A highly regioselective azidolysis of 2,3-epoxy amines: An unexpected [Ti(O-i-Pr)2(N3)2] mediated C-2 opening

Article abstract of DOI:10.1016/j.tetlet.2012.07.074

The Lewis acid-catalysed regioselective azidolysis of 2,3-epoxy amines has been investigated. The results obtained demonstrated that using TMSN₃ as a source of azide, the appropriate choice of Lewis acid allowed to direct the regiochemistry of the ring opening. The present methodologies provide a powerful tool in organic synthesis for the preparation of diaminoalcohol moieties.

Full text of DOI:10.1016/j.tetlet.2012.07.074

Tetrahedron Letters 53 (2012) 5582–5584
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Tetrahedron Letters
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A highly regioselective azidolysis of 2,3-epoxy amines: an unexpected
[Ti(O-i-Pr)2(N3)2] mediated C-2 opening
Giuliana Righi a, , Roberto Antonioletti a, Romina Pelagalli b,
⇑
⇑
a Institute of Biomolecular Chemistry, UOS Rome-CNR c/o Department of Chemistry, ‘Sapienza’ University of Rome, p.le A. Moro 5, 00185 Rome, Italy
b Department of Chemistry, ‘Sapienza’ University of Rome, p.le A. Moro 5, 00185 Rome, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
The Lewis acid-catalysed regioselective azidolysis of 2,3-epoxy amines has been investigated. The results
obtained demonstrated that using TMSN3 as a source of azide, the appropriate choice of Lewis acid
allowed to direct the regiochemistry of the ring opening. The present methodologies provide a powerful
tool in organic synthesis for the preparation of diaminoalcohol moieties.
Received 15 May 2012
Revised 12 July 2012
Accepted 18 July 2012
Available online 27 July 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Azidolysis
Regioselectivity
Epoxy amines
Ring opening
Lewis acids
Epoxides are important synthons in organic chemistry because
they can be easily prepared in an optically active form and their
reactions with various nucleophiles lead to interesting regio- and
stereoselective ring opened products.
Among these, the diaminoalcoholic moiety is widespread in
nature as part of many biologically active natural products and also
as the key component of a variety of synthetic compounds with
multiple applications in medicinal chemistry as therapeutically ac-
tive agents or as pharmacological tools.
successfully employed on 2,3-epoxy alcohols or esters.11 The C-3
opening always observed with these methods was generally ex-
plained invoking a cyclic chelate transition state model 3 between
the Lewis acid and the two oxygens of epoxy derivatives (Fig. 2)
with an intermolecular attack of the nucleophiles.12
Our preliminary studies were restricted, for convenience, to
racemic compounds;13 the 2,3-epoxy amines were synthesized in
satisfactory yield from the corresponding allylic alcohols through
the sequence described in Scheme 1: (i) epoxidation of allylic alco-
hol, (ii) transformation of the hydroxyl function in a good leaving
group such as the mesylate, (iii) nucleophilic substitution with
the suitable amine (Scheme 1).
When 2,3-epoxy amines 10a–f were submitted to A or B meth-
ods, the expected 3-azido-2-hydroxy amines 11a–f were obtained
(as demonstrated by spin–spin decoupling experiments on the per-
acetylated derivatives) in good chemical yield and excellent regio-
isomeric ratio, independently from the steric hindrance of R0
(Table 1).
On the contrary, an unexpected behaviour was observed when
the same 2,3-epoxy amines 10a–c and 10e–f were treated with
[Ti(O-i-Pr)2(N3)2], prepared in situ by refluxing Ti(O-i-Pr)4 and
TMSN3 in benzene for at least 5 h (until the solution became clear)
and adding successively the substrates.14 Under these reaction
conditions, the only isolated products were 12a–c and 12e–f, high-
lighting the nucleophilic attack at C-2 position, rarely reported for
any epoxy derivatives.
Examples are the hydroxyethylamine (HEA) transition state iso-
stere, found in many peptidomimetic protease inhibitors such as
HIV protease,1 renine,2
c
-secretase,3 human b-secretase (BACE-
1),4 malarial plasmepsins I and II5 and in the natural products as
(ꢀ)-balanol6 and its regioisomer ophiocordin7 (Fig. 1).
The azidolysis of epoxides is a subject of continuous interest.8
During our study concerning the synthesis of new HIV-protease
inhibitors,9 we were intrigued by the controlled azidolysis of 2,3-
epoxy amines to obtain the corresponding azido derivatives, direct
precursors of hydroxyethylamine (HEA) isosters.
Since apart from few reports concerning only cyclic sub-
strates,10 to our best knowledge this reactivity has never been
extensively exploited, we focused our attention towards this goal.
With this purpose we decided to use TMSN3 as the azide source in
the presence of three different Lewis acids: BF3ꢁOEt2 (method A),
ZnCl2 (method B) and Ti(O-i-Pr)4 (method C), which were already
Apart from particular cases with steric and/or electronic bias
and an epoxide opening developed by using NaN3-(CH3O)3B sys-
tem,15 in general this regioselectivity is presumed to be due to
⇑
Corresponding authors. Tel.: +39 3 6 490422; fax: +39 6 9913628.
E-mail addresses: giuliana.righi@uniroma1.it (G. Righi), romina.pelagalli@hot-
mail.it (R. Pelagalli).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.07.074

G. Righi et al. / Tetrahedron Letters 53 (2012) 5582–5584
5583
O
H
Ph
O
N
H
N
O
O
H
N
HN
N
N
N
H
N
H
H
H
O
OH
OH
NH2
O
H3CO
HIV-protease inhibitor
BACE-1 inhibitor
HO
O
O
HO2C
HO
Ph
O
O
O
OH
NH
H
N
N
N
OH
NH2
N
H
HN
OH
O
O
Plasmepsin I inhibitor
Balanol
HO
Figure 1. Examples of HEA isoster containing compounds.
Table 1
Lewis acid-mediated azidolysis of 2,3-epoxy amines17,18
Nu
N3
R
H
O
O
OH
N3
3
2
R'
R'
method
A, B
or C
3
O
3
R
R
2
1
1
2
2
2
3
1
+
R'
NR2
3
1
3
1
M+n
R'
NR2
H
R'
NR2
OH
2
R' = CH2OH, CH2OR, CO2R
N3
1
OH
O
H
C-3 attack
C-2 attack
3
1
2
10 a-f
11 a-f
12 a-f
Methoda
C3:C2b
Yield azidec
Time (h)
Figure 2. Hypothesized cyclic chelate T.S.
Entry
Epoxide
11
12
1
2
3
10a
10a
10a
A
B
C
>95:5
>95:5
<5:95
85
76
—
—
—
82
6
45
0.8
4 (R' = n-C H )
3
7
R'
R'
OH
5 (R' = c-C H
)
6
11
i)
4
5
6
10b
10b
10b
A
B
C
>95:5
>95:5
<5:95
98
97
—
—
—
84
4
45
1
O
6 (R' = n-C H )
3
7
7 (R' = c-C H
)
7
8
9
10c
10c
10c
A
B
C
>95:5
>95:5
<5:95
78
87
—
—
—
97
1.5
45
2
OH
6
11
ii)
10
11
12
10d
10d
10d
A
B
C
>95:5
>95:5
>95:5
98
88
94
—
—
—
5
45
8
O
O
iii)
R'
NR2
R'
OMs
13
14
15
10e
10e
10e
A
B
C
>95:5
>95:5
<5:95
92
98
—
—
—
96
3
45
4
8 (R' = n-C H )
10a (R' = n-C H NR = piperidinyl 78%)
3 7 2
10b (R' = n-C H NR = morpholinyl 70%)
3
6
7
9 (R' = c-C H
)
11
3
7
2
10c (R' = n-C H NR = di-i-propylaminyl 84%)
3
7
2
16
17
18
10f
10f
10f
A
B
C
>95:5
>95:5
<5:95
86
95
—
—
—
92
4
45
2
10d (R' = n-C H NR = c-hexylaminyl 74%)
3
7
2
10e (R' = c-C H NR = piperidinyl 80%)
6
11
11
2
10f (R' = c-C H
NR = morpholinyl 87%)
6
2
a
Method A: TMSN3 (1 mmol), BF3ꢁEt2O (2 mmol), CH2Cl2, rt; method B: TMSN3
Scheme 1. Synthesis of 2,3-epoxy amines; (i) m-CPBA, CH2Cl2, rt, 97–98%; (ii)
CH3SO2Cl, Et3N, DMAP, CH2Cl2, rt, 88–95%; (iii) amine R2NH, neat, 50 °C, 70–87%.
(1.2 mmol), ZnCl2 (0.04 mmol), neat, 70 °C; method C: TMSN3 (1.04 mmol), Ti(O-i-
Pr)4 (1.84 mmol), benzene, 90 °C.
b
The major regioisomer was the only product detected (NMR analysis).
Isolated yield based on epoxides 10a–f.
c
an initial coordination of the reagent to the C-1 functional group
(often a hydroxyl), followed by an intramolecular delivery of nucle-
ophile to the proximal C-2 carbon.16 It is noteworthy that also in
this case the regiochemistry is independent of the steric hindrance
in C-3.
Since the reaction of [Ti(O-i-Pr)2(N3)2] on 2,3-epoxy alcohols is
reported to give a strong C-3 regioselectivity, we prepared the 2,3-
epoxy amine 10d with a secondary amine at C-1 (entry 12), to test
whether the presence of a proton at the C-1 heteroatom was cru-
cial for the course of the reaction.
Actually, the latter example (entry 12) showed that the pres-
ence of the proton seemed to be important to direct the regioselec-
tivity of the nucleophilic attack, since in this case only the C-3
derivative 11d was detected.
To better understand the particular behaviour of the [Ti(O-i-
Pr)2(N3)2], we have recently undertaken quantum mechanic stud-
ies. The preliminary results seemed to be in agreement with the
experimental data, indicating that there are different orientations

5584
G. Righi et al. / Tetrahedron Letters 53 (2012) 5582–5584
Serra, A. A.; Luche, M. J. J. Org. Chem. 1986, 51, 46–50; (c) Sharpless, K. B.; Caron,
M.; Carlier, P. R. J. Org. Chem. 1988, 53, 5185–5187.
12. Infante, I.; Bonini, C.; Lelj, F.; Righi, G. J. Org. Chem. 2003, 68, 3773–3780.
13. For the purpose of this work, it is not mandatory to have optically active
compounds, all the molecules are intended as racemates and the
stereochemistry is only reported as the relative one.
between the epoxides and the source of nucleophile, namely [Ti(O-
i-Pr)2(N3)2], depending on whether NR2 is a tertiary or secondary
amine. More comprehensive computational studies as well as the
extension of the methodologies at the 2,3-aziridine amines are cur-
rently under investigation.
14. (a) Chong, J. M.; Sharpless, K. B. J. Org. Chem. 1985, 50, 1560–1563; (b) Caron,
M.; Sharpless, K. B. J. Org. Chem. 1985, 50, 1557–1560; (c) ref. 10c.
15. Sasaki, M.; Tanino, K.; Hirai, A.; Miyashita, M. Org. Lett. 2003, 5, 1789–1791.
16. (a) Sasaki, M.; Tanino, K.; Miyashita, M. Org. Lett. 2001, 3, 1765–1767; (b) Finan,
J. M.; Kishi, Y. Tetrahedron Lett. 1982, 23, 2719–2722; (c) Ma, P.; Martin, V. S.;
Masamune, S.; Sharpless, K. B.; Viti, S. M. J. Org. Chem. 1982, 47, 1378–1380.
17. Typical procedure for method A: To a stirred solution of the 2,3-epoxy amine
(1 mmol) in dry CH2Cl2 (3 mL) were added TMSN3 (1 mmol) and BF3 OEt2
(2 mmol) dropwise and the solution was stirred at room temperature. After 2 h
(TLC monitoring), the reaction was diluted with CH2Cl2, washed with NaHCO3
(3 mL), brine (3 ꢂ 3 mL), dried over Na2SO4 and the solvent removed under
reduced pressure. The crude product was characterized without further
purification.
In conclusion, we have reported a Lewis acid-mediated regiose-
lective azidolysis of 2,3-epoxy amines, using TMSN3 as the source
of azide. It is of interest to note that the appropriate choice of Lewis
acid allows to direct, when NR2 is a tertiary amine, the regioselec-
tivity of the ring opening in C-3 or C-2 position.
Considering the occurrence of the diaminoalcohol moieties in
the structure of many biologically active compounds, the present
methodologies could represent a powerful tool in organic synthesis
for the preparation of interesting molecules.
Typical procedure for method B: 1 mmol of the 2,3-epoxy amine (1 mmol),
azidotrimethylsilane (1.2 mmol) and zinc chloride (0.04 mmol) were stirred at
68 °C for 15 h, at which time an additional 0.04 mmol of zinc chloride was
added. After a total reaction time of 48 h, the reaction mixture at 20 °C was
treated with THF (0.64 mL), acetic acid (0.064 mL) and HCl conc. (0.027 mL)
and then stirred for 30 min. The reaction mixture was diluted with EtOAc
(10 mL) and washed with NaHCO3 sol.sat (3 mL). The aqueous phase was
extracted with EtOAc (3 ꢂ 3 mL). The combined organic phases were washed
with brine (3 ꢂ 4 mL), dried (Na2SO4), and concentrated in vacuo.
Typical procedure for method C: A solution of 1.84 mmol of Ti(O-i-Pr)4 and
1.04 mmol of TMSN3 in 4 mL of benzene was heated at 90 °C for 4 h. To the
heating yellow solution was added 1 mmol of 2,3-epoxy amine in 1 mL of
benzene and reflux was continued for 0.8–4 h. The solution was then cooled to
0 °C, 15% H2SO4 (8.2 mL) solution was added, and the mixture was stirred
vigorously for 1 h. Then the reaction mixture was diluted with EtOAc (10 mL),
washed with NaHCO3 sol.sat. (3 mL)) and brine (1 mL), dried (Na2SO4) and the
solvent was removed in vacuo. The resulting product was characterized
without further purification.
Acknowledgment
We thank MIUR (Ministry of University and Research – Rome)
for partial financial support (PRIN 2008: Stereoselective synthesis
and biological evaluation of new compounds active towards prote-
ic targets involved in viral pathologies, cell growth and apoptosis).
References and notes
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18. NMR data for representative compounds.
(3R⁄,2S⁄)-3-Azido-1-piperidin-1-yl-hexan-2-ol 11a: 1H NMR (300 MHz, CDCl3,
25 °C): d = 0.94 (t, J = 6.9 Hz, 3H), 1.24–1.68 (m, 10H), 2.23–2.47 (m, 4H), 2.50–
2.68 (m, 3H), 3.34–3.48 (m, 1H), 3.67 (ddd, J = 5.1, 5.1, 9.6 Hz, 1H); 13C NMR
(75.4 MHz, CDCl3, 25 °C): 13.8, 19.6, 24.2, 26.1, 32.5, 54.6, 59.9, 65.5, 68.5.
(3R⁄,2S⁄)-3-Azido-1-morpholin-4-yl-hexan-2-ol 11b: 1H NMR (300 MHz, CDCl3,
25 °C): d = 0.92 (t, 3H), 1.20-1.72 (m, 4H), 2.34–2.50 (m, 4H), 2.55–2.82 (m, 3H),
3.33–3.55 (m, 1H), 3.58–3.89 (m, 5H); 13C NMR (75.4 MHz, CDCl3, 25 °C): 13.6,
19.5, 32.3, 53.5, 59.8, 65.1, 66.7, 68.4.
(3R⁄,2S⁄)-3-Azido-1-diisopropylamino-hexan-2-ol 11c: 1H NMR (300 MHz, CDCl3,
25 °C): d = 0.89 (t, J = 6.9 Hz, 3H), 1.01 (d, J = 6.6 Hz, 6H), 1.05 (d, J = 6.6 Hz, 6H),
1.28–1.34 (m, 5H), 2.81 (dd, J = 5.3, 14.1 Hz, 1H), 2.74 (dd, J = 6.9, 14.1 Hz, 1H),
3.07 (sep, J = 6.5 Hz, 2H), 3.42 (ddd, J = 3.0, 5.3, 8.3 Hz, 1H), 3.60 (m, 1H); 13C
NMR (75.4 MHz, CDCl3, 25 °C): 13.9, 18.8, 19.7, 20.6, 34.2, 46.8, 49.3, 64.9, 68.2.
(3R⁄,2S⁄)-3-Azido-1-cyclohexylamino-hexan-2-ol 11d: 1H NMR (300 MHz, CDCl3,
25 °C): d= 0.95 (t, J = 7.0 Hz, 3H), 1.01-1.85 (m, 14H), 2.31–2.55 (m, 1H), 2.62
(dd, J = 8.9, 12.2 Hz, 1H), 2.82 (dd, J = 3.6, 12.2 Hz, 1H), 2.87–3.05 (br s, 2H),
3.31–3.45 (m, 1H), 3.56 (ddd, J = 3.6, 5.3, 8.9 Hz, 1H); 13C NMR (75.4 MHz,
CDCl3, 25 °C): 13.7, 19.4, 24.4, 24.5, 24.8, 29.3, 29.5, 32.6, 47.2, 58.1, 65.4, 69.3.
(2S⁄,3R⁄)-2-Azido-1-piperidin-1-yl-hexan-3-ol 12a: 1H NMR (300 MHz, CDCl3,
25 °C): d = 0.95 (t, J = 7.0 Hz, 3H), 1.30–1.68 (m, 10H), 2.24–2.63 (m, 5H), 2.69
(dd, J = 5.9, 13.4 Hz, 1H), 3.53 (td, J = 5.9, 2.8 Hz, 1H), 3.64–3.76 (m, 1H), 4.58
(br s, 1H); 13C NMR (75.4 MHz, CDCl3, 25 °C): 14.0, 19.0, 23.8, 25.9, 35.6, 55.4,
60.1, 61.8, 73.0.
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25 °C): d= 0.93 (t, J = 7.0 Hz, 3H), 1.36–1.64 (m, 4H), 2.59 (dt, J = 4.6, 14.0 Hz,
4H), 2.68 (d, J = 6.0 Hz, 2H), 3.44–3.60 (m, 2H), 3.60–3.68 (m, 1H), 3.70 (t,
J = 4.5 Hz, 4H); 13C NMR (75.4 MHz, CDCl3, 25 °C): 13.9, 18.9, 36.1, 54.2, 60.1,
62.2, 66.8, 72.6.
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(2S⁄,3R⁄)-2-Azido-1-diisopropylamino-hexan-3-ol 12c: 1H NMR (300 MHz, CDCl3,
25 °C): d = 0.80 (t, J = 7.0 Hz, 3H), 0.98 (d, J = 6.6 Hz, 6H), 1.02 (d, J = 6.6 Hz, 6H),
1.43 (m, 5H), 2.75 (t, J = 4. 4 Hz, 2H), 3.07 (quint, J = 6.7 Hz, 2H), 3.40 (m, 1H),
3.58 (m, 1H); 13C NMR (75.4 MHz, CDCl3, 25 °C): 13.8, 18.8, 19.9, 20.7, 36.2,
46.8, 48.3, 64.5, 71.8.
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