A new, simple, and mild azidolysis of vinylepoxides

Article abstract of DOI:10.1016/j.tetlet.2011.05.085

A new, simple, and mild regio-and stereocontrolled azidolysis of vinylepoxides with TMSN₃/BF₃ system is reported. The method appears of general value and works very well particularly in the presence of electron-poor olefins, regardless of the size of substituents on the heterocyclic ring.

Full text of DOI:10.1016/j.tetlet.2011.05.085

Tetrahedron Letters 52 (2011) 3895–3896
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A new, simple, and mild azidolysis of vinylepoxides
Giuliana Righi a, , Livia Salvati Manni c, Paolo Bovicelli b, Romina Pelagalli c,
⇑
⇑
a Istituto di Chimica Biomolecolare, Dip. Chimica, Università Sapienza di Roma, p.le Aldo Moro 5, 00185 Roma, Italy
b Istituto di Chimica Biomolecolare, Traversa La Crucca 3, Baldinca, I-07040 Sassari, Italy
c Dip.Chimica, Università Sapienza di Roma, p.le Aldo Moro 5, 00185 Roma, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
A new, simple, and mild regio-and stereocontrolled azidolysis of vinylepoxides with TMSN3/BF3 system is
reported. The method appears of general value and works very well particularly in the presence of elec-
tron-poor olefins, regardless of the size of substituents on the heterocyclic ring.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 8 February 2011
Revised 12 May 2011
Accepted 17 May 2011
Available online 25 May 2011
Keywords:
Vinylepoxides
Azidolysis
Regioselectivity
Azido alcohols
Nucleophilic ring-opening of epoxides is a powerful tool in
organic synthesis due to their highly functionalized nature and
versatile reactivity. Among the variously functionalized epoxides,
the vinylepoxides are a very interesting subclass having several
positions for nucleophilic attack (Fig. 1) and a judicious choice of
nucleophile directs the ring-opening in SN2 and SN20 (route A)
modes.1 Generally the vinylic moiety functions as a regiochemical
directing element (route B) and the homoallylic attack (route C) is
not normally observed.
In the light of the excellent results recently obtained on the Le-
wis acid-mediated regioselective opening of epoxy amines using
TMSN3 as source of azide group,15 we decided to employ the
TMSN3/BF3ꢁOEt2 system16 to attempt the regio-and stereocon-
trolled azidolysis of the vinylepoxides.
To study the reactivity of these substrates we prepared com-
pounds with various R and R0 (Scheme 1) to investigate the influ-
ence of the steric hindrance of R on the oxirane ring and the
electronic effects of R0 on the double bond.
The ring-opening reaction of vinylepoxides is a key step of total
Vinyloxiranes were easily prepared from the corresponding
allylic alcohol in three efficient steps: epoxidation of the double
bond (by m-CPBA for racemic compounds, by Sharpless AE for
optically active compounds),17 oxidation of the alcohol group and
Wittig18 or Horner–Emmons19 olefination (Scheme 1).
All substrates were submitted to the reaction with TMSN3
(1 equiv) and BF3ꢁOEt2 (2 equiv) in dry CH2Cl2 at room tempera-
ture.20 Under these conditions, in a few hours (0.75–4.1 h) the
starting material disappeared and the corresponding anti azido
alcohol was generally obtained in a satisfactory yield. The allylic
synthesis of many natural products as (ꢀ)-Balanol,2 Hyacinthacine
A1,3 (ꢀ)-Muricatacin,4 (ꢀ)-LL-C10037a 5
, methyl b-D-vicenisami-
nide,6 etc. Moreover, they are useful synthons for the synthesis of
biologically active products as iminosugars,7 inositol derivatives,8
sphingosines,9 macrolide antibiotics,10 benzazepine skeletons.11
Despite the rich literature on the chemistry of epoxide opening,
to the best of our knowledge there are few reports concerning a
systematic study on the ring-opening of vinyloxiranes by azide.12
The azide moiety is one of the most popular amine precursors in
organic synthesis and the starting material for the Huisgen 1,3-
dipolar cycloaddition reaction with alkynes to form stable
aromatic 1,2,3-triazoles (click chemistry).13
OH
R'
SN2
Nu-
B
R
As we are interested in synthetic methodologies to prepare
highly functionalised chiral fragments by stereo-and regioselective
ring opening of functionalised 3-membered heterocyclic rings,14
we planned to extend our studies on the azidolysis of
vinylepoxides.
A
OH
Nu
Nu-
O
R'
SN2'
R'
R
R
Nu-
A
Nu
C
C
Nu
B
R'
SN2
R
OH
Figure 1. Position for nucleophilic attack on a vinylepoxide.
⇑
Corresponding authors.
E-mail address: giuliana.righi@uniroma1.it (G. Righi).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.05.085

3896
G. Righi et al. / Tetrahedron Letters 52 (2011) 3895–3896
(a)
O
(b)
O
uents on the heterocyclic ring. Moreover, considering the versatil-
R
OH
R
OH
R
O
ity of azide group and the possibility to further functionalize the
double bond, the obtained products are promising intermediates
for the preparation of highly functionalized chiral fragments.
Further work is currently in progress in order to extend this
methodology to vinyl aziridines.
R = n-C3H7; c-C6H11; Ph
(c)
O
R'
R
Acknowledgments
R' = COOEt, Ph, CN
Scheme 1. Reagents and conditions: (a) m-CPBA, CH2Cl2, rt, 90–95%; (b) TEMPO,
IBDA, CH2Cl2, rt, 68–87%; (c) (i) for R0 = CO2Et:TEPA, LiOH, THF, reflux, 89–92%; (ii)
for R0 = Ph:Ph3PCH2PhBr, LiOH, i-PrOH, rt, 59–75%; (iii) for R0 = CN:(EtO)2POCH2CN,
LiOH, THF, reflux, 63–86%.
We thank MIUR (Ministry of University andResearch, Rome) for
partial financial support (PRIN 2008: Stereoselective synthesis and
biological evaluation of new compounds active toward proteic tar-
gets involved in viral pathologies, cell growth, and apoptosis).
References and notes
Table 1
19
Azidolysis of vinylepoxides with TMSN3 and BF3ꢁOEt2
1. Olofsson, B.; Somfai, P. In Aziridines and Epoxides in Organic Synthesis; Yudin, A.
K., Ed.; Wiley-VCH: Weinheim, 2006; pp 315–443.
2. Yaragorla, S.; Muthyala, L. Tetrahedron Lett. 2010, 51, 467–470.
3. Chandrasekhar, S.; Parida, B. B.; Rambabu, C. J. Org. Chem. 2008, 73, 7826–7828.
4. Baylon, C.; Prestat, G.; Heck, M. P.; Mioskowsky, C. Tetrahedron Lett. 2000, 41,
3833–3835.
5. Murphy, S. T.; Bencsik, J. R.; Johnson, C. R. Org. Lett. 1999, 1, 1483–1485.
6. Ehara, T.; Fujii, M.; Ono, M.; Akita, H. Tetrahedron: Asymmetry 2010, 21, 494–
499.
TMSN3
OH
N3
BF3.OEt2
R'
R'
O
2
R'
+
R
R
3
R
CH2Cl2
rt
N3
OH
C-2 opened
C-3 opened
product
product
7. Afarinkia, K.; Bahar, A. Tetrahedron: Asymmetry 2005, 16, 1239–1245.
8. (a) Podeschwa, M. A. L.; Plettenburg, O.; Altenbach, H. J. Org. Biomol. Chem.
2003, 1, 1919–1929; (b) Bellomo, A.; Bonilla, J. B.; López-Prados, J.; Martín-
Lomas, M.; Gonzalez, D. Tetrahedron: Asymmetry 2009, 20, 2061–2064.
9. (a) Olofsson, B.; Somfai, P. J. Org. Chem. 2003, 68, 2514–2517; (b) Nugent, T. C.;
Hudlicky, T. J. Org. Chem. 1998, 63, 510–520.
Entry Substrate
R
R0
Isomer
ratio
Product Time Yield
(h) (%)
C2:C3a
1
2
1
3
n-
C3H7
c-
CO2Et
CO2Et
>95:5
>95:5
2
4
1
96
10. Miura, T.; Kurihara, K.; Furuuchi, T.; Yoshida, T.; Ajito, K. Bioorg. Med. Chem.
2008, 16, 3985–4002.
1.3
96
11. Nagumo, S.; Mizukami, M.; Wada, K.; Miura, T.; Bando, H.; Kawahara, N.;
Hashimoto, Y.; Miyashita, M.; Akita, H. Tetrahedron Lett. 2007, 48, 8558–8561.
12. (a) Miyashita, M.; Mizutani, T.; Tadano, G.; Iwata, Y.; Miyazawa, M.; Tanino, K.
Angew. Chem., Int. Ed. 2005, 44, 5094–5097; (b) Marié, J.-C.; Courillon, C.;
Malacria, M. Arkivoc 2007, 277–292 (part V).
13. In 2002, Sharpless and Meldal independently discovered that copper catalysis
dramatically accelerates the rate of formal cycloaddition between azides and
terminal alkynes; ‘click chemistry’ describe a set of chemical reactions that
efficiently link two components in high yield and with minimal by products (a)
Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem., Int. Ed.
2002, 41, 2596–2599; (b) Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org.
Chem. 2002, 67, 3057–3064; (c) Huisgen, R. Proc. Chem. Soc. 1961, 357–396.
14. Righi, G.; Bonini, C. In Targets in Heterocyclic System; Attanasi, O., Spinelli, D.,
Eds.; Società Chimica Italiana: Roma, 2000; 4, pp 139–165.
C6H11
Ph
n-
C3H7
c-
C6H11
n-
C3H7
c-
C6H11
n-
C3H7
c-
3
4
5
8
CO2Et
CN
40:60
>95:5
6:7
9
3
1.2
78b
87
5
6
7
8
9
10
12
14
16
19
CN
Ph
Ph
>95:5
>95:5
>95:5
55:45
52:48
11
1
94
13
4
52
15
4.1
3.5
4.3
48
n-
C5H11
n-
17:18
20:21
75b
68b
15. Manuscript in preparation.
C6H11
C5H11
16. Rodrigues, J. A. R.; Milagre, H. M. S.; Milagre, C. D. F.; Moran, P. J. S. Tetrahedron:
Asymmetry 2005, 16, 3099–3106.
17. Our preliminary studies were restricted, for convenience, to racemic
compounds.
a
Ratio determined by 1H NMR of the crude product.
Yields of the isomeric mixture.
b
18. Antonioletti, R.; Bonadies, F.; Ciammaichella, A.; Viglianti, A. Tetrahedron 2008,
64, 4644–4648.
19. (a) Lattanzi, A.; Orelli, L. R.; Barone, P.; Massa, A.; Iannece, C.; Scettri, A.
Tetrahedron Lett. 2003, 44, 1333–1337; (b) Bonadies, F.; Scettri, A.; Di Campli, C.
Tetrahedron Lett. 1996, 37, 1899–1900.
position of the azide group was established by spin–spin decou-
pling experiments and the anti configuration was assigned based
on a SN2 mechanism, since only one diastereisomer was detected.
As shown in Table 1, the steric hindrance of R did not affect the
regio-and stereoselectivity of the epoxide ring opening. Only with
R = Ph (entry 3) the reaction proceeded with poor regioselectivity,
as already noted for several other phenyl substituted epoxides,20
due to the simultaneous presence of the activated benzylic
position.
General procedure: To a stirred solution of the vinylepoxides (1 mmol) in dry
CH2Cl2 (3 mL) were added TMSN3 (1 mmol) and BF3ꢁOEt2 (2 mmol) dropwise
and the solution was stirred at room temperature. Then, the reaction was
diluted with CH2Cl2, the organic phase was washed with NaHCO3 (3 mL), brine
(3 ꢂ 3 mL), dried over Na2SO4 and the solvent removed under reduced
pressure. Often the crude product was characterized without further
purification, unless otherwise stated. All reactions were carried out under
nitrogen and were monitored by TLC.
NMR data for representative compounds: Compound 2: 1H NMR (300 MHz,
CDCl3): d 0.84 (t, J = 7.1 Hz, 3H), 1.22 (t, J = 7.1 Hz, 3H), 1.25–1.47 (m, 4H), 2.95
(b s, 1H, OH), 3.68 (m, 1H), 4.01 (m, 1H), 4.13 (q, J = 7.1 Hz, 2H), 6.01 (d,
J = 15.9 Hz, 1H), 6.82 (dd, J = 6.6, 15.9 Hz, 1H). 13C NMR (75.4 MHz, CDCl3): d
13.3; 13.6; 18.3; 34.2; 60.3; 66.9; 72.2; 124.7; 140.4; 165.1.
Regarding the effect of the R0 group, a complete regioselective
nucleophilic attack in the allylic position was observed when an
electron-withdrawing substituent on the double bond (R0 = COOEt,
CN and Ph; entries 1, 2, 4–7), although for R0 = Ph the ring opening
occurred in moderate yields and longer reaction time.
Finally, when a poor electron-withdrawing group was present
on the double bond (R0 = Alk; entries 8 and 9), the azidolysis oc-
curred without any regioselectivity.
In summary we have developed a new, simple, and mild regio-
and stereocontrolled azidolysis of vinyl epoxides. The method
appears of general value and works very well particularly in the
presence of electron poor olefins, regardless of the size of substit-
Compound 9: 1H NMR (300 MHz, CDCl3): d 0.92 (t, J = 7.0 Hz, 3H), 1.25–1.55
(m, 4H), 3.75 (q, J = 4.4 Hz, 1H), 4.06 (ddd, J = 1.4 4.4 6.4 Hz, 1H), 5.66 (dd,
J = 1.4 16.3 Hz, 1H), 6.70 (dd, J = 6.4 16.3 Hz, 1H). 13C NMR (75.4 MHz, CDCl3): d
13.7; 18.6; 34.7; 67.1; 72.6; 103.3; 116.7; 148.1.
Compound 13: 1H NMR (300 MHz, CDCl3): d 0.83 (t, J = 7.4 Hz, 3H), 1.57–1.87
(m, 4H), 3.90 (dd, J = 1.8, 7.1 Hz, 1H), 4.03 (dd, J = 6.8, 7.3 Hz, 1H), 5.82 (dd,
J = 7.2, 11.4 Hz, 1H), 6.77 (d, J = 11.4 Hz, 1H), 7.22–7.47 (m, 5H). 13C NMR
(75.4 MHz, CDCl3): d 13.5; 18.3; 36.5; 68.3; 71.7; 122.1;126.4; 127.3; 127.5;
131.9; 152.1.
20. Bonini, C.; Righi, G.; Rumboldt, G. Tetrahedron 1995, 48, 13401–13404.