Regio- and Stereoselective C-2 and C-3 Cleavage of 2-(1-Aminoalkyl)aziridines with Alcohols, Carboxylic Acids, and Sodium Iodide

Article abstract of DOI:10.1021/jo0350514

Ring opening of nonactivated aziridines 1 using several nucleophiles, such as alcohols, carboxylic acids, and sodium iodide, is described. Depending on the nucleophile used, aziridines 1 are cleaved at C-3 or C-2 with total regio- and stereoselectivity, a

Full text of DOI:10.1021/jo0350514

Regio- a n d Ster eoselective C-2 a n d C-3 Clea va ge of
2-(1-Am in oa lk yl)a zir id in es w ith Alcoh ols, Ca r boxylic Acid s, a n d
Sod iu m Iod id e
J ose´ M. Concello´n,* Estela Riego, and J ose´ Ramo´n Sua´rez
Departamento de Qu´ımica Orga´nica e Inorga´nica, Facultad de Qu´ımica, Universidad de Oviedo,
J ulia´n Claverı´a, 8, 33071 Oviedo, Spain
jmcg@sauron.quimica.uniovi.es
Received J uly 22, 2003
Ring opening of nonactivated aziridines 1 using several nucleophiles, such as alcohols, carboxylic
acids, and sodium iodide, is described. Depending on the nucleophile used, aziridines 1 are cleaved
at C-3 or C-2 with total regio- and stereoselectivity, affording chiral 2-alkoxy-1,3-diamines 2 with
alcohols, or O-acylated-1-hydroxy-2,3-diamines 6 with carboxylic acids in moderate or high yield.
In the case of the aziridines derived from phenylalanine, treatment with NaI afford trans-4-
phenylbut-3-en-1,2-diamines 9, generating the alkene with total diastereoselectivity. Mechanisms
have been proposed to explain these reactions.
In tr od u ction
Herein, we report a generalization of the ring opening
of chiral, nonactivated amino aziridines 1 with other
nucleophiles, such as alcohols, carboxylic acids, and
sodium iodide.
The ability of aziridines to undergo highly regio- and
stereoselective ring-opening reactions gives them great
value in organic synthesis.1 For this reason, a large
number of ring-opening reactions of chiral, activated
aziridines have been reported.1c,2 However, to the best
of our knowledge, there are a very few examples in the
literature concerning the ring opening of nonactivated
aziridines.3
Recently, we described the synthesis of enantiopure
2-(1-aminoalkyl)aziridines4 and the ring opening of these
nonactivated amino aziridines5 by water with total regio-
and stereoselectivity at C-2 and C-3, obtaining chiral 1,3-
diaminoalkan-2-ols and 2,3-diaminoalkan-1-ols, respec-
tively.
Resu lts a n d Discu ssion
Rea ction of 1 w ith Alcoh ols. Ring-opening reactions
of amino aziridines 1 with different alcohols were carried
out in the presence of BF3‚OEt2, to activate the aziridine
ring.6 Thus, a solution of nonactivated amino aziridines
1 in the corresponding alcohol was treated with 1 equiv
of BF3‚OEt2, and heated at reflux for 2 h. The hydrolysis
of the reaction mixture led to 2-alkoxy-1,3-diamines 2 in
high yields (Scheme 1, Table 1).
The ring-opening reaction of amino aziridines 1 was
highly regio- and stereoselective (no others isomers of 2
were detected by 1H and 13C NMR spectra). In this
reaction, the aziridine undergoes an unusual ring open-
ing at C-2, with retention of the configuration at this
center.
(1) (a) Tanner, D. Angew. Chem., Int. Ed. Engl. 1994, 33, 599. (b)
Pearson, W. H.; Lian, B. W.; Bergmeier, B. W. In Comprehensive
Heterocyclic Chemistry II; Padwa, A. Ed.; Pergamon: Oxford, 1996;
Vol. 1a, pp 1-60. (c) McCoull, W.; Davis, F. A. Synthesis 2000, 1347.
(d) Armarego, Stereochemistry of Heterocyclic Compounds; Wiley: New
York, 1977; Part 1.
(2) (a) Wu, J .; Hou, X.-L.; Dai, L.-X. J . Org. Chem. 2000, 65, 1344.
(b) Kim, B. M.; Bae, S. J .; So, S. M.; Yoo, H. T.; Chang, S. K.; Lee, J .
H.; Kang, J . Org. Lett. 2001, 3, 2349. (c) Vicario, J . L.; Bad´ıa, D.;
Carrillo, L. J . Org. Chem. 2001, 66, 5801. (d) Sabitha, G.; Babu, R. S.;
Rajkumar, M.; Reddy, C. S.; Yadav, J . S. Tetrahedron Lett. 2001, 42,
3955. (e) Paul, B. J .; Hobbs, E.; Buccino, P.; Hudlicky, T. Tetrahedron
Lett. 2001, 42, 6433. (f) Mao, H.; J oly, G. J .; Peeters, K.; Hoornaert,
G. J .; Compernolle, F. Tetrahedron 2001, 57, 6955. (g) Xiong, C.; Wang,
W.; Cai, C.; Hruby, V. J . J . Org. Chem. 2002, 67, 1399-1402. (h)
Aggarwal, V. K.; Alonso, E.; Ferrara, M.; Spey, S. E. J . Org. Chem.
2002, 67, 2335. (i) Yadav, J . S.; Reddy, B. V. S.; Sadashiv, K.;
Harikishan, K. Tetrahedron Lett. 2002, 43, 2099.
(3) (a) Lim, Y.; Lee, W.-K. Tetrahedrom Lett. 1995, 36, 8431. (b) Choi,
S.-K.; Lee, J .-S.; Kim, J .-H.; Lee, W.-K. J . Org. Chem. 1997, 62, 743.-
(c) Shin, S.-H.; Han, E. Y.; Park, C. S.; Lee, W. K.; Ha, H.-J .
Tetrahedron Asymmtry 2000, 11, 3293. (d) Anand, R. V.; Pandey, G.;
Singh, V. K.Tetrahedron Lett. 2002, 43, 3975. (e) Deyrup, J . A. In Small
Ring Heterocycles; Hassner, A. Ed.; Interscience: New York, 1983; Vol.
42, pp 1-215.
(4) Concello´n, J . M.; Bernad, P. L.; Riego, E.; Garc´ıa-Granda, S.;
Force´n-Acebal, A. J . Org. Chem. 2001, 66, 2764.
(5) Concello´n, J . M.; Riego, E. J . Org. Chem. 2003, 68, 6407.
To establish unambiguously this regio- and stereo-
chemistry, compound 2c was debenzylated, by reaction
with HCO2H in the presence of Pd/C, and treated with
triphosgene, affording the corresponding tetrahydropy-
rimidin-2-one 3c (Scheme 2). The 1H NMR coupling
constant between CHBn and CHOMe (J ) 7.4 Hz),7 and
a NOESY experiment on compound 3c show a cis relative
(6) BF3‚OEt2 is commonly used in Lewis acid-catalyzed ring openings
of aziridines. See: (a) Reference 1c. (b) Reference 2g. (c) Bodenan, J .;
Chanet-Ray, J .; Vessiere, R. Synthesis 1992, 288. (d) Dauban, P.; Dodd,
R. H. J . Org. Chem. 1997, 62, 4277. (e) Cantrill, A. A.; Osborn, H. M.
I.; Sweeney, J . Tetrahedron 1998, 54, 2181.
(7) The coupling constant of CHBn and CHOMe was established
by irradiation of signals of 1H NMR of 3c. Irradiations at 3.16 and
3.46 (CH2Ph) transformed the m at 3.75-3.69 (CHBn) into a dd with
J ) 7.3, 5.0 Hz and 7.5, 4.6 Hz, respectively. Irradiation at 3.75-3.69
(CHBn) transformed the t at 3.16 and 3.46 into a d with J ) 4.9 and
5.0 Hz (CH2Ph), respectively.
10.1021/jo0350514 CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/28/2003
9242
J . Org. Chem. 2003, 68, 9242-9246

Cleavage of 2-(1-Aminoalkyl)aziridines
SCHEME 1. C-2 Rin g Op en in g of Am in o 1 w ith
Alcoh olsa
SCHEME 4. C-3 Rin g Op en in g of Am in o
Azir id in es 1 w ith Ca r boxylic Acid sa
a
Reagents and conditions: (i) BF3‚OEt2, R3OH, ∆; (ii) NaHCO3,
a
Reagents and conditions: (i) BF3‚OEt2, R3CO2H, CH3CN, ∆;
H2O.
(ii) NaHCO3/H2O.
TABLE 1. C-2 Rin g Op en in g of Am in o Azir id in es 1 w ith
Alcoh ols
TABLE 2. C-3 Rin g Op en in g of Am in o Azir id in es 1 w ith
Ca r boxylic Acid s
entry
product
R1
R2
R3
yield (%)a
entry
product
R1
R2
R3
yield (%)a
1
2
3
4
5
2a
2b
2c
2d
2e
Me
i-Bu
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Cy
i-Pr
Me
Me
i-Pr
Me
78
80
83
88
85
1
2
3
4
6a
6b
6c
6d
Bn
i-Bu
Bn
Bn
Bn
Bn
allyl
Me
Me
HCdCHPh
63
69
58
57
i-Bu
Me
a
Isolated yield after column chromatography based on the
starting amino aziridine 1.
a
Isolated yield after column chromatography based on the
starting amino aziridine 1.
SCHEME 5. Red u ction of 6a a n d 6ba
SCHEME 2. P r ep a r a tion of
Tetr a h yd r op yr im id in -2-on e 3ca
a
Reagents and conditions: (i) Pd/C, HCO2H, MeOH, ∆; (ii)
(Cl3CO)2CO, CH2Cl2, 0 °C.
a
Reagents and conditions: (i) LiAlH4, THF, 0 °C; (ii) H2O/TsOH.
SCHEME 3. Rea ction of Azir id in e 1 w ith
ter t-Bu tyl Alcoh ola
with BF3‚OEt2 at 0 °C in CH2Cl2 for 2 h,8 affording the
corresponding product 4.
The reaction of amino aziridines 1 was also carried out
with alcohols in the presence of p-toluenesulfonic acid
in 7/1 CH3CN/ROH, to open the aziridine ring at C-3.9
However, no reaction of aziridine 1 with ROH was
observed.
Rea ction of 1 w ith Ca r boxylic Acid s. The reaction
was also performed in the presence of BF3‚OEt2 to
activate the aziridine ring. Thus, treatment of amino
aziridines 1 with different carboxylic acids in refluxing
acetonitrile for 2 h afforded O-acylated 2,3-diaminoalkan-
1-ols 6 in good yields (Scheme 4 and Table 2).
Once more, 1H and 13C NMR spectra showed the
presence of only one isomer, indicating that the regiose-
lectivity of the reaction was total.
The structure of compounds 6, as depicted in Scheme
4, was established after reduction of compounds 6a and
6b with LiAlH4 (Scheme 5).
By comparison of 1H and 13C NMR spectra of the
reduction products from 6a and 6b with the correspond-
ing 2,3-diaminoalkan-1-ols 4 obtained from reaction of 1
with H2O in the presence of p-toluenesulfonic acid,5 we
confirmed that both diamino alcohols are the same.
Mech a n ism . To explain the different regio- and ster-
eochemistry of the reaction of 1 with alcohols and
a
Reagents and conditions: (i) BF3‚OEt2, t-BuOH, ∆; (ii) BF3‚OEt2
and then NaHCO3/H2O.
configuration between these hydrogens. This regio- and
stereochemistry are in accordance with those observed
in the reaction of aziridines 1 with H2O in the presence
of BF3‚OEt2.5
Reaction of tert-butyl alcohol with the amino aziridine
1 with R1 ) i-Bu, R2 ) allyl at reflux temperature for
1.5 h afforded a mixture of the 2,3-diaminoalkan-1-ol 45
(55%) and 1-tert-butoxy-2,3-diamine 5 (28%). A longer
reaction time (15 h) gave the 2,3-diaminoalkan-1-ol 4 as
the only one product (73%). These results could be
explained by assuming that tert-butyl alcohol opens the
aziridine ring at C-3 instead of C-2, due to steric
hindrance, affording the 1-tert-butoxy-2,3-diamine 5.
Under the reaction conditions, compound 5 would be
O-deprotected by BF3‚OEt2, giving 2,3-diaminoalkan-1-
ol (Scheme 3). To support this mechanism, compound 5
(R1 ) i-Bu, R2 ) allyl) was obtained by reaction of 1 with
tert-butyl alcohol for 1.5 h at reflux temperature. After
purification by column chromatography, 5 was treated
(8) The reaction of 5 with TiCl4 at 0 °C in CH2Cl2 also affords the
alcohol 4.
(9) In those conditions, treatment of 1 with H2O afforded 2,3-
diaminoalkan-1-ols. See: Reference 5.
J . Org. Chem, Vol. 68, No. 24, 2003 9243

Concello´n et al.
TABLE 3. Rea ction of 1 w ith Sod iu m Iod id e
entry
product
R2
yield (%)a
1
2
9a
9b
Bn
Cy
67
60
a
Isolated yield after column chromatography based on the
starting amino aziridine 1.
F IGURE 1. Attack on the aziridinium salt 8 at C-2.
SCHEME 7. Rea ction of 1 w ith Sod iu m Iod id ea
SCHEME 6. P r op osed Mech a n ism for
Tr a n sfor m a tion of 1 in to 2 a n d 6
a
Reagents and conditions: (i) BF3‚OEt2, NaI, CH3CN, ∆; (ii)
NaHCO3/H2O.
SCHEME 8. P r op osed Mech a n ism for
Tr a n sfor m a tion of 1 in to 9
carboxylic acids, we propose the mechanism depicted in
Scheme 6. After coordination of the aziridine nitrogen to
the Lewis acid, an intramolecular ring opening at C-2
by nucleophilic attack of the dibenzylamino group, with
subsequent inversion of configuration, would afford the
aziridinium salt 8.10 Alcohols would react through 8 to
afford 2-alkoxy-1,3-diamines 2, with subsequent second
inversion of the configuration at C-2. In the case of tert-
butyl alcohol the reaction takes place through 7 instead
8, due to steric hindrance. In the presence of carboxylic
acids, the prevalence of 8 may be diminished via proto-
nation of the dibenzylamino group, reducing its ability
to open the aziridine to form 8, and consequently car-
boxylic acid would react through 7.
The total regioselectivity observed in the ring opening
of intermediate aziridinium salt 8 with different alcohols
could be explained by formation of a hydrogen bond
between alcohol and a fluorine atom in 8, as shown in
structure A in Figure 1, or alternatively between alcohol
and the nitrogen (B in Figure 1). Thus, the C-2 would be
the carbon most accessible to the oxygen atom of the
alcohol, and the reaction would take place through this
carbon.
Rea ction of 1 w ith Sod iu m Iod id e. The use of NaI
as nucleophile in the ring-opening reaction of amino
aziridine 1, in the presence of BF3‚OEt2, led to a complex
mixture of products when R1 ) Me, i-Bu. However, with
R1 ) Bn, the treatment of a solution of amino aziridines
and BF3‚OEt2 in acetonitrile with NaI at reflux temper-
ature for 12 h gave 4-phenylbut-3-en-1,2-diamines 9a and
9b (Scheme 7). In this process the double bond was
generated with total diastereoselectivity (1H NMR, 300
MHz).
between the olefinic protons of compounds 9a and 9b.
The values of J ) 15.8 and 15.9 Hz (9a and 9b,
respectively) are in agreement with a trans relationship.
Mech a n ism . The behavior of the amino aziridines 1
with R1 ) Bn when iodide is used, could be explained by
assuming that the iodide attacks the aziridine ring at
C-3, affording a diamino iodide compound 10. This
intermediate could experience two equilibrated ring-
closure process to produce the starting compound 1 or
the azetidinium salt 11, being in equilibrium both spe-
cies. But, when R1 ) Bn, the intermediate 11 could
undergo a spontaneous â-elimination, with concurrent
ring opening, yielding diamine 9.
To explain the stereochemistry of the double bond, we
tentatively propose an anti elimination by assuming a
transition state generated from intermediate I, as de-
picted in Scheme 8.
In conclusion, we have achieved the ring opening of
nonactivated amino aziridines 1 with different nucleo-
philes, such as alcohols, carboxylic acids, and iodide.
These transformations were carried out with total regio-
and stereoselectivity, obtaining chiral 2-alkoxy-1,3-di-
amines 2, O-acylated 2,3-diaminoalkan-1-ols 6, and
4-phenylbut-3-en-1,2-diamines 9 in high yields. The
prepared compounds 2, 6, and 9 bear two differently
substituted amine groups.
The E-stereochemistry of the double bond was estab-
lished on the basis of the 1H NMR coupling constants
Exp er im en ta l Section
(10) Previously, other N,N-dibenzylated aziridinium salts are pro-
posed as intermediates in reactions of 2,3-epoxyamines: (a) Liu, Q.;
Marchington, A. P.; Boden, N.; Rayner, C. M. J . Chem. Soc., Perkin
Trans. 1 1997, 511. (b) Liu, Q.; Marchington, A. P.; Rayner, C. M.
Tetrahedron 1997, 53, 15729.
Gen er a l P r oced u r e of Syn th esis of 2-Alk oxy-1,3-d i-
a m in es 2. To a stirred solution of the corresponding amino
aziridine 1 (0.2 mmol) in the corresponding alcohol (1 mL) was
9244 J . Org. Chem., Vol. 68, No. 24, 2003

Cleavage of 2-(1-Aminoalkyl)aziridines
added BF3‚OEt2 (0.025 mL, 0.2 mmol) at room temperature.
After stirring at reflux temperature for 2 h, an aqueous
saturated solution of sodium bicarbonate (5 mL) was added
and the mixture was stirred at room temperature for 5 min.
Then, the aqueous phase was extracted with diethyl ether
(3 × 5 mL), and the combined organic layers were dried
(Na2SO4), filtered, and concentrated in vacuo. Flash column
chromatography over silica gel (hexane/EtAcO 3:1) provided
pure compounds 2. (Yields are given in Table 1.)
456.3136; IR (neat) 3308, 3027, 2926, 2852, 1609, 1494, 1098
cm-1; Rf ) 0.41 (hexane/EtOAc 1:1).
(2S,3S)-N2-Allyl-N3,N3-d iben zyl-1-ter t-bu toxy-5-m eth -
ylh exa n -2,3-d ia m in e (5): [R]25D -11.3 (c 0.2, CHCl3); 1H NMR
(300 MHz, CDCl3) δ 7.40-7.21 (m, 10 H), 6.02-5.92 (m, 1 H),
5.27-5.13 (m, 2 H), 3.82 (AB syst, J ) 13.4 Hz, 4 H), 3.81-
3.71 (m, 1 H), 3.32-3.26 (m, 2 H), 3.04-2.88 (m, 2 H), 2.79-
2.77 (m, 1 H), 1.91-1.76 (m, 1 H), 1.71 (br s, 1 H), 1.31-1.20
(m, 2 H), 1.09 (s, 9 H), 0.80 (d, J ) 6.6 Hz, 3 H), 0.77 (d, J )
6.3 Hz, 3 H); 13C NMR (75 MHz, CDCl3) δ 141.1 (2 × C), 137.1,
129.4, 129.0, 128.0, 126.6 (11 × CH), 115.5 (CH2), 73.1 (C),
71.3 (CH), 58.8 (CH), 55.9 (2 × CH2), 52.4 (CH2), 45.2 (CH2),
41.7 (CH2), 28.8 (3 × CH3), 24.3 (CH), 23.1 (CH3), 22.5 (CH3);
MS (70 eV, EI) m/z (%) 422 (M+, 2), 352 (72), 296 (44), 279
(52), 91 (100), 57 (51); HRMS (70 eV) calcd for C28H42N2O
422.3292, found 422.3278; IR (neat) 3063, 3027, 2956, 2868,
2454, 1364, 1193 cm-1; Rf ) 0.30 (hexane/EtOAc 1:1).
P r ep a r a tion of (4S,5S)-4-Ben zyl-5-m eth oxym eth yltet-
r a h yd r op yr im id in -2-on e (3c). A solution of the diamine 2c
(0.3 g, 0.66 mmol) in 30 mL of MeOH/HCO2H 5% (28.5:1.5),
in the presence of Pd/C (0.3 g), was heated 2 h at reflux. Then,
the mixture was filtered through Celite and concentrated. The
residue was solved in CH2Cl2 (10 mL) and washed with a
saturated solution of K2CO3 (2 × 10 mL). The organic layer
was dried over Na2SO4 and the solvent was evaporated.
(2S,3S)-N1,N3,N3-Tr ib en zyl-2-isop r op oxybu t a n -1,3-d i-
a m in e (2a ): [R]25 -20.7 (c 1.45, CHCl3); 1H NMR (300 MHz,
D
CDCl3) δ 7.37-7.23 (m, 15 H), 3.86 (AB syst, J ) 13.4 Hz, 4
H), 3.84-3.60 (m, 2 H), 3.60 (AB syst, J ) 13.1 Hz, 2 H), 2.79-
2.71 (m, 3 H), 1.19 (d, J ) 6.6 Hz, 3 H), 1.17 (d, J ) 6.0 Hz, 3
H), 1.16 (d, J ) 6.0 Hz, 3 H); 13C NMR (75 MHz, CDCl3) δ
140.8 (2 × C), 140.4 (C), 129.0, 128.2, 128.0, 127.9, 126.6 (15
× CH), 73.1 (CH), 68.8 (CH), 61.1 (CH), 55.1 (2 × CH2), 53.6
(CH2), 46.2 (CH2), 23.6 (CH3), 22.1 (CH3), 18.2 (CH3); MS (70
eV, EI) m/z (%) 416 (M+, <1), 297 (100), 254 (26), 181 (25),
162 (25); HRMS (70 eV) calcd for C28H36N2O 416.2828, found
416.2848; IR (neat) 3313, 2970, 2928, 1748, 1494, 1454 cm-1
;
Rf ) 0.38 (hexane/EtOAc 1:1). Anal. Calcd for C28H36N2O: C,
80.73; H, 8.71; N, 6.72. Found: C, 80.76; H, 8.73; N, 6.70.
(2S,3S)-N1,N3,N3-Tr iben zyl-2-m eth oxy-5-m eth ylh exa n -
1
1,3-d ia m in e (2b): [R]25 -6.2 (c 0.72, CHCl3); H NMR (300
D
MHz, CDCl3) δ 7.40-7.22 (m, 15 H), 3.82 (AB syst, J ) 13.4
Hz, 4 H), 3.70 (AB syst, J ) 13.4 Hz, 2 H), 3.54-3.50 (m, 1
H), 3.33 (s, 3 H), 2.95-2.76 (m, 3 H), 1.80 (br s, 1 H), 1.60-
1.42 (m, 3 H), 0.93 (d, J ) 6.0 Hz, 3 H), 0.91 (d, J ) 6.0 Hz, 3
H); 13C NMR (75 MHz, CDCl3) δ 140.6 (C), 140.5 (2 × C), 128.9,
128.8, 128.2, 128.1, 128.0, 126.7 (15 × CH), 80.3 (CH), 58.7
(CH), 57.5 (CH3), 55.2 (2 × CH2), 53.7 (CH2), 45.8 (CH2), 40.3
(CH2), 24.6 (CH), 23.3 (CH3), 22.5 (CH3); MS (70 eV, EI) m/z
(%) 430 (M+, 2), 339 (24), 266 (48), 181 (46), 132 (39), 91 (100);
HRMS (70 eV) calcd for C29H38N2O 430.2984, found 430.3007;
The obtained debenzylated diamine (0.1 g, 0.52 mmol) was
treated with a solution of triphosgene (0.17 g, 0.57 mmol) and
NEt3 (0.10 mL, 1.14 mmol) in CH2Cl2 (2 mL) at 0 °C for 12 h.
Then, a saturated solution of NH4Cl (4 mL) was added to
quench the reaction. The layers were separated, and the
aqueous layer was extracted with CH2Cl2 (3 × 5 mL). The
combined organic layers were dried over Na2SO4, and the
solvent was removed in vacuo. The product was purified by
column chromatography (silica gel, EtOAc) yielding pure
compound 3c (90 mg, 0.41 mmol, 62%): [R]25 -7.9 (c 2.0,
D
IR (neat) 3320, 3084, 3062, 3027, 2821, 1603, 1494, 1454 cm-1
;
CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.34-7.10 (m, 5 H), 5.13
(br s, 1 H), 5.06 (br s, 1 H), 3.75-3.69 (m, 1 H), 3.46 (t, J ) 7.7
Hz, 1 H), 3.41-3.37 (m, 1 H), 3.36 (s, 3 H), 3.16 (t, J ) 7.7 Hz,
1 H), 2.80 (2 × dd, J ) 6.3, 4.8 Hz, 2 H); 13C NMR (75 MHz,
CDCl3) δ 163.4 (C), 137.1 (C), 129.4 (2 × CH), 128.4 (2 × CH),
126.6 (CH), 84.5 (CH), 58.7 (CH3), 55.8 (CH), 43.0 (CH2), 36.3
(CH2); Rf ) 0.10 (EtOAc). Anal. Calcd for C12H16N2O2: C, 65.43;
H, 7.32; N, 12.72. Found: C, 65.48; H, 7.35; N, 12.71.
Rf ) 0.28 (hexane/EtOAc 3:1).
(2S,3S)-N1,N3,N3-Tr iben zyl-2-m eth oxy-4-p h en ylbu ta n -
1,3-d ia m in e (2c): [R]25 +7.1 (c 1.0, CHCl3); 1H NMR (300
D
MHz, CDCl3) δ 7.39-7.19 (m, 20 H), 3.90 (AB syst, J ) 13.4
Hz, 4 H), 3.70-3.52 (m, 3 H), 3.29 (s, 3 H), 3.05-2.81 (m, 5
H), 1.78 (br s, 1 H); 13C NMR (75 MHz, CDCl3) δ 140.5, 139.3
(4 × C), 129.4, 129.0, 128.2, 128.1, 127.9, 126.6, 125.8 (20 ×
CH), 84.0 (CH), 59.0 (CH), 58.2 (CH3), 55.2 (2 × CH2), 53.3
(CH2), 46.0 (CH2), 37.9 (CH2); IR (neat) 3314, 3084, 3061, 3027,
2826, 1602, 1495, 1454 cm-1; Rf ) 0.49 (hexane/EtOAc 1:1).
Anal. Calcd for C32H36N2O: C, 82.72; H, 7.81; N, 6.03. Found:
C, 82.90; H, 7.84; N, 6.01.
Gen er a l P r oced u r e for th e Syn th esis of O-Acyla ted
2,3-Dia m in oa lk a n -1-ols 6. To a stirred solution of the cor-
responding amino aziridine 1 (0.2 mmol) in acetonitrile (1 mL)
were added BF3‚OEt2 (0.025 mL, 0.2 mmol) and the corre-
sponding carboxylic acid (0.6 mmol) at room temperature. After
stirring at reflux temperature for 2 h, an aqueous saturated
solution of sodium bicarbonate (5 mL) was added and the
mixture was stirred at room temperature for 5 min. Then, the
aqueous phase was extracted with diethyl ether (3 × 5 mL),
and the combined organic layers were dried (Na2SO4), filtered,
and concentrated in vacuo. Flash column chromatography over
silica gel (hexane/EtOAc 3:1) provided pure compounds 6.
Yields are given in Table 2.
(2R,3S)-2-(Ben zyla m in o)-3-(d iben zyla m in o)-4-p h en yl-
bu tyl a ceta te (6a ): [R]25D +4.70 (c 1.0, CHCl3); 1H NMR (300
MHz, CDCl3) δ 7.40-7.10 (m, 20 H), 5.46-5.40 (m, 1 H), 3.79
(AB syst, J ) 13.4 Hz, 4 H), 3.66 (AB syst, J ) 13.4 Hz, 2 H),
3.11-3.01 (m, 3 H), 2.90-2.69 (m, 2 H), 1.96 (s, 3 H), 1.85 (br
s, 1 H); 13C NMR (75 MHz, CDCl3) δ 170.2 (C), 140.2, 140.0,
137.7 (4 × C), 129.3, 129.1, 128.2, 128.1, 128.0, 126.9, 126.8,
126.3 (20 × CH), 75.0 (CH), 59.3 (CH), 55.2 (2 × CH2), 53.5
(CH2), 45.1 (CH2), 38.7 (CH2), 21.1 (CH3); MS (70 eV, EI) m/z
(%) 492 (M+, <1), 401 (9), 373 (85), 91 (100); HRMS (70 eV)
calcd for C33H36N2O2 492.2777, found 492.2712; IR (neat) 3323,
3062, 3027, 2924, 2846, 1736, 1495, 1454, 1369, 1237 cm-1; Rf
) 0.25 (hexane/EtOAc 3:1). Anal. Calcd for C33H36N2O2: C,
80.45; H, 7.37; N, 5.69. Found: C, 80.49; H, 7.40; N, 5.67.
(2S,3S)-N1,N3,N3-Tr ib en zyl-2-isop r op oxy-4-p h en ylb u -
1
ta n -1,3-d ia m in e (2d ): [R]25 -1.4 (c 0.23, CHCl3); H NMR
D
(300 MHz, CDCl3) δ 7.42-7.10 (m, 20 H), 3.93 (AB syst, J )
13.4 Hz, 4 H), 3.90-3.85 (m, 1 H), 3.68 (AB syst, J ) 14.7 Hz,
2 H), 3.44-3.37 (m, 1 H), 3.04-2.85 (m, 5 H), 1.78 (br s, 1 H),
1.08 (d, J ) 6.0 Hz, 3 H), 0.92 (d, J ) 6.3 Hz, 3 H); 13C NMR
(75 MHz, CDCl3) δ 140.7 (2 × C), 140.5 (C), 139.9 (C), 129.4,
129.1, 128.2, 128.1, 128.0, 127.9, 126.7, 126.6, 125.6 (20 × CH),
79.2 (CH), 70.1 (CH), 59.3 (CH), 55.4 (2 × CH2), 53.6 (CH2),
45.3 (CH2), 38.6 (CH2), 22.7 (CH3), 22.1 (CH3); IR (neat) 3331,
3085, 3062, 3027, 1602, 1495 cm-1; Rf ) 0.49 (hexane/EtOAc
1:1). Anal. Calcd for C34H40N2O: C, 82.88; H, 8.18; N, 5.69.
Found: C, 82.90; H, 8.20; N, 5.71.
(2S ,3S )-N 1-Cycloh e xyl-N 3,N 3-d ib e n zyl-2-m e t h oxy-4-
p h en ylbu ta n -1,3-d ia m in e (2e): [R]25 +7.4 (c 1.0, CHCl3);
D
1H NMR (300 MHz, CDCl3) δ 7.39-7.23 (m, 15 H), 3.85 (AB
syst, J ) 13.3 Hz, 4 H), 3.66-3.64 (m, 1 H), 3.28 (s, 3 H), 3.00-
2.70 (m, 5 H), 2.07-1.98 (m, 1 H), 1.78-1.65 (m, 5 H), 1.32-
0.98 (m, 6 H); 13C NMR (75 MHz, CDCl3) δ 140.5 (2 × C), 139.1
(C), 129.4, 129.1, 128.0, 126.6, 125.9 (15 × CH), 83.7 (CH),
59.2 (CH), 58.0 (CH3), 56.2 (CH), 55.1 (2 × CH2), 43.4 (CH2),
37.8 (CH2), 33.4 (2 × CH2), 26.0 (CH2), 24.9 (CH2), 24.8 (CH2);
MS (70 eV, EI) m/z (%) 456 (M+, <1), 345 (51), 344 (100), 91
(81); HRMS (70 eV) calcd for C31H40N2O 456.3135, found
(2R,3S)-2-(Ben zyla m in o)-3-(d iben zyla m in o)-4-m eth yl-
h exyl a ceta te (6b): [R]25D +1.30 (c 1.3, CHCl3); 1H NMR (300
J . Org. Chem, Vol. 68, No. 24, 2003 9245

Concello´n et al.
MHz, CDCl3) δ 7.42-7.23 (m, 15 H), 5.39-5.36 (m, 1 H), 3.78
(AB syst, J ) 13.4 Hz, 4 H), 3.71 (AB syst, J ) 13.4 Hz, 2 H),
2.94-2.83 (m, 2 H), 2.68 (dd, J ) 11.4, 6.2 Hz, 1 H), 2.11 (s, 3
H), 1.83 (br s, 1 H), 1.74-1.68 (m, 1 H), 1.39-1.33 (m, 2 H),
0.93 (d, J ) 8.9 Hz, 3 H), 0.90 (d, J ) 6.2 Hz, 3 H); 13C NMR
(75 MHz, CDCl3) δ 170.5 (C), 140.3, 140.1, (3 × C), 129.0, 128.2,
128.1, 127.9, 126.8, 126.7 (15 × CH), 72.6 (CH), 59.7 (CH),
55.1 (2 × CH2), 53.7 (CH2), 45.2 (CH2), 41.2 (CH2), 24.3 (CH),
23.3 (CH3), 22.0 (CH3), 21.3 (CH3); IR (neat) 3323, 3062, 3027,
2924, 2846, 1736, 1495, 1454, 1369, 1237 cm-1; Rf ) 0.25
(hexane/EtOAc 3:1). Anal. Calcd for C30H38N2O2: C, 78.56; H,
8.35; N, 6.11. Found: C, 78.55; H, 8.39; N, 6.13.
ing amino aziridine 1 (0.2 mmol) in acetonitrile (1 mL) were
added BF3‚OEt2 (0.025 mL, 0.2 mmol) and NaI (0.09 g, 0.6
mmol) at room temperature. After stirring at reflux temper-
ature for 12 h, an aqueous saturated solution of sodium
bicarbonate (5 mL) was added and the mixture was stirred at
room temperature for 5 min. Then, the aqueous phase was
extracted with diethyl ether (3 × 5 mL), and the combined
organic layers were dried (Na2SO4), filtered, and concentrated
in vacuo. Flash column chromatography over silica gel (hexane/
EtOAc 5:1) provided pure compounds 9. Yields are given in
Table 3.
(2R)-(E)-N1,N1,N2-Tr ib en zyl-4-p h en ylb u t -3-en -1,2-d i-
(2R,3S)-2-(Ben zyla m in o)-3-(d iben zyla m in o)-4-p h en yl-
1
a m in e (9a ): [R]25 +3.8 (c 0.98, CHCl3); H NMR (300 MHz,
D
bu tyl 3-p h en ylp r op ion a te (6c): [R]25 +16.3 (c 3.5, CHCl3);
D
CDCl3) δ 7.43-7.24 (m, 20 H), 6.55 (d, J ) 15.9 Hz, 1 H), 6.01
(dd, J ) 15.9, 8.2 Hz, 1 H), 3.71 (AB syst, J ) 13.4 Hz, 2 H),
3.60 (AB syst, J ) 13.4 Hz, 4 H), 3.39 (ddd, J ) 10.0, 8.2, 4.0
Hz, 1 H), 2.76 (dd, J ) 12.5, 10.0 Hz,1 H), 2.50 (dd, J ) 12.5,
4.0 Hz, 1 H), 2.42 (br s, 1 H); 13C NMR (75 MHz, CDCl3) δ
140.5 (C), 139.0 (2 × C), 136.9 (C), 131.9, 131.4, 128.8, 128.4,
128.3, 128.2, 128.1, 127.3, 127.0, 126.7, 126.2 (22 × CH), 59.3
(CH2), 58.7 (2 × CH2), 58.0 (CH), 51.3 (CH2); MS (70 eV, EI)
m/z (%) 432 (M+, 2), 341 (49), 300 (61), 223 (100); HRMS (70
eV) calcd for C31H32N2 432.2565, found 432.2515; IR (neat)
3308, 3084, 3061, 3026, 1651, 1601, 1494, 1454 cm-1; Rf ) 0.28
(hexane/EtOAc 3:1). Anal. Calcd for C31H32N2: C, 86.07; H,
7.44; N, 6.47. Found: C, 86.10; H, 7.44; N, 6.47.
1H NMR (300 MHz, CDCl3) δ 7.61 (d, J ) 15.9 Hz, 1 H), 7.47-
7.10 (m, 25 H), 6.38 (d, J ) 15.9 Hz, 1 H), 5.61-5.55 (m, 1 H),
3.83 (AB syst, J ) 13.4 Hz, 4 H), 3.66 (AB syst, J ) 13.4 Hz,
2 H), 3.20-3.07 (m, 2 H), 2.96-2.74 (m, 3 H), 1.82 (br s, 1 H);
13C NMR (75 MHz, CDCl3) δ 166.1 (C), 145.0 (CH), 140.3,
140.1, 137.7, 134.1 (5 × C), 130.2, 129.3, 129.1, 128.7, 128.2,
128.1, 128.0, 127.9, 126.9, 126.7, 126.2 (25 × CH), 117.8 (CH),
75.2 (CH), 59.3 (CH), 55.4 (2 × CH2), 53.5 (CH2), 45.1 (CH2),
38.7 (CH2); MS (70 eV, EI) m/z (%) 580 (M+, <1), 330 (13), 300
(91), 238 (39), 131 (80), 91 (100); HRMS (70 eV) calcd for
C
40H40N2O2 580.2090, found 580.3088; IR (neat) 3421, 3027,
2924, 2342, 1707, 1636, 1495, 1452 cm-1; Rf ) 0.28 (hexane/
EtOAc 3:1).
(2R)-(E)-N1,N1,-Diben zyl-N2-cycloh exyl-4-p h en ylbu t-3-
en -1,2-d ia m in e (9b): [R]25D +6.1 (c 1.1, CHCl3); 1H NMR (300
MHz, CDCl3) δ 7.38-7.23 (m, 15 H), 6.45 (d, J ) 15.8 Hz, 1
H), 5.98 (dd, J ) 15.8, 8.0 Hz, 1 H), 3.62 (AB syst, J ) 13.5
Hz, 4 H), 2.72-2.64 (m, 1 H), 2.48-2.36 (m, 2 H), 1.98-1.83
(m, 1 H), 1.70-1.60 (m, 3 H), 1.30-0.88 (m, 8 H); 13C NMR
(75 MHz, CDCl3) δ 139.0 (2 × C), 137.0 (C), 132.9, 130.7, 128.9,
128.4, 128.2, 127.2, 127.0, 126.2 (17 × CH), 59.6 (CH2), 58.6
(2 × CH2), 56.3 (CH), 54.5 (CH), 34.9 (CH2), 33.2 (CH2), 26.1
(CH2), 25.2 (CH2), 25.1 (CH2); IR (neat) 3309, 3026, 2926, 2851,
2342, 1752, 1494, 1450 cm-1; Rf ) 0.14 (hexane/EtOAc 3:1).
Anal. Calcd for C30H36N2: C, 84.86; H, 8.55; N, 6.60. Found:
C, 84.83; H, 8.57; N, 6.62.
(2R,3S)-2-(Allylam in o)-3-(diben zylam in o)-5-m eth ylh ex-
yl a ceta te (6d ): [R]25D +4.0 (c 1.8, CHCl3); 1H NMR (300 MHz,
CDCl3) δ 7.34-7.23 (m, 10 H), 5.89-5.78 (m, 1 H), 5.33-5.27
(m, 1 H), 5.18-5.08 (m, 2 H), 3.76 (AB syst, J ) 13.4 Hz, 4 H),
3.15-3.01 (m, 2 H), 2.91-2.84 (m, 1 H), 2.75 (dd, J ) 12.0,
7.7 Hz, 1 H), 2.60 (dd, J ) 12.2, 6.7 Hz, 1 H), 2.09 (s, 3 H),
1.75 (br s, 1 H), 1.71-1.62 (m, 1 H), 1.45-1.28 (m, 2 H), 0.89
(d, J ) 6.6 Hz, 3 H), 0.87 (d, J ) 6.6 Hz, 3 H); 13C NMR (75
MHz, CDCl3) δ 170.5 (C), 140.0 (2 × C), 136.8 (CH), 129.0,
128.1, 126.9 (10 × CH), 115.6 (CH2), 72.5 (CH), 59.7 (CH), 55.0
(2 × CH2), 52.0 (CH2), 45.3 (CH2), 41.3 (CH2), 24.3 (CH), 23.4
(CH3), 21.9 (CH3), 21.3 (CH3); MS (70 eV, EI) m/z (%) 408 (M+,
<1), 338 (100), 321 (76), 296 (74), 236 (36); HRMS (70 eV) calcd
for C26H36N2O2 408.2777, found 408.2773; IR (neat) 3325, 3028,
2957, 2930, 1733, 1454, 1368, 1240 cm-1; Rf ) 0.23 (hexane/
EtOAc 3:1).
Red u ction of 6a a n d 6b. To a stirred solution of the
corresponding O-acylated 1-hydroxy-2,3-diamine 6 (0.2 mmol)
in THF (2 mL) was added LiAlH4 (0.2 mL, 0.2 mmol, 1 M in
THF) at 0 °C. After stirring at this temperature for 12 h, the
reaction was quenched with an aqueous saturated solution of
NH4Cl (5 mL). Then, the mixture was filtered through Celite,
and the layers were separated. The aqueous phase was
extracted with diethyl ether (3 × 5 mL), and the combined
organic layers were dried (Na2SO4), filtered, and concentrated
in vacuo. The products were purified by flash column chro-
matography over silica gel (hexane/EtOAc 3:1) yielding pure
diamino alcohols 4.5
Ack n ow led gm en t. We thank III Plan Regional de
Investigacio´n del Principado de Asturias (FC-01-PB-
EXP-11)and MinisteriodeCiencia yTecnologı´a (BQU2001-
3807) for financial support. J .M.C. thanks Carmen
Ferna´ndez-Flo´rez for her time. E.R. thanks Ministerio
de Ciencia y Tecnolog´ıa for a predoctoral fellowship.
J .R.S. thanks Principado de Asturias for a predoctoral
fellowship (FC-01-PB-EXP-11).
Su p p or tin g In for m a tion Ava ila ble: General methods
1
and H and 13C NMR spectra of compounds 2, 3c, 5, 6, and 9.
This material is available free of charge via Internet at http://
pubs.acs.org.
Gen er a l P r oced u r e for th e Syn th esis of 4-P h en ylbu t-
3-en -1,2-d ia m in es 9. To a stirred solution of the correspond-
J O0350514
9246 J . Org. Chem., Vol. 68, No. 24, 2003