General route to a new class of homochiral azetidine-derived 1,2 diamines

Article abstract of DOI:10.1002/ejoc.200400233

A short access to novel azetidine-derived anti-1,2-diamines starting from easily accessible 2-cyanoazetidines has been developed. A one-pot sequence, including a nucleophilic addition and reduction of the resulting imine, allows for a dia-stereoselective synthesis of variously substituted diamines. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200400233

FULL PAPER
General Route to a New Class of Homochiral Azetidine-Derived 1,2-Diamines
[a]
[a]
[a]
[b]
´
Francois Couty,* Gwilherm Evano, Damien Prim,* and Jerome Marrot
¸
Keywords: Aminonitriles / Azetidines / Vicinal diamines
A short access to novel azetidine-derived anti-1,2-diamines
starting from easily accessible 2-cyanoazetidines has been
developed. A one-pot sequence, including a nucleophilic ad-
dition and reduction of the resulting imine, allows for a dia-
stereoselective synthesis of variously substituted diamines.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
Several studies have established the role of this class of
compounds 1 as chiral ligands, valuable synthetic inter-
mediates and biologically active chemicals. For example, (2-
aminomethyl)piperidines 1a are key synthetic intermediates
in the preparation of 3-aminoazepanes, obtained through
a ring-enlargement procedure.[5] Nonracemic (2-amino-
methyl)pyrrolidines 1b have recently been used as con-
strained chiral ligands in Rh-based catalytic hydrogen-
ation[6] and Zn-mediated asymmetric reactions.[7] Enantio-
pure (2-aminomethyl)aziridines 1c, synthesized from α-
chloro ketimines,[8] have been shown to be prone to undergo
a regio- and stereoselective ring-opening, yielding various
diaminoalkanols.[9] While (2-aminomethyl)azetidines 1d,
prepared as racemates, have been described as G-protein
receptor ligands[10a] and antimicrobial agents,[10b] the syn-
thesis of chiral nonracemic (2-aminomethyl)azetidines re-
mains, to the best of our knowledge, unreported. This is
certainly due to the lack of general and efficient methods
for the synthesis of enantiopure azetidines. Driven by our
continuing interest in the synthesis and reactivity of these
heterocycles,[11] we envisioned the preparation of enantio-
pure azetidine-derived vicinal diamines using a sequence of
nucleophilic addition and reduction, starting from enantio-
pure 2-cyanoazetidine, which is summarized in Figure 2.
Vicinal diamines are commonly found in biologically ac-
tive compounds[1] that display a wide range of useful bio-
logical activities, and they have recently been shown to have
excellent properties in asymmetric synthesis as chiral lith-
ium or magnesium amides[2] and in transition-metal-as-
sisted[3] or metal-free[4] asymmetric catalysis. Although
these applications have stimulated the synthesis of a large
variety of vicinal diamines, there is a steady demand for
new enantiopure 1,2-diamines. In addition to having novel
structural features, these diamines must be easily accessible
and available in both enantiomeric forms, and their syn-
thesis should allow for an easy modification of both steric
and electronic effects in order to finely tune the targeted
properties. Among the 1,2-diamines reported to date, di-
amines of general structure 1, in which one of the nitrogen
atoms is included in a ring, have attracted recent attention
(Figure 1).
Figure 1. Vicinal diamines 1
Figure 2. Synthesis of azetidine-based diamines from commercially
available β-amino alcohols
[a]
´
Laboratoire SIRCOB, UMR CNRS 8086 Universite de
Versailles Saint-Quentin-en-Yvelines,
78035 Versailles Cedex, France
Fax: (internat.) ϩ 33-1-39254452
E-mail: couty@chimie.uvsq.fr
In this paper, we report the first general preparation of
azetidine-derived vicinal diamines 4 from 2-cyanoazetidines
that are easily accessible in a few steps from the chiral
pool.[11]
[b]
´
Institut Lavoisier, UMR CNRS 8637, Universite de Versailles
Saint-Quentin-en-Yvelines,
78035 Versailles Cedex, France
Eur. J. Org. Chem. 2004, 3893Ϫ3897
DOI: 10.1002/ejoc.200400233
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3893

F. Couty, G. Evano, D. Prim, J. Marrot
FULL PAPER
would induce the formation of a strained four-membered
azetidinium ion.
Results and Discussion
In a preliminary study, 2-cyanoazetidine 2a was allowed
to react with MeLi in toluene at 5Ϫ10 °C to give the corre-
sponding imine 3a. In a one-pot, two-step process, in situ
reduction of this imine using NaBH4 in methanol at 0 °C
afforded the expected diamine as a single diastereoisomer
which was converted, for easier isolation and purification,
to its N-Boc derivative 4a (Boc2O, EtOAc, reflux) in good
overall yield (55%) (Scheme 1).[12]
Figure 4. Addition of an organometallic reagent to 2-cyanoazetid-
ine
The relative stereochemistry in 5 results from a hydride
attack on the Re face of the imine moiety. The diastereosel-
ectivity could be explained by using the models depicted in
Figure 3. In these models, which are analogous to the well-
established Cram chelate model in carbonyl chemistry, chel-
ation could result either from an intramolecular hydrogen
bond between the tertiary amine and imino moieties (Fig-
ure 3, top case) or from the formation of a five-membered
lithio chelate (Figure 3, bottom case). The proposed chelate
model and the observed anti selectivity are in good agree-
ment with the chelation-controlled products obtained by
addition of organometallic reagents to aziridinyl aldim-
ines[16] and α-silyloxy imines.[17] It is worth noting that the
hydride addition proceeds with no detectable epimerization
at the C-2 stereocenter.
Scheme 1. Synthesis of vicinal diamines 4a and 5
In order to elucidate the configuration of the stereocenter
created in this process, diamine 4a was converted, in high
yield, into its crystalline di-N-Boc derivative 5 by reaction
We next studied the synthesis of other diamines, starting
with Pd(OH)2, cyclohexene as an H2 source, and (Boc)2O from various 2-cyanoazetidines. Treatment of trans-2,3-cy-
in ethyl acetate. X-ray crystallographic analysis[13] of com- anoazetidine 2a with various organometallic reagents (ar-
pound 5 clearly demonstrates that the reaction sequence ylLi, alkylLi, allylMgBr), followed by hydride addition and
from 2-cyanoazetidines 2 leads to anti-1,2-diamines 4, as N-protection, gave diastereomerically pure diamines 4aϪ4e
can be seen from the ORTEP view in Figure 3.
(Table 1, Entries 1Ϫ5) with yields ranging from 53 to 72%,
Since the addition of organometallic reagents onto an α- regardless of the nature and bulkiness of the introduced R4
aminonitrile A usually results in the displacement of the group. At this stage, we were interested in determining
cyanide (Bruylants reaction[14]), leading to the formation of whether the substitution pattern on the azetidine ring and
B instead of the imine C (Figure 4), the stereoselectivity of its relative configuration could affect the stereoselectivity of
the reduction of C has been studied in very few cases.[15] In this reaction. Thus, the addition/reduction/protection se-
the present work, the formation of B is highly disfavored quence was next examined on five different azetidines
by the presence of the azetidine ring, since this reaction 2bϪ2f. Starting from cis-2,3-cyanoazetidine 2b, diamines 4f
Figure 3. Stereochemistry of hydride addition and X-ray structure of diamine 5
3894
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 3893Ϫ3897

A New Class of Homochiral Azetidine-Derived 1,2-Diamines
FULL PAPER
Table 1. Synthesis of azetidine-based vicinal diamines 4
Figure 5. Postulated chelation-controlled hydride addition
Figure 6. Azetidine-based vicinal diamines
[a]
[b]
Yields of isolated, analytically pure materials. Determined by
1H NMR spectroscopic analysis of crude reaction mixtures.
Conclusion
In conclusion, we have developed the first diastereoselec-
tive synthesis of azetidine-derived 1,2-diamines. This meth-
odology conveniently gives access to novel anti-1,2-diam-
ines by a short reaction sequence using starting materials
taken from the chiral pool. Additionally, there is scope for
the flexible introduction of additional substituents.
and 4g were readily obtained as single diastereomers in 68
and 42% yields respectively (Table 1, Entries 6 and 7).
Subsequently, N-methyl- or N-allyl-protected azetidines
2cϪ2f were subjected to the addition/reduction sequence
(Entries 8Ϫ12). In all cases, diastereomerically pure diam-
ines 4hϪ4l were successfully obtained in good yields. Iso-
lation and purification of diamines 4hϪ4j did not require
protection of the polar newly formed amino group. Appli-
cation of the proposed chelate model shown in Figure 3 to
Experimental Section
General Remarks: Melting points were determined with a Reichert
the imines derived from substrates 2bϪe, with different sub- apparatus and are uncorrected. NMR spectra were recorded with
a Bruker AC spectrometer at 200 or 300 (1H) and 75 (13C) MHz,
stitution patterns on the azetidine ring, is depicted in Fig-
using CDCl3 as the solvent. Optical rotations were determined with
ure 5. For clarity, the absolute configurations of the C-2
a PerkinϪElmer 141 instrument. THF and toluene were distilled
stereocenter in 2bϪe have been fixed as in 2a. Construction
of these rigid chelated structures with molecular models
from sodium/benzophenone ketyl.
shows that there is no severe steric interaction between the
R group of the imine and the substituents on the azetidine The appropriate organolithium reagent (2 mmol) was added to a
General Procedure for the Addition/Reduction/Protection Sequence:
solution of 2-cyanoazetidine 2 (1 mmol) in dry THF (10 mL) at 0
°C under argon. After stirring for 20 min, MeOH (10 mL) and
NaBH4 (1.2 mmol) were successively added. After a further 1 h,
the reaction was quenched with saturated aqueous NH4Cl solution
(5 mL), and extracted with EtOAc (3 ϫ 10 mL). The combined
organic extracts were washed with brine, dried with magnesium
sulfate and concentrated under reduced pressure. Amines 4f and
4hϪj were purified by silica gel column chromatography at this
stage. (Boc)2O (1.2 mmol) was added to a solution of crude amines
4aϪe, 4g and 4kϪl in EtOAc (10 mL).The reaction mixture was
ring (Ph on C-3 in 2b,e or Me on C-4 in 2c,e). In fact, the
shielding of the Si face by these substituents should be a
positive parameter to enhance the stereoselectivity towards
Re-face attack, particularly for the imines generated from
2b,c,e. The relative anti stereochemistry was therefore ra-
tionalized on the basis of the chelate model depicted above.
Further functionalization of the diamine skeleton 4 pro-
ved to be particularly flexible. As exemplified in Figure 6,
we were able to introduce additional substituents at the ex-
tracyclic nitrogen atom in compound 4h. For instance, 4h heated at reflux for 2 h. The solvent was then removed to give a
crude product which was purified by silica gel column chromatog-
raphy.
can be converted into its N-tosyl derivative 6 (TsCl, Et3N,
CH2Cl2, room temp.) or N-benzyl derivative 7 (PhCHO,
MgSO4, CH2Cl2, room temp. then NaBH4, MeOH) in 71%
and 82% yields, respectively. In addition, reduction of 2-
cyanoazetidine 2a with LiAlH4 afforded the primary diam-
ine 8 in 68% yield.
Diamine 4a: Yield 201 mg, 55%, m.p. 82 °C. [α]2D0 ϭ Ϫ6.1 (c ϭ 4.3,
CHCl3). Rf (C6H12/Et2O, 2:1) ϭ 0.46. 1H NMR (200 MHz): δ ϭ
1.08 (d, J ϭ 6.6 Hz, 3 H), 1.44 (s, 9 H), 2.95 (dd, J ϭ 4.0, 6.6 Hz,
1 H), 3.32 (dd, J ϭ 5.5, 6.7 Hz, 1 H), 3.50 (q, J ϭ 8.1 Hz, 1 H),
Eur. J. Org. Chem. 2004, 3893Ϫ3897
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 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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F. Couty, G. Evano, D. Prim, J. Marrot
FULL PAPER
3.70 (m, 2 H), 3.85 (d, J ϭ 13.1 Hz, 1 H), 4.69 (d, J ϭ 6.6 Hz, 1 154.8 ppm. C23H30N2O2 (366.23): calcd. C 75.37, H 8.25, N 7.64;
H), 7.22Ϫ7.41 (m, 10 H) ppm. 13C NMR (75 MHz): δ ϭ 26.9, 28.5, found C 75.26, H 8.37, N 7.59.
39.1, 49.2, 58.3, 62.6, 76.32, 78.9, 126.5, 127.2, 127.6, 128.4, 128.8,
Diamine 4h: Yield 165 mg, 62%. [α]2D0 ϭ ϩ149.1 (c ϭ 4.4, CHCl3).
138.1, 141.6, 155.7 ppm. C23H30N2O2 (366.23): calcd. C 75.37, H
8.25, N 7.64; found C 74.99, H 8.42, N 8.12.
Rf (C6H12/Et2O, 1:1) ϭ 0.34. 1H NMR (200 MHz): δ ϭ 1.27 (d,
J ϭ 6.6 Hz, 3 H), 1.64 (br. s, 2 H), 2.12 (s, 3 H), 2.83 (m, 1 H),
Diamine 4b: Yield 227 mg, 53%, m.p. 182 °C. [α]2D0 ϭ ϩ42.8 (c ϭ
4.9, CHCl3). Rf (C6H12/Et2O, 1:1) ϭ 0.62. 1H NMR (200 MHz):
δ ϭ 1.46 (s, 9 H), 3.01 (dd, J ϭ 6.1, 7.5 Hz, 1 H), 3.39 (s, 2 H),
3.70 (m, 3 H), 4.77 (br. s, 1 H), 5.27 (d, J ϭ 6.1 Hz, 1 H), 7.08 (d,
J ϭ 7.6 Hz, 2 H), 7.22Ϫ7.35 (m, 13 H) ppm. 13C NMR (75 MHz):
δ ϭ 26.9, 28.3, 39.9, 57.8, 61.8, 76.2, 79.2, 125.8, 126.3, 126.9,
127.2, 127.4, 127.5, 127.6, 128.2, 128.3, 128.4, 128.5, 128.8, 155.3
ppm. C28H32N2O2 (428.25): calcd. C 78.47, H 7.53, N 6.54; found
C 78.57, H 7.46, N 6.22.
3.17 (m, 2 H), 4.12 (d, J ϭ 5.4 Hz, 1 H), 7.10Ϫ7.41 (m, 10 H) ppm.
13C NMR (75 MHz): δ ϭ 20.2, 42.7, 48.0, 59.2, 67.9, 76.9, 126.2,
127.1, 127.6, 128.2, 141.2 ppm. C18H22N2 (266.18): calcd. C 81.16,
H 8.32, N 10.52; found C 80.93, H 8.51, N 10.47.
Diamine 4i: Yield 202 mg, 76%. [α]2D0 ϭ Ϫ20.3 (c ϭ 2.85, CHCl3).
1
Rf (Et2O) ϭ 0.50. H NMR (200 MHz): δ ϭ 0.99 (d, J ϭ 6.8 Hz,
3 H), 1.33 (d, J ϭ 5.4 Hz, 3 H), 2.38 (s, 3 H), 2.79 (q, J ϭ 6.8 Hz,
1 H), 3.19 (m, 2 H), 3.19 (dq, J ϭ 2.6, 6.8 Hz, 1 H), 7.03Ϫ7.45 (m,
10 H) ppm. 13C NMR (75 MHz): δ ϭ 11.0, 35.6, 42.9, 59.7, 59.8,
73.7, 125.9, 127.3, 127.9, 128.3, 138.2, 143.1 ppm. C18H22N2
(266.18): calcd. C 81.16, H 8.32, N 10.52; found C 80.98, H 8.37,
Diamine 4c: Yield 293 mg, 72%, m.p. 106 °C. [α]2D0 ϭ ϩ15.5 (c ϭ
6.0, CHCl3). Rf (C6H12/Et2O, 2:1) ϭ 0.27. 1H NMR (200 MHz):
δ ϭ 0.85 (t, J ϭ 6.0 Hz, 3 H), 1.16Ϫ1.53 (m, 6 H), 1.49 (s, 9 H), N 10.55.
2.96 (t, J ϭ 8.1 Hz, 1 H), 3.35 (t, J ϭ 6.4 Hz, 1 H), 3.50 (m, 1 H),
Diamine 4k: Yield 155 mg, 41%, m.p. 141 °C. [α]2D0 ϭ ϩ43.4 (c ϭ
3.8, CHCl3). Rf (Et2O) ϭ 0.50. H NMR (200 MHz): δ ϭ 1.37 (s,
3.61 (d, J ϭ 12.7 Hz, 1 H), 3.70 (t, J ϭ 7.4 Hz, 1 H), 3.95 (d, J ϭ
13.0 Hz, 1 H), 4.54 (d, J ϭ 8.3 Hz, 1 H), 7.23Ϫ7.40 (m, 10 H) ppm.
13C NMR (75 MHz): δ ϭ 14.0, 22.6, 27.9, 28.5, 31.0, 39.7, 54.2,
58.2, 62.8, 75.7, 78.8, 126.5, 127.2, 127.7, 128.4, 128.8, 138.3, 141.7,
156.0 ppm. C26H36N2O2 (408.28): calcd. C 76.43, H 8.88, N 6.86;
found C 76.35, H 8.94, N 6.85.
1
9 H), 2.79 (d, J ϭ 6.6 Hz, 2 H), 2.89 (dd, J ϭ 6.6, 8.3 Hz, 1 H),
3.38 (t, J ϭ 7.5 Hz, 1 H), 3.57 (q, J ϭ 7.9 Hz, 1 H), 3.73 (t, J ϭ
6.6 Hz, 1 H), 4.78 (br. s, 1 H), 5.05Ϫ5.21 (m,3 H), 5.75 (m, 3 H),
5.75 (m, 1 H), 7.05 (d, J ϭ 7.8 Hz, 2 H), 7.15Ϫ7.22 (m, 8 H) ppm.
13C NMR (75 MHz): δ ϭ 28.3, 40.1, 57.5, 59.1, 60.5, 76.2, 79.4,
117.5, 126.4, 126.9, 127.5, 128.2, 128.4, 134.3, 141.2, 155.5 ppm.
C24H30N2O2 (378.23): calcd. C 76.16, H 7.99, N 7.40; found C
Diamine 4d: Yield 245 mg, 60%, m.p. 145 °C. [α]2D0 ϭ ϩ25.0 (c ϭ
2.62, CHCl3). Rf (petroleum ether/Et2O, 4:1): 0.39. 1H NMR
(200 MHz): δ ϭ 0.78 (s, 3 H), 1.52 (s, 9 H), 2.80 (dd, J ϭ 6.6, 76.15, H 8.08, N 7.31.
8.3 Hz, 1 H), 3.30 (m, 1 H), 3.43 (d, J ϭ 12.5 Hz, 1 H), 3.60 (t,
Diamine 4l: Yield 280 mg, 82%. [α]2D0 ϭ ϩ125.8 (c ϭ 1.2, CHCl3).
Rf (C6H12/Et2O, 1:1) ϭ 0.17. H NMR (200 MHz): δ ϭ 1.40 (s, 9
J ϭ 7.4 Hz, 1 H), 3.70 (m, 1 H), 4.08 (d, J ϭ 12.9 Hz, 1 H), 4.71
(d, J ϭ 10.8 Hz, 1 H), 7.20Ϫ7.38 (m, 10 H) ppm. 13C NMR
(75 MHz): δ ϭ 22.1, 27.2, 28.5, 34.1, 39.8, 59.4, 60.5, 60.8, 71.9,
126.7, 126.8, 128.1, 128.3, 128.4, 128.9, 138.3, 141.3, 156.6 ppm.
C26H36N2O2 (408.28): calcd. C 76.43, H 8.88, N 6.86; found C
76.51, H 8.92, N 6.65.
1
H), 2.24 (t, J ϭ 7.0 Hz, 2 H), 2.89 (dd, J ϭ 7.0, 8.6 Hz, 1 H), 3.05
(dd, J ϭ 12.0, 6.8 Hz, 1 H), 3.23 (t, J ϭ 7.0 Hz, 1 H), 3.43 (m, 2
H), 3.73 (d, J ϭ 7.2 Hz, 1 H), 3.82 (m, 1 H), 4.57 (br. s, 1 H), 5.12
(m, 4 H), 5.74 (m, 2 H), 7.24Ϫ7.39 (m, 5 H) ppm. 13C NMR
(75 MHz): δ ϭ 28.4, 35.6, 39.8, 56.4, 57.9, 61.4, 74.7, 79.1, 117.5,
117.7, 126.6, 127.7, 128.3, 134.1, 134.5, 141.4, 155.8 ppm.
C21H30N2O2 (342.23): calcd. C 72.69, H 8.86, N 8.07; found C
Diamine 4e: Yield 239 mg, 61%. [α]2D0 ϭ ϩ52.6 (c ϭ 3.95, CHCl3).
1
Rf (C6H12/Et2O, 4:1) ϭ 0.62. H NMR (200 MHz): δ ϭ 1.42 (s, 9
H), 2.25 (t, J ϭ 6.8 Hz, 2 H), 2.94 (dd, J ϭ 6.6, 8.2 Hz, 1 H), 3.40 72.81, H 9.09, N 7.88.
(m, 3 H), 3.60 (d, J ϭ 12.8 Hz, 1 H), 3.68 (t, J ϭ 7.5 Hz, 1 H),
Diamine 5: Pd(OH)2 (87.5 mg) was added to a solution of com-
3.90 (d, J ϭ 12.8 Hz, 1 H), 4.57 (d, J ϭ 7.6 Hz, 1 H), 4.89 (m, 2
H), 5.68 (m, 1 H), 7.20Ϫ7.38 (m, 10 H) ppm. 13C NMR (75 MHz):
δ ϭ 28.4, 35.4, 39.5, 53.1, 58.2, 62.5, 74.7, 77.3, 79.0, 117.6, 126.6,
127.2, 127.7, 128.4, 128.8, 134.3, 138.2, 141.4, 155.9 ppm.
C25H32N2O2 (392.25): calcd. C 76.49, H 8.22, N 7.14; found C
76.56, H 8.11, N 7.18.
pound 4a (179 mg, 0.49 mmol), (Boc)2O (133 mg, 0.61 mmol) and
cyclohexene (2.3 mL) in ethanol (4 mL). The mixture was refluxed
for 3 h and then filtered through a short pad of Celite. The filtrate
was concentrated under reduced pressure, and the residue was puri-
fied by silica gel column chromatography (EtOAc) to give 5 as a
solid (183 mg, 97%). M.p. 136 °C. [α]2D0 ϭ Ϫ44.0 (c ϭ 5.8, CHCl3).
Rf (EtOAc) ϭ 0.64. 1H NMR (200 MHz): δ ϭ 1. 27 (d, J ϭ 6.6 Hz,
3 H), 1.41 (s, 9 H), 1.49 (s, 9 H), 3.35Ϫ3.45 (m, 1 H), 3.88Ϫ3.95
(t, J ϭ 6.6 Hz, 2 H), 4.13 (t, J ϭ 8.6 Hz, 1 H), 4.25 (m, 1 H),
Diamine 4f: Yield 223 mg, 68%. [α]2D0ϭ ϩ218.2 (c ϭ 2.25, CHCl3).
1
Rf (C6H12/Et2O, 1:1) ϭ 0.19. H NMR (200 MHz): δ ϭ 1.21 (br.
s, 2 H), 2.81 (m, 2 H), 3.14 (t, J ϭ 4.9 Hz, 1 H), 3.34 (d, J ϭ
5.2 Hz, 1 H), 3.50 (t, J ϭ 5.6 Hz, 1 H), 3.70 (dt, J ϭ 1.5, 5.4 Hz, 7.22Ϫ7.35 (m, 5 H) ppm. 13C NMR (75 MHz): δ ϭ 15.3, 27.4,
1 H), 3.80 (d, J ϭ 6.2 Hz, 1 H), 7.14Ϫ7.34 (m, 13 H), 7.64 (d, J ϭ 28.4, 37.3, 48.9, 53.7, 73.9, 79.1, 80.4, 126.8, 127.1, 128.7, 140.9,
8.4 Hz, 2 H) ppm. 13C NMR (75 MHz): δ ϭ 28.2, 39.2, 56.8, 61.7,
71.9, 79.1, 126.7, 126.8, 127.2, 127.3, 128.1, 128.2, 128.3, 128.5,
129.1, 138.3, 139.6, 140.8, 156.1 ppm. C28H32N2O2 (328.19): calcd.
C 78.47, H 7.53, N 6.54; found C 78.31, H 7.69, N 6.47.
146.7, 155.3 ppm. C21H32N2O4 (376.24): calcd. C 66.99, H 8.57, N
7.44; found C 66.92, H 8.64, N 7.40.
Diamine 6: p-Toluenesulfonyl chloride (232 mg, 1.25 mmol) was ad-
ded to a solution of compound 4h (250 mg, 0.94 mmol) and Et3N
(135 mg, 1.35 mmol) in CH2Cl2 (20 mL). After 16 h at room tem-
perature, saturated aqueous NH4Cl solution (5 mL) and CH2Cl2
Diamine 4g: Yield 153 mg, 42%, m.p. 179 °C. [α]2D0 ϭ ϩ134.2 (c ϭ
1
1.55, CHCl3). Rf (C6H12/Et2O, 6:4) ϭ 0.42. H NMR (200 MHz):
δ ϭ 1.30 (d, J ϭ 6.4 Hz, 3 H), 1.34 (s, 9 H), 3.16 (t, J ϭ 7.7 Hz, 1 (20 mL) were added. The organic extract was washed with brine,
H), 3.40 (d, J ϭ 13.2 Hz, 1 H), 3.44Ϫ3.57 (m, 3 H), 3.86 (br. s, 1 dried with magnesium sulfate, concentrated under reduced pressure
H), 4.06 (d, J ϭ 12.8 Hz, 1 H), 7.24Ϫ7.40 (m, 10 H), 7.48 (d, J ϭ and purified by silica gel column chromatography (CH2Cl2/Et2O,
8.2 Hz, 2 H) ppm. 13C NMR (75 MHz): δ ϭ 17.7, 28.4, 38.8, 47.3,
56.9, 62.8, 72.2, 78.6, 126.6, 126.9, 128.2, 128.4, 129.0, 138.5, 140.1,
3:1) to give 6 as a solid (280 mg, 71%). M.p. 62 °C. [α]2D0 ϭ Ϫ20.8
(c ϭ 3.65, CHCl3). Rf (CH2Cl2/Et2O, 3:1) ϭ 0.31. 1H NMR
3896
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 3893Ϫ3897

A New Class of Homochiral Azetidine-Derived 1,2-Diamines
FULL PAPER
J. Org. Chem. 1999, 64, 498. [1g] D. Lucet, T. Le Gall, C. Mios-
kowski, Angew. Chem. Int. Ed. 1998, 37, 2580.
(200 MHz): δ ϭ 1.23 (d, J ϭ 6.6 Hz, 3 H), 1.45 (s, 3 H), 2.32 (s, 3
H), 3.21 (dd, J ϭ 2.6, 7.9 Hz, 1 H), 3.64 (t, J ϭ 8.1 Hz, 1 H), 3.73
(dd, J ϭ 2.4, 6.6 Hz, 1 H), 3.99 (d, J ϭ 9.0 Hz, 1 H), 5.13 (br. s, 1
H), 6.95 (d, J ϭ 7.9 Hz, 2 H), 7.15 (m, 3 H), 7.35 (m, 7 H), 7.51
(m, 2 H) ppm. 13C NMR (75 MHz): δ ϭ 14.4, 21.3, 35.8, 47.4,
58.5, 62.1, 71.3, 126.9, 127.3, 127.8, 127.9, 128.4, 128.9, 129.1,
136.8, 137.7, 138.9, 142.3 ppm. C25H28N2O2S (420.19): calcd. C
71.40, H 6.71, N 6.66; found C 71.12, H 6.09, N 7.01.
[2] [2a]
O. Parisel, C. Fressigne, J. Maddaluno, C. Giessner-Prettre,
J. Org. Chem. 2003, 68, 1290. [2b] K. H. Yong, N. J. Taylor, J. M.
Chong, Org. Lett. 2002, 4, 3553. [2c] Z. Xu, M. C. Kozlowski, J.
Org. Chem. 2002, 67, 3072.
[3] [3a]
M ϭ Cu: X. Li, J. B. Hewgley, C. A. Mulrooney, J. Yang,
[3b]
M. C. Kozlowski, J. Org. Chem. 2003, 68, 5500.
M ϭ Ln:
P. N. O ’Shaughnessy, P. Scott, Tetrahedron: Asymmetry 2003,
14, 1979. [3c] M ϭ Ru: T. Ohkuma, M. Koizumi, K. Muniz, G.
Hilt, C. Kabuto, R. Noyori, J. Am. Chem. Soc. 2002, 124, 6508.
Diamine 7: MgSO4 (1 g) was added to a solution of compound 4h
(340 mg, 1.3 mmol) and benzaldehyde (139 mg, 1.3 mmol) in
CH2Cl2 (3 mL). After 3 h at room temperature, the mixture was
filtered and the filtrate concentrated under reduced pressure. The
residue was dissolved in EtOH (5 mL), and NaBH4 (60 mg,
1.6 mmol) was added at 0 °C. After 1 h, the reaction was quenched
by addition of a saturated aqueous NH4Cl solution (5 mL) and
extracted with EtOAc (3 ϫ 10 mL). The combined organic extracts
were washed with brine, dried with magnesium sulfate, concen-
trated under reduced pressure and purified by silica gel column
chromatography (C6H12/Et2O, 2:1) to give 7 as an oil (378 mg,
82%). [α]2D0 ϭ Ϫ20.5 (c ϭ 4.45, CHCl3). Rf (C6H12/Et2O, 2:1) ϭ
[3d] M ϭ Zn: P. Saravanan, A. Bisai, S. Baktharaman, M. Chan-
[3e]
drasekhar, V. K. Singh, Tetrahedron 2002, 58, 4693.
M ϭ
Pd: K. Mikami, K. Aikawa, Y. Yusa, Org. Lett. 2002, 4, 95. [3f]
[3g]
M ϭ Ni: K. Mikami, K. Aikawa, Org. Lett. 2002, 4, 99.
M ϭ Ir: K. Murata, T. Ikariya, J. Org. Chem. 1999, 64, 2186.
[3h]
M ϭ Rh: M. Bernard, V. Guiral, F. Delbecq, F. Fache, P.
Sautet, M. Lemaire, J. Am. Chem. Soc. 1998, 120, 1441. [3i] For
a recent review see: F. Fache, E. Schulz, M. L. Tommasino, M.
Lemaire, Chem. Rev. 2000, 100, 2159.
[4] [4a]
[4b]
A. Alexakis, O. Andrey, Org. Lett. 2002, 4, 3611.
Betancort, C. F. Barbas, III, Org. Lett. 2001, 3, 3737.
J. M.
[4c]
A.
Alexakis, A. Tomassini, C. Chouillet, S. Roland, P. Mangeney,
G. Bernardelli, Angew. Chem. Int. Ed. 2000, 39, 4093. [4d] S. A.
Modin, P. G. Andersson, J. Org. Chem. 2000, 65, 6736.
S. Cutri, M. Bonin, L. Micouin, H.-P. Husson, A. Chiaroni, J.
Org. Chem. 2003, 68, 2645.
1
0.38. H NMR (200 MHz): δ ϭ 1.28 (d, J ϭ 6.6 Hz, 3 H), 1.54 (s,
3 H), 2.78 (d, J ϭ 12.6 Hz, 1 H), 3.24 (m, 2 H), 3.47 (d, J ϭ 9.8 Hz,
1 H), 3.67 (m, 1 H), 3.80 (m, 1 H), 6.75 (m, 2 H), 7.16 (m, 3 H),
7.27Ϫ7.44 (m, 8 H), 7.61 (m, 2 H) ppm. 13C NMR (75 MHz): δ ϭ
14.8, 36.3, 47.9, 50.9, 62.1, 63.7, 73.1, 126.1, 126.9, 127.3, 128.1,
128.2, 128.3, 128.5, 128.6, 129., 139.9, 140.1, 141.3 ppm. C25H28N2
(356.23): calcd. C 84.23, H 7.92, N 7.86; found C 84.09, H 8.13,
N 8.01.
[5]
[6]
M. D. Jones, R. Raja, J. M. Thomas, B. F. G. Johnson, D. W.
Lewis, J. Rouzaud, K. D. M. Harris, Angew. Chem. Int. Ed.
2003, 42, 4326.
[7]
O. Munoz-Muniz, E. Juaristi, J. Org. Chem. 2003, 68, 3781.
W. K. Lee, H.-J. Ha, Aldrichim. Acta 2003, 36, 57. [8b] J. M.
[8] [8a]
´
Concellon, P. L. Bernad, E. Riego, S. Garcia-Granda, A. For-
cen-Acebal, J. Org. Chem. 2001, 66, 2764.
J. M. Concellon, E. Riego, J. R. Suarez, J. Org. Chem. 2003,
´
Diamine 8: A solution of cyanoazetidine 2a (400 mg, 1.6 mmol) in
dry THF (4 mL) was added to a suspension of LiAlH4 (72 mg,
1.8 mmol) in dry THF (5 mL). After 1 h at room temperature, the
reaction was quenched by addition of a saturated aqueous NH4Cl
solution (5 mL), and extracted with EtOAc (3 ϫ 10 mL). The com-
bined organic extracts were washed with brine, dried with mag-
nesium sulfate and concentrated under reduced pressure. Com-
pound 8 was purified by silica gel column chromatography (EtOAc
[9]
´
68, 9242.
[10] [10a]
W.-L. Wu, M. A. Caplen, M. S. Domalski, H. Zhang, A.
Fawzi, D. A. Burnett, Bioorg. Med. Chem. Lett. 2002, 12, 3157.
[10b]
F. Masahiro, C. Katsumi, Y. Hiroaki, Japanese Patent
JP11147883, 1999.
[11]
[12]
C. Agami, F. Couty, G. Evano, Tetrahedron: Asymmetry 2002,
13, 297.
then EtOAc/MeOH, 8:2) to give 8 as an oil (274 mg, 68%). [α]2D0
ϭ
Alternatively, the N-Boc protected diamine 4a could also be
obtained in two steps. Indeed, the intermediate imine 3 proved
to be stable enough to be isolated, and could then be reduced
and protected under similar conditions to afford 4a.
X-ray crystallographic data of 5: C21H32N2O4, orthorhombic,
ϩ4.7 (c ϭ 4.65, CHCl3). Rf (EtOAc) ϭ 0.18. 1H NMR (200 MHz):
δ ϭ 1.45 (br. s, 2 H), 2.72 (d, J ϭ 4.4 Hz, 2 H), 3.05 (dd, J ϭ 8.6,
6.6 Hz, 1 H), 3.35 (m, 1 H), 3.56 (m, 1 H), 3.75 (d, J ϭ 12.5 Hz, 1
H), 3.73Ϫ3.83 (m, 2 H), 7.28Ϫ7.37 (m, 10 H) ppm. 13C NMR
(75 MHz): δ ϭ 38.6, 44.6, 58.4, 62.9, 75.1, 126.5, 127.2, 127.3,
128.4, 128.5, 128.8, 138.3, 141.5 ppm. C17H20N2 (256.16): calcd. C
80.91, H 7.91, N 11.10; found C 80.72, H 8.12, N 11.01.
[13]
˚
˚
space group P2(1)2(1)2(1), a ϭ 9.4465(4) A, b ϭ 11.5992(5) A,
3
c ϭ 19.9718(9) A, V ϭ 2188.35(16) A , Dcalcd. ϭ 1.143 g cmϪ3
,
˚
˚
Z ϭ 4, µ(Mo-Kα) ϭ 0.079 mmϪ1, total reflections collected:
15280, independent reflections: 5647 (3421 I Ͼ 2σ(I)], number
of variables: 252, R1 ϭ 0.0462, wR2ϭ 0.1090 (all data). X-ray
data for 5 were collected with a three-circle diffractometer
equipped with a 2-dimensional CCD detector. CCDC-230430
contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge at
www.ccdc.cam.ac.uk/conts/retrieving.html [or from the Cam-
bridge Crystallographic Data Centre, 12 Union Road, Cam-
bridge CB2 1EZ, UK; Fax: (internat.) ϩ 44-1223-336-033; E-
mail: deposit@ccdc.cam.ac.uk].
Acknowledgments
´
We thank the CNRS and the Universite de Versailles Saint-Quen-
tin-en-Yvelines for financial support.
[1]
[1a]
For recent examples, see:
Wei, Y.-P. Ruan, Org. Lett. 2003, 5, 1927.
Kakefuda, T. Watanabe, N. Ishii, K. Wada, N. Masuda, S. Sak-
P.-Q. Huang, L.-X. Liu, B.-G.
[1b]
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H. Kubota, A.
C. Agami, F. Couty, G. Evano, Org. Lett. 2000, 2, 2085.
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J. Zhu, J.-C. Quirion, H.-P. Husson, Tetrahedron Lett.
[1c]
amoto, S.-I. Tsukamoto, J. Med. Chem. 2003, 46, 4728.
E. Hu, N. K. Kim, J. L. Gray, J.-I. K. Almstead, W. L. Seibel,
X.
1989, 30, 5137. [15b] J. Zhu, J.-C. Quirion, H.-P. Husson, Tetra-
[15c]
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E. Leclerc, E. Vrancken, P.
[1d]
B. Ledoussal, J. Med. Chem. 2003, 46, 3655.
S. Caron, S.
Mangeney, J. Org. Chem. 2002, 67, 8928.
W. K. Lee, H.-J. Ha, Aldrichim. Acta 2003, 36, 57.
J. Brussee, F. Dofferhoff, C. G. Kruse, A. Van Der Gen, Tetra-
hedron 1990, 46, 1653.
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S. Massett, D. E. Bogle, M. J. Castaldi, T. F. Braish, Org. Proc.
Res. Dev. 2001, 5, 254. [1e] H.-S. Lee, P. R. LePlae, E. A. Porter,
[1f]
S. H. Gellman, J. Org. Chem. 2001, 66, 3597.
Bechor, A. Nudelman, A. Hassner, A. Albeck, H. E. Gottlieb,
E. Falb, Y.
Received April 5, 2004
Eur. J. Org. Chem. 2004, 3893Ϫ3897
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3897