0394,
indices (all data) R1 = 0.0429,
R
wR2 = 0.0976, GOF = 1.039, restrained GOF = 1.039 for
all data. ORTEP diagram is given in Figure 1. Crystal-
lographic data have been deposited with the Cambridge
Crystallographic Data Centre (CCDC 253421). Data for
8a: C20H22N2O5S, MW = 402, colourless crystal, crystal
system: orthorhombic, space group: P2(1)2(1)2(1), cell
1
(KBr) 1747, 1718, 1350, 1160 cmꢀ1; H NMR (300 MHz,
CDCl3) d 7.95 (d, 2H, J = 6.8), 7.39–7.17 (m, 7H), 5.2 (q,
1H, J = 6.7 Hz), 3.8 (m, 3H), 3.75 (s, 3H), 2.49 (s, 3H),
1.48 (d, 3H, J = 7.0 Hz); 13C NMR (75 MHz, CDCl3) d
171.08, 144.91, 138.67, 134.68, 129.62, 128.72, 128.13,
127.14, 52.85, 52.26, 52.09, 45.95, 21.65, 16.79; FAB MS
(m/z) 403 (M++1, 100%). Anal. Calcd for C20H22N2O5S:
C, 59.69; H, 5.51; N, 6.96. Found: C, 59.61; H, 5.55; N,
˚
˚
˚
parameters:
˚
a = 7.592(9) A,
b = 13.110(15) A,
19.385(2) A, V = 1929.7(4) A , Z = 4, Dc = 1.615 g cm
c =
,
3
ꢀ3
F(000) = 950, total number of 1s parameters = 256, final R
indices [I > 2 r(I)] R1 = 0.0356, wR2 = 0.0949, R indices
(all data) R1 = 0.0375, wR2 = 0.0968, GOF = 1.044,
restrained GOF = 1.044 for all data. ORTEP diagram is
given in Figure 2. Crystallographic data have been
deposited with the Cambridge Crystallographic Data
Centre (CCDC 253420).
25
6.98; (c) Optical rotation ½aꢁD of S-(+)-2,3-diaminoprop-
anoic acid hydrochloride 10a: +24.8 (c 0.5 in 1 N HCl)
[lit.15d +25.0 (c 0.5 in 1 N HCl)]; optical rotation ½aꢁ2D5 of R-
(ꢀ)-2,3-diaminopropanoic acid hydrochloride 11a: ꢀ24.5