New one-pot procedure for the synthesis of diprotected amino alcohols from unprotected vinyl aziridines

Article abstract of DOI:10.1016/j.tetlet.2013.09.047

An unprecedented one-pot reaction that allows the synthesis of diprotected amino alcohols from unprotected vinyl aziridines is reported. The results demonstrate the possibility to use various acyl chlorides in order to obtain differently functionalised fragments. Mechanistic insights are given.

Full text of DOI:10.1016/j.tetlet.2013.09.047

Tetrahedron Letters 54 (2013) 6439–6442
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
New one-pot procedure for the synthesis of diprotected amino
alcohols from unprotected vinyl aziridines
b
c,
Giuliana Righi a, , Paolo Bovicelli , Ilaria Tirotta
⇑
⇑
a CNR-ICB Unity of Rome, P.le A. Moro, 5-00185 Rome, Italy
b CNR-ICB Unity of Sassari, Traversa La Crucca 3, Baldanica I, 07040 Sassari, Italy
c 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:
Received 30 June 2013
Revised 7 September 2013
Accepted 13 September 2013
Available online 20 September 2013
An unprecedented one-pot reaction that allows the synthesis of diprotected amino alcohols from unpro-
tected vinyl aziridines is reported. The results demonstrate the possibility to use various acyl chlorides in
order to obtain differently functionalised fragments. Mechanistic insights are given.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Vinyl aziridines
Amino alcohols
Acyl derivatives
Ring opening
Oxazolines
The functionalisation of the aziridine nitrogen with electron-
withdrawing groups is a broadly used strategy for the activation
of the heterocyclic ring towards nucleophilic attack.
these peculiar rearrangements nor a one-pot procedure for the for-
mation of diprotected syn-amino alcohols from vinyl aziridines.
For these reasons the reaction was investigated in order to ver-
ify its reproducibility and scope, to understand its mechanism and
the influence that the aziridine functionalisations have on its ste-
reo- and regioselectivity. Therefore three different vinyl aziridines
During an attempt in this direction, an unexpected reactivity
was observed when particular aziridines were submitted to the
usual acylation conditions1 (Scheme 1): when vinyl aziridine A
was reacted with 1.2 mmol of Et3N and 1.2 mmol of CH3COCl in
dry dichloromethane at room temperature, instead of the expected
N-protected aziridine, the main product recovered was the dipro-
tected amino-alcohol B. NMR studies revealed the complete regio-
and stereoselectivity of the reaction, detecting in the crude only
one diastereomer with the oxygen in the allylic position was
obtained.
Scheme 1. Unexpected opening reaction.
The first mechanistic hypothesis was the formation of an oxaz-
oline C that could open to give monoprotected syn-amino alcohol
D, which then could react with acetyl chloride to give
B
(Scheme 2).
N-Acyl or N-carboxyl vinyl aziridines are known to undergo
rearrangements in a wide range of conditions,2 in particular Cardil-
lo et al.3 reported a three steps strategy that leads to syn monopro-
tected amino-alcohols. Nonetheless, to the best of our knowledge,
there does not seem to be in the literature a thorough study on
⇑
Corresponding authors at present address: NFMLab-DCMIC ‘Giulio Natta’ Via L.
Mancinelli 7, 20131 Milano, Italy. Tel./fax: +39 02 23994745 (I.T.).
Scheme 2. Proposed mechanism.
E-mail address: ilaria.tirotta@gmail.com (I. Tirotta).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.09.047

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G. Righi et al. / Tetrahedron Letters 54 (2013) 6439–6442
were prepared: the R group was changed in order to evaluate the
influence that its steric hindrance and electronic effects have on
the reaction. In addition, to investigate the possibility of a broader
scope, different acyl chlorides were chosen: CH3COCl, CH3(CH2)8-
COCl (interesting for its long alkyl chain, which is found in many
natural products), and PhCOCl (interesting for the possible effects
of the phenyl group on the reaction).
verted into the corresponding aziridines 6a–c via a well-known
procedure.8
When all substrates were submitted to the same conditions
used the first time the reaction failed to prove reproducible and
very unsatisfactory yields were obtained (50% overall) (Scheme 4).
Besides the formation of the diprotected amino alcohol, there
always was a significant amount of monoprotected derivative
(30%). Moreover, compound 6c led to derivatives 7c and 8c both
characterised by the presence of the O-protected group in the ben-
zylic position instead of the allylic one. The reaction proved to be
regioselective nonetheless, and the regioselectivity seemed to be
driven by the peculiar reactivity of the allylic position for com-
pounds 6a and 6b, whereas for compound 6c the benzylic position
proved to be more reactive than the allylic one. The recovery of
monoprotected derivatives 8a, 8b, and 8c could be explained by
the insufficient amount of acetyl chloride in the reaction media.
Another possible explanation would be that not all the oxazoline
is opened during the reaction, but a small part opens during the
work-up, hence leading to the monoprotected derivative.
Therefore the reaction conditions were varied in order to iden-
tify the best suitable ones for the synthesis of diprotected deriva-
tives and the results are summarised in Table 1.
All the substrates were easily and in fairly good yield prepared
starting from the corresponding allylic alcohols 1a–c4 (Scheme 3).
An epoxydation reaction5 followed by an oxidation of the hy-
droxyl groups afforded epoxy aldehydes 3a–c. A subsequent Horn-
er–Emmons reaction6 yielded
a,b-unsaturated epoxy esters 4a–c,
the oxirane ring of which was then regio-selectively and stereo-
specifically opened, using a methodology recently developed by
our group,7 to afford azidoalcohols 5a–c, which were finally con-
When the aziridines were reacted with 1.2 equiv of CH3COCl
and Et3N as well as when the equivalents were doubled (Entries
1 and 2), the amount of diprotected amino alcohol and monopro-
tected derivative were, on average, 70–100% for the former and
0–30% for the latter, with an overall yield of 50%. It is also impor-
tant to note that in some cases it was possible to identify the oxaz-
oline in the reaction crude and to isolate it in very small amount
after purification. In both cases (Entries 1 and 2) the reaction led
to a complex mixture of products, failing to prove reproducible
and to give reasonable yields of the desired diacylated compound.
Interestingly, when aziridines 6a and 6b (R = propyl, cyclo-
hexyl) were reacted with an excess of Et3N (entry 3) it was possible
to recover the oxazoline as the only product even after purification
of the reaction crude, even though only in small amounts (40%
yield). However, these data are not reproducible: performing the
reaction on compound 6c (R = phenyl) only the correspondent pro-
tected aziridine was detected in the reaction crude. This has led to
the conclusion that the reaction evolves through very labile equi-
libria that are difficult to control so much to obtain only one of
the intermediates. What seemed more plausible was the possibility
to drive the reaction towards the last product, the diprotected ami-
no alcohol.
Scheme 3. Reagents and conditions: (a) m-CPBA, CH2Cl2, 0 °C, 3 h (85–90%); (b)
TEMPO, IBDA, CH2Cl2, rt 2 h or Py/SO3, DMSO, Et3N, CH2Cl2, rt 2 h (70–80%); (c)
LiOH, TEPA, THF, 70 °C, 2 h (85–95%); (d) BF3OEt2, TMSN3, CH2Cl2, rt 1 h (95%); (e)
PPh3, acetonitrile, rt À70 °C, o/n (90%).
Finally, when all three aziridines were reacted with 3 equiv of
CH3COCl and only 1 equiv of Et3N (entry 4), the diprotected deriv-
ative was recovered in a very satisfactory yield (70%). Therefore
Scheme 4. Reagents and conditions: (a) Et3N (1.2 equiv), CH3COCl (1.2 equiv), dry
CH2Cl2, rt 3–5 h (50% overall).
Table 1
Different reaction conditions for the acetyl chloride mediated ring-opening15: results
Entry
CH3COCl (equiv)
Et3N (equiv)
Solvent
Overall yield (%)
A (%)
B (%)
C (%)
D (%)
1
2
3
4
1.2
2.4
1.6
3
1.2
2.4
2
Dry CH2Cl2
Dry CH2Cl2
Dry CH2Cl2
Dry CH2Cl2
50
50
—
—
70–100
70–100
0–30
0–30
Traces
Traces
Variable results
>95
1
70
—
—
Traces

G. Righi et al. / Tetrahedron Letters 54 (2013) 6439–6442
6441
these conditions were identified as the most suitable for our pur-
poses and used with the other acyl chlorides chosen for the study.
In light of these findings, we believe that, when the reaction
media is sufficiently acidic, oxazoline C (see Scheme 2) is directly
converted into the diprotected compound B (Table 1, entry 4).
However, when this is not the case, part of it stays intact and then
gets cleaved during work-up leading to the monoprotected com-
pound D (Table 1, Entries 1 and 2).
comparison with the literature value of the coupling constants
J4,5 and allowed a first confirmation of the proposed mechanism.
To confirm the stereochemical assignment of all products ob-
tained, compound 7c was converted into the corresponding oxa-
zolidine 12 (Scheme 7), via a selective deprotection10 of the
hydroxyl moiety, followed by an intramolecular cyclisation.
9
Oxazolidines are characterised by a peculiar value for the cou-
11
pling constants J4,5
:
the approximate value is 5 Hz for trans
Performing the reactions on all three substrates, using 3 equiv
of decanoyl chloride and 1 equiv of Et3N, the expected diprotected
derivatives (9a–c) were recovered in, on average, 70% yield
(Scheme 5).
The reactions with benzoyl chloride required 4 equiv of chloride
and 1 equiv of Et3N in order to obtain diprotected derivatives
10a–c in a 60% yield alongside with small amounts of the
corresponding oxazolines in a 90:10 ratio (Scheme 6). In these
cases the amount of oxazoline recovered was higher than what
was previously observed and this can be explained by the
stabilisation given to the molecule by the phenyl group. The
trans stereochemistry for oxazolines 11a–11c was assigned by
oxazolidines and 0 Hz for cis ones. Compound 12 proved to be
a trans oxazolidine, thus confirming the hypothesised syn stereo-
chemistry for both the mono and the diprotected derivatives.
This also corroborates our proposed mechanism, however ongo-
ing studies will allow us to have a more thorough understanding
of it.
To the best of our knowledge this is the first one-pot procedure
reported for the synthesis of diprotected amino alcohols from vinyl
aziridines. The data collected showed the complete regio- and ste-
reoselectivity of the reaction: in all cases only the syn diastereomer
was recovered, characterised by the O-protected group in the
allylic position for compounds with R = propyl and cyclohexyl,
and in the benzylic position for the compound with R = phenyl.
The steric hindrance of the R group does not influence the reaction
at all; the influence exerted by the phenyl group can be ascribed to
the particular reactivity of the benzylic position, which proved to
be sensibly more reactive than the allylic one. Regarding the group
on the double bond, we believe its role is crucial and its electron
withdrawing nature essential for the regioselectivity of the reac-
tion, as we have already observed in previous work on similar com-
pounds.12 The reaction performed with 3 or 4 equiv of acyl chloride
and 1 equiv of triethylamine proved to be reproducible and appli-
cable to different substrates and acyl chlorides. It is fast (2–5 h),
fairly clean, and leads with good yields (60–70%) to unsaturated
diprotected amino alcohols, useful precursors of a wide range of
biologically active compounds. For example, they are used as read-
ily available precursors in the preparation of (E)-alkene dipeptide
isosteres, frequently employed in SAR (structure–activity relation-
ship) studies for the close resemblance with the three-dimensional
structure of the amide bond.13,14 Studies in this directions are cur-
rently undergoing in our laboratories and will allow the broaden-
ing of the reaction scope.
Scheme 5. Reagents and conditions: (a) decanoyl chloride (3 equiv), Et3N (1 equiv),
dry CH2Cl2, rt, 2–5 h.
Acknowledgements
We thank MIUR (Ministry of University and Research, Rome) for
partial financial support (PRIN 2010–2011: Design and stereoselec-
tive synthesis of compounds active towards protein targets in-
volved in viral and tumoral pathologies).
Scheme 6. Reagents and conditions: (a) benzoyl chloride (4 equiv), Et3N (1 equiv),
dry CH2Cl2, rt, 2 h.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
09.047.
References and notes
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3. (a) Cardillo, G.; Gentilucci, L.; Tolomelli, A. Tetrahedron Lett. 1999, 40, 8261–
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2000, 13, 2489–2494; (c) Olofsson, B.; Somfai, P. J. Org. Chem. 2002, 67, 8574–
8583.
Scheme 7. Reagents and conditions: (a) Na2CO3, MeOH, rt, o/n (70%); (b) CSA, DMP,
CH2Cl2, rt, o/n (40%).

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G. Righi et al. / Tetrahedron Letters 54 (2013) 6439–6442
4. For the substrates with R = cyclohexyl the appropriate alcohol 1b is not
commercially available and it was synthesized from the
cyclohexanecarboxaldehyde. Horner–Emmons reaction, followed by
reduction of the ester using DIBAL, led to alcohol 1b with an overall yield of
97%.
5. For the purposes 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.
6. Bonadies, F.; Scettri, A.; Di Campli, C. Tetrahedron Lett. 1996, 37, 1899–1900.
7. Righi, G.; Salvati Manni, L.; Bovicelli, P.; Pelagalli, R. Tetrahedron Lett. 2011, 52,
3895–3896.
8. Legters, J.; Thijs, L.; Zwanemburg, B. Recl. Trav. Chim. Pays-Bas. 1992, 111, 1–15.
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therein cited.
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Kluijver, M. J.; Gomez, R. J. Nat. Prod. 2000, 63, 978–980.
11. Cui, P.; McCalmont, W. F.; Tomsig, J. L.; Lynch, K. R.; Macdonald, T. L. Bioorg.
Med. Chem. 2008, 16, 2212–2225.
12. Righi, G.; Bovicelli, P.; Tirotta, I. Synthesis 2012, 44, 3202–3208.
13. Wipf, P.; Fritch, P. C. J. Org. Chem. 1994, 59, 4875–4886.
14. Tamamura, H.; Hiramatsu, K.; Ueda, S.; Wang, Z.; Kusano, S.; Terakubo, S.;
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the solution cooled to 0 °C. Et3N (1 mmol, 0.17 ml) and the appropriate acyl
chloride (3 mmol) were added drop-wise and the mixture left stirring at room
temperature until complete consumption of the substrate (TLC monitoring).
The reaction mixture was diluted with dichloromethane, washed with ice cold
water and neutralised with a saturated solution of NaHCO3, the organic layer
was dried over Na2SO4 and the solvent removed in vacuo to leave the crude,
which was purified by flash chromatography. (4R⁄,5R⁄, E)-ethyl 5-(N-
acetyl)amino-4-acetoxy-oct-2-enoate (7a): pale yellow oil (200 mg, 70%); IR
(neat): 3320, 2980, 1716, 1640, 1250 cmÀ1; dH (300 MHz, CDCl3): 6.81 (1H, dd,
J = 5.1, 15.8 Hz, CH@CHCO), 5.91 (1H, dd, J = 1.6, 15.8 Hz, CHCO), 5.49 (1H, ddd,
J = 1.6, 5.1, 5.3 Hz, CH-OAc), 5.4 (1H, d, J = 9.9 Hz, NH), 4.31–4.08 (3H, m,
COCH2CH3 + CHNAc), 2.14 (3H, s, COCH3), 1.99 (3H, s, COCH3), 1.53–1.15 (7H,
m, COCH2CH3 + CH2CH2CH3), 0.89 (3H, t, J = 7.1 Hz, CH2CH2CH3); dC (75 MHz
CDCl3): 170.1, 169.9, 165.7, 142.5, 123.3, 73.7, 60.8, 51.1, 33.9, 23.3, 20.9, 19.2,
14.3, 13.9; HRMS (ES Q-TOF): [M+H]+, found 286.1659. C14H23NO5 requires
286.1654. (4R⁄,5R⁄, E)-ethyl 4-(N-acetyl)amino-5-hydroxy-5-phenyl pent-2-
enoate (8c): yellow oil (30 mg, 10%); IR (neat): 3444, 2986, 1715, 1656,
1190 cmÀ1; dH (300 MHz CDCl3): 7.62–7.22 (5H, m, Ph); 6.94 (1H, dd, J = 8.4,
17.6 Hz, CH@CHCO), 5.95 (1H, dd, J = 1.7, 17.6 Hz, CHCO), 5.87 (1H, d, J = 8.8 Hz,
NH), 5.22 (1H, dddd, J = 1.7, 4.6, 8.4, 8.8 Hz, CH-NHAc), 5.11 (1H, d, J = 4.6 Hz,
CHOH), 4.18 (2H, q, J = 7.2 Hz, COCH2CH3), 2.5 (1H, br s, OH), 1.99 (3H, s,
COCH3), 1.2 (3H, t, J = 7.2 Hz, COCH2CH3); dC (75 MHz CDCl3): 169.9; 165.6;
143,2; 136.1, 128.7; 128.5; 126.7, 123.1; 70.6; 60.5, 53.9; 22.7; 13.9; HRMS (ES
Q-TOF): [M+H]+, found 278.1396. C15H19NO4 requires 278.1392.
A
a
15. General procedure for the acyl chloride mediated ring-opening reactions: 1 mmol
of the appropriate substrate was dissolved in 1 ml of dry dichloromethane and