Lewis acid-catalyzed hetero Diels-Alder cycloadditions of 3-alkyl, 3-phenyl and 3-carboxylated 2H-azirines

Article abstract of DOI:10.1016/S0040-4039(01)02042-1

Activation by Lewis acids of 3-alkyl and 3-phenyl 2H-azirines promotes their participation in hetero Diels-Alder reactions with a variety of dienes. This methodology circumvents the previous requirement of an electron-withdrawing carboxyl moiety at the 3-position of the 2H-azirine.

Full text of DOI:10.1016/S0040-4039(01)02042-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 9289–9291
Lewis acid-catalyzed hetero Diels–Alder cycloadditions of
3-alkyl, 3-phenyl and 3-carboxylated 2H-azirines
Colin A. Ray, Erik Risberg and Peter Somfai*
Organic Chemistry, Department of Chemistry, The Royal Institute of Technology, S-100 44 Stockholm, Sweden
Received 7 September 2001; revised 25 October 2001; accepted 30 October 2001
Abstract—Activation by Lewis acids of 3-alkyl and 3-phenyl 2H-azirines promotes their participation in hetero Diels–Alder
reactions with a variety of dienes. This methodology circumvents the previous requirement of an electron-withdrawing carboxyl
moiety at the 3-position of the 2H-azirine. © 2001 Elsevier Science Ltd. All rights reserved.
azaphilicity, as highlighted by Kobayashi.8 Heating an
The furnishing via hetero Diels–Alder chemistry of
equimolar mixture of azirine 1 with 2 at 75°C in toluene
in the absence of a Lewis acid after 72 h provided only
starting materials (Table 1, entry 1). This failure to
nitrogen containing cycloadducts, which have potential
as synthetic intermediates in alkaloid synthesis, is a
valuable manoeuvre.1 While the use of aza-dienes is
well established,2 incorporation of the nitrogen het-
eroatom as part of the 2p moiety of the [4+2] process is
limited for the most part to imines bearing electron-
withdrawing groups.3 The strained, electron-rich car-
bonꢀnitrogen double bond in the 2H-azirine is more
reactive than the corresponding double bond in an
imine4 and, while 2H-azirines participate in reversed
electron-demand Diels–Alder reactions,5 there are only
a few publications describing the normal electron-
demand Diels–Alder reaction of 2H-azirines,6 the
requirement being an activation of the three-membered
ring by an electron-withdrawing substituent. An obvi-
ous strategy to circumvent this structural limitation,
and thus broadening the scope of the process, would be
to use Lewis acids for activation of the CꢁN moiety in
the three-membered ring. However, care has to be
exercised since it is known that azirines are prone to
acid-catalyzed decomposition.
R3
R3
N
Lewis
acid
+
N
R1
R2
R2
R1
Scheme 1. Lewis acid-catalyzed Diels–Alder cycloaddition of
a 3-substituted 2H-azirine.
Table 1. Diels–Alder reactions between 1 and 2 to give 3
in the presence of Lewis acidsa
OMe
N
OMe
N
Ph
TMSO
TMSO
Ph
2
1
3
Entry
Lewis acid
Temp. (°C) Time (h)
Yield (%)b
Herein is described the results of our preliminary inves-
tigation of the Lewis acid-catalyzed hetero Diels–Alder
reactions of 3-alkyl, 3-phenyl and 3-carboxylated 2H-
azirines with some model dienes (Scheme 1).
1
2
3
4
5
6
7
8
–
75
75
75
75
75
−70
−70
−70
72
8
6
12
12
0.3
0
40
55
30
35
42
ZnCl2
YbCl3
ScCl3
CuCl2
BF3·Et2Oc
InCl3
To identify suitable catalysts, 2H-azirine 17 and Dan-
ishefsky’s diene 2 were chosen as a model [4+2] system,
while the Lewis acid candidates were selected for their
d
48
12
–
–
d
Cu(OTf)2
a Reactions were conducted in PhMe using 0.3 equiv. Lewis acid,
unless otherwise stated.
b Isolated product. No starting material was recovered.
c Conducted in CH2Cl2 with 0.2 equiv. BF3·Et2O.
d The reaction was conducted until decomposition of 1 was evident.
* Corresponding author. Tel.: +46 8 790 6960; fax: +46 8 791 2333;
e-mail: somfai@kth.se
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02042-1

9290
C. A. Ray et al. / Tetrahedron Letters 42 (2001) 9289–9291
effect a cycloaddition indicated the expected lack of
reactivity exhibited by 1 in the normal electron-demand
[4+2] cycloaddition. However, treatment of a mixture of
azirine 1 and diene 2 with 0.3 equiv. of ZnCl2, YbCl3,
ScCl3 or CuCl2 at 75°C provided endo cycloadduct 39
exclusively and in moderate yield (Table 1, entries 2–5).
The boron trifluoride-catalyzed cycloaddition was a
notable exception (Table 1, entry 6). In this case treat-
ment of a mixture of 1 and 2 with 0.2 equiv. of the
Lewis acid provided after typically 0.3 h at −70°C,
aziridine 3 in 42% yield. Other Lewis acids, such as
InCl3 and Cu(OTf)2, failed to promote the cycloaddi-
tion (Table 1, entries 7 and 8).
The regiochemistry associated with ring-opening
bicyclic aziridines appears to be a complex phe-
nomenon.10 Aziridine 3 could conceivably experience
attack of a nucleophile at either C6 or C7. It has
previously been shown that when systems related to 3
are subjected to an acidic medium the corresponding
dihydroazepinone was isolated, in which all stereo-
chemical information created during the preceding
cycloaddition was destroyed.6 In the present case, treat-
ment of 3 with 2 M HCl resulted in selective cleavage of
the aziridine providing 12 via protonation of the
aziridine nitrogen and selective attack of chloride,
seemingly favored over hydroxyl, as the only product
(Scheme 2).9 Under identical conditions 11 provided the
bicyclic compound 13.9 When subjected to dilute
perchloric acid in water 11 experienced selective nucle-
ophilic attack of hydroxyl to provide amino alcohol 14
in 90% yield.9 These results suggest that the observed
selective aziridine ring-cleavage may occur with a range
of nucleophilic species.
To investigate further the scope of this Lewis acid-cata-
lyzed process the cycloaddition of a series of azirines 1,
4 and 5 with dienes 6–8 was studied (Table 2 and Fig.
1). Reaction of 1 with 6 and 4 with 7 gave exclusively
endo isomers 9 and 10,9 respectively, in moderate yields
(Table 2, entries 1 and 2). Interestingly, each individual
transformation requires careful optimization of the
reaction temperature and catalyst. Both ZnCl2 and
Rh2(OAc)4 promote the cycloaddition of ester deriva-
tive 5 and cyclopentadiene 8 at reduced temperatures to
afford endo bicycle 11 (Table 2, entries 3 and 4).9 The
corresponding thermal process, in comparison, only
proceeds at room temperature, indicating the beneficial
influence of the Lewis acids on the reaction rate (Table
2, entry 5).
The Lewis acid-mediated activation of the car-
bonꢀnitrogen double bond in 2H-azirines described
herein is a novel procedure illustrating that the previous
requirement of an activating 3-subtituent to promote
participation of the 2H-azirine in normal electron-
demand Diels–Alder chemistry can, if so required, be
avoided. It has also been shown that 3-carboxylated
azirines, previously believed to be unstable to such
conditions, can be activated by Lewis acids, promoting
a Diels–Alder reaction at sub-zero temperature. The
N
N
N
OMe
Ph
BnO2C
NH
Ph
i
N
Ph
1
4
5
O
TMSO
OMe
Ph
Cl
12
3
Me3SiO
7
6
8
ii
NH
CO2Bn
OMe
N
N
CO2Bn
Cl
N
13
Ph
Me3SiO
iii
10
NH
Ph
9
CO2Bn
11
N
CO2Bn
HO
14
11
Scheme 2. Reagents and conditions: (i) 2 M HCl, THF, rt,
Figure 1. Azirines, dienes and products in Table 2.
80%; (ii) 2 M HCl, THF, rt, 85%; (iii) HClO4, THF, rt, 90%.
Table 2. Lewis acid-catalyzed hetero Diels–Alder reactionsa
Entry
Diene/Azirine
Lewis acid
Temp. (°C)
Time (h)
Product, yield (%)b
1
2
3
4
5
6/1
7/4
8/5
8/5
8/5
ZnCl2
YbCl3
ZnCl2
75
90
−20
−45
Rt
6
72
12
24
24
9, 50
10, 36
11, 35
11, 35
11, 45
c
d
Rh2(OAc)4
c
–
a Reactions were conducted in PhMe using 0.3 equiv. Lewis acid, unless otherwise stated.
b Isolated product.
c Conducted in Et2O.
d Conducted in CH2Cl2.

C. A. Ray et al. / Tetrahedron Letters 42 (2001) 9289–9291
9291
References
yields reported are moderate and we are endeavoring
to improve this element of the methodology. How-
ever, the possibility now exists to conduct Diels–Alder
chemistry using a greater variety of 3-substituted 2H-
azirines via Lewis acid-mediated catalysis. Work is in
progress to investigate the scope of this process.
1. Carruthers, W. Cycloaddition Reactions in Organic Synthe-
sis; Pergamon: Oxford, 1990.
2. Boger, D. L.; Weinreb, S. M. In Hetero Diels–Alder
Methodology in Organic Chemistry; Academic Press: San
Diego, 1987; Chapter 9, pp. 239–299
3. (a) Weinreb, S. M. In Comprehensive Organic Synthesis;
Trost, B. M.; Fleming, I.; Paquette, L. A., Eds.; Pergamon:
Oxford, 1991; Vol. 3, p. 141; (b) Buonora, P.; Olsen, J.-C.;
Oh, T. Tetrahedron 2001, 57, 6099.
4. (a) Nair, V. In Small Ring Heterocycles, Part 1; Hassner,
A., Ed.; Wiley-Interscience: New York, 1983; p. 213; (b)
Palacios, F.; Ochoa de Retana, A. M.; Martinez de
Marigorta, E.; de los Santos, J. M. Eur. J. Org. Chem. 2001,
13, 2401.
General procedure: synthesis of 3 catalyzed by YbCl3:
To a solution of azirine 1 (23 mg, 0.19 mmol) in
toluene (3 mL) under a nitrogen atmosphere at ambi-
ent temperature, was added YbCl3 (16 mg, 0.06
mmol, 0.3 equiv.). After 5 min a solution of diene 2
(33 mg, 0.2 mmol) in toluene (1 mL) was added and
the reaction mixture was heated to 75°C. The reac-
tion temperature was maintained until TLC indicated
the absence of 1 (6 h). Once cool, the reaction mix-
ture was washed with sat. aq. NaHCO3 (2×4 mL)
and the aqueous phases were extracted with CH2Cl2
(2×5 mL). The combined organic layers were dried
(MgSO4) and evaporated. Filtration of the residue
through basic alumina (pentane:ethyl acetate 7:1) gave
3 (31 mg, 55%) as a yellow oil. Rf=0.70 (7:1 pen-
5. Boger, D. L.; Weinreb, S. M. Hetero Diels–Alder Method-
ology in Organic Chemistry; Academic Press: San Diego,
1987; Chapter 2, pp. 57–59.
6. (a) Bhullar, P.; Gilchrist, T. L.; Maddocks, P. Synthesis
1997, 271; (b) Alves, M. J.; Gilchrist, T. L. Tetrahedron Lett.
1998, 39, 7579; (c) Alves, M. J.; Gilchrist, T. L. J. Chem.
Soc., Perkin Trans. 1 1998, 299; (d) Alves, M. J.; Bickley,
J. F.; Gilchrist, T. L. J. Chem. Soc., Perkin Trans. 1 1999,
1399; (e) Gilchrist, T. L. Aldrichim. Acta 2001, 34, 51.
7. Azirines 1, 4 and 5 were prepared by dissolving the vinyl
azide precursors in pentane or ether and heating at 125°C
in a sealed tube. This method is a modification of a literature
procedure: (a) Hortmann, A. G.; Robertson, D. A.; Gillard,
B. K. J. Org. Chem. 1972, 37, 322; (b) Gilchrist, T. L.;
Mendoca, R. Synlett 2000, 12, 1843.
1
tane:ethyl acetate); H NMR (400 MHz, CDCl3): l=
7.47–7.23 (m, 5 H), 5.07 (br. s, 1 H), 4.66 (d, J=1.5,
1 H), 3.68 (s, 3 H), 2.56 (d, J=17.3 Hz, 1 H), 2.52
(d, J=17.5 Hz, 1 H), 2.24 (s, 1 H), 1.69 (s, 1 H),
0.00 (s, 9 H); 13C NMR (100 MHz, CDCl3): l=
147.5, 128.8, 128.3, 126.7, 125.9, 99.9, 88.1, 56.1,
40.0, 32.1, 31.3, 0.00; IR (neat):wmax=2100, 1696,
1395, 1265, 1073, 913; MS (CI, NH3): m/z (%) 290
[M+H]+; HRMS calcd for C16H23NO2Si [M+H]+:
290.1576; found: 290.1581.
8. Kobayashi, S.; Busujima, T.; Nagayama, S. Chem. Eur. J.
2000, 6, 3491.
9. All new compounds showed spectroscopic data in complete
agreement with the assigned structures (1H, 13C NMR,
HRMS). The endo stereochemistry of 3, 9–11 were shown
by COSY experiments and analyzing the relevant coupling
constants. For analogous assignments, see Ref. 6.
10. (a) Kametani, T.; Honda, T. In Advances in Heterocyclic
Chemistry; Katritsky, A. L., Ed.; Academic Press: London,
1986; Vol. 39, p. 232; (b) Tanner, D. Angew. Chem., Int.
Ed. Engl. 1994, 33, 599; (c) McCoull, W.; Davis, F. A.
Synthesis 2000, 1347.
Acknowledgements
The authors thank the Swedish Foundation for
Strategic Research (Selchem) for financial support and
Dr. U. Jacobsson for assistance with NMR measure-
ments.