MgBr2-mediated opening of 2,3-three membered heterocyclic amines

Article abstract of DOI:10.1002/jhet.354

(Chemical Equation Presented) Regio- and stereo-controlled opening of 2,3-epoxy amines and 2,3-aziridine amines by the commercially available MgBr₂ is described. As reported, this new method could represent a general and useful approach for the preparation of promising intermediates. Moreover, in particular cases, the reaction evolves toward an interesting oxazolidin-2-one structure.

Full text of DOI:10.1002/jhet.354

564
MgBr2-Mediated Opening of 2,3-Three Membered Heterocyclic
Amines
Vol 47
Giuliana Righi,* Simona Ciambrone,* Evelina Esuperanzi, Francesca Montini,
and Romina Pelagalli
`
Istituto di Chimica Biomolecolare, Dip. Chimica, Universita ‘‘La Sapienza,’’ p.le A. Moro 5,
00185 Roma, Italy
*E-mail: giuliana.righi@cnr.it; simona.ciambrone@uniroma1.it
Received November 3, 2009
DOI 10.1002/jhet.354
Published online 15 April 2010 in Wiley InterScience (www.interscience.wiley.com).
Regio- and stereo-controlled opening of 2,3-epoxy amines and 2,3-aziridine amines by the commer-
cially available MgBr2 is described. As reported, this new method could represent a general and useful
approach for the preparation of promising intermediates. Moreover, in particular cases, the reaction
evolves toward an interesting oxazolidin-2-one structure.
J. Heterocyclic Chem., 47, 564 (2010).
INTRODUCTION
In this field, we synthesized two analogues of Saqui-
navir 1, where the anti stereochemistry of the hydroxy-
ethylene isoster core (anti HEA) was substituted with a
syn one, as shown in Figure 1 [2].
The human immunodeficiency virus (HIV) is the
causative agent of the acquired immunodeficiency syn-
drome (AIDS); the HIV-protease (PR) is one of the
essential viral enzymes to its maturation and infectivity.
Actually, synergy of the two RT and PR inhibitors rep-
resents the most efficacious therapy for the treatment of
this disease called Highly Active Antiretroviral Therapy
(HAART). All the same, the widespread diffusion of the
disease and the development of numerous mutant resist-
ant viruses to this therapy have prompted the research
toward new and selective inhibitors of HIV-PR, see
review [1].
Among the methods already reported for obtaining
syn amino alcohols, see review [3], certainly the multi-
steps strategy largely used by us consisting in (1) Sharp-
less AE of allylic alcohols, (2) regio- and stereoselective
opening of oxirane ring with halides, (3) substitution of
the halogen with azide, and (4) catalytic hydrogenation
to amine, represents, despite the number of steps, a very
general and flexible route to build up the chiral b-amino
alcohols. Following up this approach, we considered the
epoxy amine 3, having the Saquinavir characteristic
Figure 1. Saquinaver and syn HEA analog.
C
V
2010 HeteroCorporation

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MgBr2-Mediated Opening of 2,3-Three Membered Heterocyclic Amines
565
Scheme 1
residue (S,S,S)-decahydroisoquinoline-3-carboxylamide
residue (DIQ) already introduced in the molecule, a
straightforward precursor for our purpose. In fact, its
stereo- and regioselective opening by halide, followed
by steps (3) and (4), would have furnished the suit-
able syn amino alcohol 5, as shown in retrosynthetic
Scheme 1.
the C-3 position, as expected for chelation-controlled
ring opening reactions. The regiochemistry of the prod-
ucts was assigned by spin–spin decoupling experiments
carried out on the corresponding acetyl derivatives,
whereas the anti stereochemistry was assigned in ac-
cordance with the SN2 mechanism of the opening
reaction.
Apart from selected examples [4], to our best knowl-
edge, the regio- and stereo-controlled opening of 2,3-
epoxy amines by halides has never been exploited;
therefore, we decided to better study this particular reac-
tivity of these compounds.
As expected, the same reaction conditions applied to
the 2,3-epoxy amine 3 afforded the desired bromoderi-
vative 4, in good yield and excellent regioselectivity
(entry 5); the further elaboration of bromine carried out
to our desired target, the syn amino alcohol 5.
For the sake of completeness and for our interest on
these compounds, the study was extended on 2,3-aziri-
dine amines. Also in this case very few examples [8],
regarding essentially aziridine-fused heterocycles,
are already reported in literature. Likewise 2,3-aziri-
dino alcohols [9], also for 2,3-aziridine amines, a
cyclic chelate may be invoked to control the regiose-
lectivity in the ring opening reaction by metal halides,
Figure 3.
RESULTS AND DISCUSSION
During our studies, we have extensively investigated
the metal halides-mediated opening of epoxy alcohols,
esters (see review [5]), and aldehydes [6]. In every case,
we established that the freshly prepared MgI2, or the
commercially available MgBr2, as well as LiX/Amb15
system were able to direct the halide in C-3 position
An expeditious sequence was employed to prepare the
starting substrates, consisting on the direct introduction
of the amines on C-1 position, followed by the usual
transformation to the aziridine ring (Scheme 3) [10]. In
this case, the chosen amines have been once again pi-
peridine and, for our specific interest regarding the syn-
thesis of D-treo-PDMP, morpholine [11].
through
a previously postulated chelated complex
between the metal (Mg2þ, Liþ) and the two oxygen of
the epoxide derivative. At this point, we hypothesized
that also in the case of 2,3-epoxy amines, a possible
chelate between metal, epoxide oxygen, and the nitrogen
atom occurred, leading to a C-3 regioselective nucleo-
philic ring opening, Figure 2.
When we submitted compounds 16–19 to MgBr2
reaction, only one product was detected (Table 2); also
Our preliminary studies were restricted, for conven-
ience, to racemic compounds; the 2,3-epoxy amines
were synthesized in satisfactory yield from the corre-
sponding 2,3-epoxy alcohols through the sequence
described in Scheme 2: (1) transformation of the
hydroxyl function in a good leaving group such as the
mesilate (2) nucleophilic substitution with the suitable
amine.
The prepared 2,3-epoxy amines were then submitted
to the MgBr2-mediated opening reaction employing dry
Et2O as solvent at low temperature [7]. As shown in Ta-
ble 1, the results confirmed our hypothesis: the nucleo-
philic attack of the bromine occurred preferentially in
Figure 2. Possible cyclic chelate.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Scheme 2
Scheme 3
Table 1
Controlled opening of 2,3-epoxy amines.
2,3-Epoxy amine
6
Main haloderivative
Yield (%)
Ratioa C-3/C-2
98:2
92
7
65
90:10
8
9
3
86
69
68
95:5
90:10
95:5
4
a Regioisomeric ratio was determined by 1H NMR spectra.

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MgBr2-Mediated Opening of 2,3-Three Membered Heterocyclic Amines
567
An unexpected behavior was observed when the C-3
position of the substrate was very reactive, as for 24 and
25; in this case, the initial 3-bromo derivative underwent
a rearrangement during the time (4–5 h), giving a new
product, the physical data of which were in agreement
with a 2-oxazolidinone structure (Scheme 4). This trans-
formation could be explained through an intramolecular
nucleophilic substitution of the bromine in benzylic and
allylic position (Fig. 4).
Figure 3. Possible cyclic chelate.
In conclusion, the described new method represents a
general and useful approach to the preparation of prom-
ising intermediates, due to the possible elaboration of
the bromine [12]. Moreover, also when the reaction
in this case, the ring opening occurred with an excellent
C-3 regioselectivity (as demonstrated through spin–spin
decoupling experiments), according to the proposed
cyclic chelate model.
Table 2
Controlled opening of 2,3-aziridine amines.
2,3-Aziridine amine
16
Main haloderivative
Yield (%)
Ratioa C-3/C-2
81
>95:5
17
18
19
78
78
69
>95:5
>95:5
>90:10
a Regioisomeric ratio was determined by 1H NMR spectra.
Scheme 4
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

568
G. Righi, S. Ciambrone, E. Esuperanzi, F. Montini, and R. Pelagalli
Vol 47
[7] Representative procedure for the ring opening of 2,3-three
membered heterocyclic amines: To a cold (ꢀ20ꢁC) stirred solution of
2,3-three membered heterocyclic amine (1 mmol) in Et2O, MgBr2
Et2O (516.5 mg, 2 mmol) was added. The mixture was stirred for 6 h
(TLC monitoring) and then filtered through a pad of Celite. The filtrate
was diluted with EtOAc, washed with saturated aq. NaCl, dried over
Na2SO4, and then evaporated in vacuum. The crude mixture was puri-
fied by column chromatography (petroleum ether/ethyl acetate 7/3).
(3S*,2R*)-3-Bromo-2-hydroxy-1-piperidine-hexane, 10. 1H NMR (200
MHz, CDCl3): d 4.31 (ddd, 1H, J 10.2 7.3 2.9 Hz, CHOH); 3.97 (ddd,
1H, J 9.2 7.3 2.9 Hz, CHBr); 3.41 (dd, 1H, J 13.2, 2.2 Hz, CHAN);
3.35–2.99 (m, 6H, CHBNþ2CH2N-piperidineþOH); 2.17–1.95 (m, 6H,
3CH2-piperidine); 1.93–1.15 (m, 4H, 2CH2); (t, 3H, J 7.3 Hz). 13C
NMR (50.3 MHz, CDCl3): d 68.0; 61.1; 58.1; 54.2; 36.1; 22.5; 21.3;
20.1;13.0. HR-MS (ES Q-TOF) Calcd for C11H23BrNO (MþH)þ:
264.0963 Found 264.0968. (1R*,2S*)-2-Bromo-1-(10-methylpiperi-
dinyl)-pentyl carbamic acid t-butyl ester, 20. 1H NMR (200 MHz,
CDCl3): d 5.17–4.98 (bs, 1H, NHBoc); 4.48–4.34 (m, 1H, CHNHBoc);
3.88–3.67 (m, 1H, CHBr); 2.62–2.20 (m, 6H, CH2Nþ2CH2N-piperi-
dine); 1.91–1.70 (m, 2H, CH2CHBr); 1.5–1.18 (m, 8H, CH2þ3CH2-pi-
peridine); 1.44 (s, 9H, C(CH3)3); 0.93 (t, 3H, J 7.3 Hz, CH3). 13C
NMR (50 MHz, CDCl3): d 154.6; 78.7; 61.4; 60.7; 59.0; 53.9; 36.3;
28.3; 27.0; 24.5; 19.8; 12.9. HR-MS (ES Q-TOF) Calcd for
C16H32BrN2O2 (MþH)þ: 363.1647 Found 363.1651. (2S,3R)-2-
Bromo-2-phenyl-1-(10-methylmorpholinyl) carbamic acid t-butyl ester,
26. 1H NMR (200 MHz, CDCl3): d 7.54–7.23 (m, 5H); 5.38 (bd, 1H, J
4.4 Hz, NHBoc); 4.96 (d, 1H, J 6.6 Hz, CHBr); 4.36-4.08 (m, 1H,
CHNH); 3.71 (t, 4H, J 4.4 Hz, 2CH2O-morpholine); 2.78–2.29 (m, 6H,
CH2Nþ2CH2N-morpholine); 1.40 (s, 9H, C(CH3)3). Calcd for
C18H28BrN2O3 (MþH)þ: 399.1283 Found 399.1288. (4R,5R)-4-Mor-
pholin-4-ylmethyl-5-phenyl-oxazolidin-2-one, 28. 1H NMR (200 MHz,
CDCl3): d 7.52–7.29 (m, 5H); 5.96 (bs, 1H, NH); 5.22 (d, 1H, J 5.9
Hz, CHO); 3.91–3.78 (m, 1H, CHNH); 3.67 (t, 4H, J 4.4 Hz, 2CH2O-
morpholine); 2.66–2.33 (m, 6H, CH2Nþ2CH2N-morpholine). 13C
NMR (50 MHz, CDCl3): d 158,7; 138,5; 128,8; 125,6; 81,5; 66,6;
62,5; 57,4; 53,8. Calcd for C19H27N2O5 (MþH)þ: 363.1920 Found
363.1924.
Figure 4. Proposed intramolecular cyclization.
evolves toward oxazolidin-2-ones, it could be of interest,
considering the importance of oxazolidinones in the ste-
reoselective synthesis of natural products and pharma-
ceuticals [13].
Acknowledgments. The authors thank MIUR (Ministry of Uni-
versity and Research, Rome) for partial financial support (PRIN
2005: Sintesi stereoselettiva e valutazione biologica di composti
`
mirati all’attivita antivirale).
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DOI 10.1002/jhet