The 2H-azirine 1 acts as an effective radical acceptor for
secondary and tertiary alkyl iodides mediated by triethylborane.
The addition proceeds with high regio- and diastereo-selectivity

Alves, Maria José Chão

Fortes, Gil

Guimaraes, Emanuel

Lemos, A.

Sapientia

LETTER 1403Intermolecular Alkyl Radical Addition to Methyl 2-(2,6-Dichlorophenyl)-2H-azirine-3-carboxylateIntermolecular Alkyl Radical Addition to Methyl 2-(2,6-Dichlorophenyl)-2H-azirine-3-carboxylateM. José Alves,b Gil Fortes,b Emanuel Guimarães,a Américo Lemos*aa Departamento de Química e Bioquímica, Faculdade de Ciências e Tecnologia, Universidade do Algarve, Campus de Gambelas, 8000-117 Faro, PortugalFax +351(289)819403; E-mail: alemos@ualg.ptb Escola de Ciências, Departamento de Química, Universidade do Minho, Campus Gualtar, 4710-057 Braga, PortugalReceived 15 May 2003Synlett 2003, No. 10, Print: 05 08 2003. Art Id.1437-2096,E;2003,0,10,1403,1406,ftx,en;G07603ST.pdf. © Georg Thieme Verlag Stuttgart · New YorkAbstract: The 2H-azirine 1 acts as an effective radical acceptor forsecondary and tertiary alkyl iodides mediated by triethylborane.The addition proceeds with high regio- and diastereo-selectivity.Key words, 2H-azirine, intermolecular radical addition, triethyl-boraneWhen compared with other functional groups, free radicaladditions to C=N have received much less attention. In re-cent years, however, much work has been carried out onintramolecular (cyclisation) radical addition to imines,oxime ethers and hydrazones.1 More recently, intermolec-ular radical additions to C=N bond have become an estab-lished and powerful method for the formation of C–Cbonds,1,2 and studies have been made in order to bringabout the addition in a stereocontrolled manner.3It has been shown that 2H-azirine-3-carboxylates are par-ticularly good electrophiles, in reactions with a variety ofelectron rich dienes and nucleophiles,4 as a consequenceof the conjugative effect of the ring strain and extra acti-vation by the ester group. From a side and fortuitous (sin-gle) reaction with tetrahydrofuranyl radical, it waspostulated that azirines could be susceptible to radicaladdition.4cThese facts provided the basis for the exploration of thepotential of 2H-azirine-3-carboxylates to act as intermo-lecular radical acceptors.In our preliminary experiments, we submitted the azirine1 to classical peroxide and tin hydride/AIBN conditions(Table 1, entries 1, 2). Although the disappearance of theazirine could be observed, the reaction product consistedof a complex mixture from which no pure compoundcould be obtained. It has been demonstrated that intermo-lecular radical reactions can be efficiently carried out un-der tin or peroxide free conditions.5 The initial sets ofexperiments with triethylborane did not produce better re-sults, only polymer like material being recovered from thereaction (entries 3, 4). However at –40 °C, the azirine wassmoothly and cleanly converted to the correspondent azir-idine in moderate to good yields (entries 5–8). A stronglyactivating Lewis acid was not needed, evidently due to thehigh reactivity of the azirine 1 rather than the role of tri-ethylborane, (acting as radical initiator and terminator butalso as Lewis acid).1a,2h,5 The reaction, with these iodides,proceeded with a high degree of selectivity. Neither ethy-lated by-products could be detected (Scheme 1) whenalkyl iodides different from ethyl iodide were used, nor N-ethylated or bis C- and N-ethylated products, as it hasbeen established with other imines.2c,2h,2i,2k  These resultsare, to some extent, in good agreement with the nucleo-philicity (and/or) stability of the radical involved.Scheme 1 i) Et3B, RI, CH2Cl2, –40 °C, 30 min.These reactions proceeded with a high degree of stereose-lectivity; only one single diastereoisomer could be detect-ed as a consequence of the addition, which is controlledby the position of the aryl group and occurs from the lesshindered face of the azirine ring. An X-ray single crystalstructure of azirine 2b is shown in Figure 1.6Having these results in hand, we then tried to apply thesame conditions of intermolecular radical addition to oth-er iodides (Table 1, entries 9–19; Scheme 2). With 4-chloroiodobenzene, cleanly, aziridine 2a was the only re-action product, in 53% yield (entry 9). Similarly, with (2-iodoethyl)benzene, n-hexyl, n-octyl and allyliodide, theaziridine 2a8 was isolated (in these cases the reaction wasnot so clean and other complicated mixtures were also iso-lated from the reaction, entries 10–13 and 16).12a : R = Et (71%)b : R= i-Pr (82%)c :  R= t-Bu (89%)d :  R= Cyclohexyl (79%i)NOOClClRHNOOClCl1404 M. J. Alves et al. LETTERSynlett 2003, No. 10, 1403–1406 © Thieme Stuttgart · New YorkScheme 2 i) Et3B, CH2Cl2, –40 ºC.These results where rather surprising and puzzling, be-cause they not only contrast with the good results previ-ously described (entries 5–8) but also with the resultsobtained in the absence of any alkyl iodide (entry 20). Io-domethyl methyl ether and allyl iodide constituted partic-ular cases. Even at much lower temperatures, the reactionwith iodomethyl methyl ether was very fast, but the prod-uct consisted of polymer like material (entries 17–19). Onthe other hand, with allyl iodide the reaction at lower tem-peratures was slow and poor (entries 13 and 16) and athigher temperatures only polymer like material was iso-lated (entries 14, 15).Under the conditions that we have investigated, the effi-ciency of the intermolecular radical addition to the azirine1 increases in the order primary < secondary < tertiaryalkyl iodide, which is usual for cyclic chain reactions,where the radical formation, its addition and the trappingof the adduct radical governs the chain.9 The rate of ab-straction of iodine atoms versus addition at the p-bond byethyl radicals (the chain carriers, Scheme 3), will governthe process and the efficiency of the desired reaction. Inthe cases where the abstraction is not fast enough (the useof lower temperatures, compelled by the high reactivity ofthe azirine, may slow down the process2c even more), theformation of the ethyl aziridine will be prevalent. Presum-ably, this is what happens with n-hexyl, n-octyl, phenethyland chlorophenyl iodides. With allyl iodide, possibly, thelow reactivity of its corresponding radical towards the p-bond is the main factor associated to the results obtained.We also briefly explored some variables such as solventand radical initiator. The addition to the reaction mixtureof 1 equivalent n-Bu3SnH (entry 21), or the use of tolueneFigure 1 X-Ray crystal structure of aziridine 2b.NOOClClRINOOClClH12ai)R = 4-chlorobenzene (53%)    = CH2CH2Ph  (45%)    = n-C6H13  (38%)    = n-C8H17  (7%)    = allyl (-)Table 1 Radical Additions to Azirine 1En-tryRadical InitiatorTempera-tureSolvent Substrate Prod-uctYield (%)1 Benzoyl PeroxideReflux THF EtI a)2 AIBN/nBu3SnHReflux THF EtI a)3 Et3B Ambient CH2Cl2 EtI b)4 Et3B –5–0 ºC CH2Cl2 EtI b)5 Et3B –40 ºC CH2Cl2 EtI 2a 716 Et3B –40 ºC CH2Cl2 i-PrI 2b 827 Et3B –40 ºC CH2Cl2 t-BuI 2c 898 Et3B –40 ºC CH2Cl2 Iodocyclohex-ane2d 799 Et3B –40 ºC CH2Cl2 4-Chloroiodo-benzene2a 5310 Et3B –40 ºC CH2Cl2 (2-Iodoethyl)benzene2a 4511 Et3B –40 ºC CH2Cl2 1-Iodooctane 2a 712 Et3B –40 ºC CH2Cl2 1-Iodohexane 2a 3813 Et3B –40 ºC CH2Cl2 Allyl iodidec) 2a d)14 Et3B r.t. CH2Cl2 Allyl iodide b)15 Et3B –5 ºC CH2Cl2 Allyl iodide b)16 Et3B –20 ºC CH2Cl2 Allyl iodidee) 2a d)17 Et3B –40 ºC CH2Cl2 MeOCH2I b)18 Et3B –70 ºC CH2Cl2 MeOCH2I b)19 Et3B –100 ºC CH2Cl2 MeOCH2I b)20 Et3B –40ºC CH2Cl2 None d)21 Et3B/nBu3SnH–40 ºC CH2Cl2 EtI 2a 3722 Et3B –40 ºC Toluene Iodocyclohex-ane2d 4523 ZnEt2 –40 ºC CH2Cl2 i-PrI –24 ZnMe2 –40 ºC CH2Cl2 i-PrI –a Complex mixture without isolable product.b Polymer like product.c 3 h Reaction.d Complex mixture from which 2a was isolated in very low yield.e Reaction time: 1.5 h.LETTER Intermolecular Alkyl Radical Addition to Methyl 2-(2,6-Dichlorophenyl)-2H-azirine-3-carboxylate 1405Synlett 2003, No. 10, 1403–1406 © Thieme Stuttgart · New Yorkas solvent (entry 22) did not bring advantages. The use ofdiethyl2h or dimethyl zinc,7 which have been successfullyapplied to intermolecular radical additions to imines,proved to be a complete failure as only degradation prod-ucts were identified (entries 23, 24).In summary, we have found that intermolecular radicaladdition of secondary and tertiary alkyl radicals to methyl2-(2,6-dichlorophenyl)-2H-azirine-3-carboxylate pro-ceeded in good yields and with high regio- and diastereo-selectivity. When the conjugation of high reactivity ofazirine and radical (e.g. methoxymethyl) is observed thereaction is (under the conditions used) incontrollable. Foriodides where the rate of iodine atom transfer is not sofast, a proper balance must be reached in order to avoidpolymerization (high reactivity of azirine) or the ethyl ad-dition from Et3B. The scope (generality) of the intermo-lecular radical additions as well the reactivity of otheractivated and unactivated 2H-azirines are under investiga-tion.Scheme 3 Plausible mechanism for the alkyl addition to 1.10AcknowledgmentThe present work has been supported by Fundação para a Ciência ea Tecnologia, Ministério da Ciência e do Ensino Superior, projectoPOCTI/32723/QUI/2000. Thanks are also expressed to Dr. T. L.Gilchrist for helpful discussions.References(1) For reviews see: (a) Friestad, G. K. Tetrahedron 2001, 57, 5461. (b) Naito, T. Heterocycles 1999, 50, 505. (c) Fallis, A. G.; Brinza, I. M. Tetrahedron 1997, 53, 17543.(2) For some examples see: (a) Miyabe, H.; Ueda, M.; Nishimura, A.; Naito, T. Org. Lett. 2002, 4, 131. (b) Kim, S.; Kavali, R. Tetrahedron Lett. 2002, 43, 7189. (c) Halland, N.; Jorgensen, K. A. J. Chem. Soc., Perkin Trans. 1 2001, 1290. (d) Miyabe, H.; Ueda, M.; Naito, T. J. Org. Chem. 2000, 65, 5043. (e) Bertrand, M. P.; Stephanie, C.; Feray, L.; Nouguier, R.; Perfetti, P. Tetrahedron 2000, 56, 3951. (f) Miyabe, H.; Ueda, M.; Yoshioka, N.; Yamakawa, K.; Naito, T. Tetrahedron 2000, 56, 2413. (g) Miyabe, H.; Fujishima, Y.; Naito, T. J. Org. Chem. 1999, 64, 2174. (h) Bertrand, M. P.; Feray, L.; Nouguier, R.; Perfetti, P. J. Org. Chem. 1999, 64, 9189. (i) Miyabe, H.; Ueda, M.; Yoshioka, N.; Naito, T. Synlett 1999, 465. (j) Miyabe, H.; Yamakawa, K.; Yoshioka, N.; Naito, T. Tetrahedron 1999, 55, 11209. (k) Miyabe, H.; Shibata, R.; Sangawa, M.; Ushiro, C.; Naito, T. Tetrahedron 1998, 54, 11431. (l) Miyabe, H.; Shibata, R.; Ushiro, C.; Naito, T. Tetrahedron Lett. 1998, 39, 631. (m) Miyabe, H.; Ushiro, C.; Naito, T. Chem. Commun. 1997, 1789.(3) (a) Miyabe, H.; Fujii, K.; Naito, T. Org. Biomol. Chem. 2003, 1, 381. (b) Friestad, G. K.; Qin, J. J. Am. Chem. Soc. 2001, 123, 9922. (c) Friestad, G. K.; Qin, J. J. Am. Chem. Soc. 2000, 122, 8329. (d) Bertrand, M. P.; Feray, L.; Nouguier, R.; Perfetti, P. Synlett 1999, 1148. (e) Miyabe, H.; Fujii, K.; Naito, T. Org. Lett. 1999, 1, 569. (f) Bertrand, M. P.; Feray, L.; Nouguier, R.; Stella, L. Synlett 1998, 780.(4) (a) Gilchrist, T. L. Aldrichimica Acta 2001, 34, 51. (b) Alves, M. J.; Azoia, N. G.; Bickley, J. F.; Fortes, A. G.; Gilchrist, T. L.; Mendonca, R. J. Chem. Soc., Perkin Trans. 1 2001, 2969. (c) Alves, M. J.; Gilchrist, T. L.; Sousa, J. H. J. Chem. Soc., Perkin Trans. 1 1999, 1305.(5) Review: Ollivier, C.; Renaud, P. Chem. Rev. 2001, 101, 3415.(6) CCDC 207633 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; fax:+44(1223)336033; e-mail: deposit@ccdc.cam.ac.uk.).(7) Yamada, K.; Fujihara, H.; Yamamoto, Y.; Miwa, Y.; Taga, T.; Tomioka, K. Org. Lett. 2002, 4, 3509.(8) Typical Procedure: A solution of triethylborane (15% in hexane) (0.4 mL, 6.12 mmol) was added to a mixture of methyl 2-(2,6-dichlorophenyl)-2H-azirine-3-carboxylate (0.3g, 1.23 mmol) and the alkyl iodide (12.4 mmol) in CH2Cl2 (20 mL) at –40 °C. The reaction was maintained at this temperature for 30 min and the mixture was then washed with a 10% aq solution of NaHCO3 the organic layer dried (Na2SO4) and evaporated. Flash chromatography (hexanes/EtOAc: 80/20) afforded the product.With iodoethane: Methyl 3-(2,6-dichlorophenyl)-2-ethylaziridine-2-carboxylate 2a, 0.24 g (71%), mp 53.0–54.5 °C (from toluene/CH2Cl2). (Found: C, 52.28; H, 4,92; N, 5,07. C12H13Cl2NO2 requires C, 52.57; H, 4.78; N, 5.11%). IR nmax = 1724, 1433, 1207, 777 cm–1. 1H NMR (300 MHz): d = 1.11 (3 H, t, J = 7.5 Hz), 1.52–1.64 (1 H, m, CH3HCH), 2.41–2.53 (2 H, m, CH3HCH and NH, integration became one after D2O shake), 3.12 (1 H, br s, H-3, turns into a sharp singlet after D2O shake), 3.57 (3 H, s,) 7.12–7.17 (1 H, m), 7.27–7.29 (2 H, m). MS (CI): m/z (%) = 274 (100), 276 (66), 278 (12) [(M + H)+].With 2-iodopropane: Methyl 3-(2,6-dichlorophenyl)-2-(1-methylethyl) aziridine-2-carboxylate 2b, 0.29 g (82%); mp 81.7–82.9 (from hexanes/EtOAc). (Found: C, 53.96; H, 5.47; N, 5.03; C13H15Cl2NO2 requires C, 54.18; H, 5.25; N, 4.86%). IR nmax = 3209, 2968, 1724, 1433, 1207, 775 cm–1. 1H NMR (300 Mz): d = 1.2 (9 H, s), 2.66 (1 H, br d, J = 7.3 Hz, aziridine NH), 3.28 (1 H, br d, J = 7.1 Hz, H-3), 3.47 (3 H, s) 7.10–7.16 (1 H, m), 7.25–7.28 (2 H, m). MS (CI): m/z (%) = 288 (100), 290 (66), 292 (12) [(M + H)+].BEt3O2NOOClClRBEt2EtR IBEt3Et INOOClClRRNOOClCl1406 M. J. Alves et al. LETTERSynlett 2003, No. 10, 1403–1406 © Thieme Stuttgart · New YorkWith 2-iodo-2-methylpropane: Methyl 3-(2,6-dichloro-phenyl)-2-(1,1-dimethylethyl)aziridine-2-carboxy-late 2c (0.33 g, 89%), as a low melting point solid. IR nmax = 3406, 2959, 1714, 1431, 1242, 774 cm–1. 1H NMR (300 Mz): d = 1.2 (9 H, s), 2.66 (1 H, bd, J = 7.3 Hz, aziridine NH), 3.28 (1 H, bd, J = 7.1 Hz, H-3), 3.47 (3 H, s) 7.10–7.16 (1 H, m), 7.25–7.28 (2 H, m).With iodocyclohexane: Methyl 3-(2,6-dichlorophenyl)-2-cyclohexylaziridine-2-carboxylate 2d, (0.32 g, 79%), mp 105.6–107.2 °C (from toluene/CH2Cl2), IR nmax = 3209, 2967, 1724, 1433, 1207, 775 cm–1. 1H NMR (300 Mz): d = 1.08–1.9 (10 H, multiplet), 2.29 (1 H, br t, J = 4.2 Hz), 2.54 (1 H, br s, NH), 3.28 (1 H, br s), 7.10–7.16 (1 H, m), 7.26–7.29 (2 H, m).(9) Giese, B. In Radicals in Organic Synthesis: Formation of Carbon-Carbon Bonds; Pergamon Press: Oxford, 1986.(10) Similar mechanisms, for borane mediated reactions, have been proposed, see references: 1a) p. 5488; 2c); 2i); 2j); 5) p. 3429; 9) p. 86.

Intermolecular alkyl radical addition to methyl 2-(2,6-Dichlorophenyl)-2H-azirine-3-carboxylate

Universidade do Algarve

LETTER 1403
Intermolecular Alkyl Radical Addition to Methyl 2-(2,6-Dichlorophenyl)-2H-
azirine-3-carboxylate
Intermolecular Alkyl Radical Addition to Methyl 2-(2,6-Dichlorophenyl)-2H-azirine-3-carboxylateM. José Alves,b Gil Fortes,b Emanuel Guimarães,a Américo Lemos*a
a Departamento de Química e Bioquímica, Faculdade de Ciências e Tecnologia, Universidade do Algarve, Campus de Gambelas, 
8000-117 Faro, Portugal
Fax +351(289)819403; E-mail: alemos@ualg.pt
b Escola de Ciências, Departamento de Química, Universidade do Minho, Campus Gualtar, 4710-057 Braga, Portugal
Received 15 May 2003
Synlett 2003, No. 10, Print: 05 08 2003. 
Art Id.1437-2096,E;2003,0,10,1403,1406,ftx,en;G07603ST.pdf. 
© Georg Thieme Verlag Stuttgart · New York
Abstract: The 2H-azirine 1 acts as an effective radical acceptor for
secondary and tertiary alkyl iodides mediated by triethylborane.
The addition proceeds with high regio- and diastereo-selectivity.
Key words, 2H-azirine, intermolecular radical addition, triethyl-
borane
When compared with other functional groups, free radical
additions to C=N have received much less attention. In re-
cent years, however, much work has been carried out on
intramolecular (cyclisation) radical addition to imines,
oxime ethers and hydrazones.1 More recently, intermolec-
ular radical additions to C=N bond have become an estab-
lished and powerful method for the formation of C–C
bonds,1,2 and studies have been made in order to bring
about the addition in a stereocontrolled manner.3
It has been shown that 2H-azirine-3-carboxylates are par-
ticularly good electrophiles, in reactions with a variety of
electron rich dienes and nucleophiles,4 as a consequence
of the conjugative effect of the ring strain and extra acti-
vation by the ester group. From a side and fortuitous (sin-
gle) reaction with tetrahydrofuranyl radical, it was
postulated that azirines could be susceptible to radical
addition.4c
These facts provided the basis for the exploration of the
potential of 2H-azirine-3-carboxylates to act as intermo-
lecular radical acceptors.
In our preliminary experiments, we submitted the azirine
1 to classical peroxide and tin hydride/AIBN conditions
(Table 1, entries 1, 2). Although the disappearance of the
azirine could be observed, the reaction product consisted
of a complex mixture from which no pure compound
could be obtained. It has been demonstrated that intermo-
lecular radical reactions can be efficiently carried out un-
der tin or peroxide free conditions.5 The initial sets of
experiments with triethylborane did not produce better re-
sults, only polymer like material being recovered from the
reaction (entries 3, 4). However at –40 °C, the azirine was
smoothly and cleanly converted to the correspondent azir-
idine in moderate to good yields (entries 5–8). A strongly
activating Lewis acid was not needed, evidently due to the
high reactivity of the azirine 1 rather than the role of tri-
ethylborane, (acting as radical initiator and terminator but
also as Lewis acid).1a,2h,5 The reaction, with these iodides,
proceeded with a high degree of selectivity. Neither ethy-
lated by-products could be detected (Scheme 1) when
alkyl iodides different from ethyl iodide were used, nor N-
ethylated or bis C- and N-ethylated products, as it has
been established with other imines.2c,2h,2i,2k  These results
are, to some extent, in good agreement with the nucleo-
philicity (and/or) stability of the radical involved.
Scheme 1 i) Et3B, RI, CH2Cl2, –40 °C, 30 min.
These reactions proceeded with a high degree of stereose-
lectivity; only one single diastereoisomer could be detect-
ed as a consequence of the addition, which is controlled
by the position of the aryl group and occurs from the less
hindered face of the azirine ring. An X-ray single crystal
structure of azirine 2b is shown in Figure 1.6
Having these results in hand, we then tried to apply the
same conditions of intermolecular radical addition to oth-
er iodides (Table 1, entries 9–19; Scheme 2). With 4-
chloroiodobenzene, cleanly, aziridine 2a was the only re-
action product, in 53% yield (entry 9). Similarly, with (2-
iodoethyl)benzene, n-hexyl, n-octyl and allyliodide, the
aziridine 2a8 was isolated (in these cases the reaction was
not so clean and other complicated mixtures were also iso-
lated from the reaction, entries 10–13 and 16).
1
2
a : R = Et (71%)
b : R= i-Pr (82%)
c :  R= t-Bu (89%)
d :  R= Cyclohexyl (79%
i)
N
O
O
Cl
Cl
R
H
N
O
O
Cl
Cl
1404 M. J. Alves et al. LETTER
Synlett 2003, No. 10, 1403–1406 © Thieme Stuttgart · New York
Scheme 2 i) Et3B, CH2Cl2, –40 ºC.
These results where rather surprising and puzzling, be-
cause they not only contrast with the good results previ-
ously described (entries 5–8) but also with the results
obtained in the absence of any alkyl iodide (entry 20). Io-
domethyl methyl ether and allyl iodide constituted partic-
ular cases. Even at much lower temperatures, the reaction
with iodomethyl methyl ether was very fast, but the prod-
uct consisted of polymer like material (entries 17–19). On
the other hand, with allyl iodide the reaction at lower tem-
peratures was slow and poor (entries 13 and 16) and at
higher temperatures only polymer like material was iso-
lated (entries 14, 15).
Under the conditions that we have investigated, the effi-
ciency of the intermolecular radical addition to the azirine
1 increases in the order primary < secondary < tertiary
alkyl iodide, which is usual for cyclic chain reactions,
where the radical formation, its addition and the trapping
of the adduct radical governs the chain.9 The rate of ab-
straction of iodine atoms versus addition at the p-bond by
ethyl radicals (the chain carriers, Scheme 3), will govern
the process and the efficiency of the desired reaction. In
the cases where the abstraction is not fast enough (the use
of lower temperatures, compelled by the high reactivity of
the azirine, may slow down the process2c even more), the
formation of the ethyl aziridine will be prevalent. Presum-
ably, this is what happens with n-hexyl, n-octyl, phenethyl
and chlorophenyl iodides. With allyl iodide, possibly, the
low reactivity of its corresponding radical towards the p-
bond is the main factor associated to the results obtained.
We also briefly explored some variables such as solvent
and radical initiator. The addition to the reaction mixture
of 1 equivalent n-Bu3SnH (entry 21), or the use of toluene
Figure 1 X-Ray crystal structure of aziridine 2b.
N
O
O
Cl
Cl
RI
N
O
O
Cl
Cl
H
1
2a
i)
R = 4-chlorobenzene (53%)
    = CH2CH2Ph  (45%)
    = n-C6H13  (38%)
    = n-C8H17  (7%)
    = allyl (-)
Table 1 Radical Additions to Azirine 1
En-
try
Radical 
Initiator
Tempera-
ture
Solvent Substrate Prod-
uct
Yield 
(%)
1 Benzoyl 
Peroxide
Reflux THF EtI a)
2 AIBN/
nBu3SnH
Reflux THF EtI a)
3 Et3B Ambient CH2Cl2 EtI b)
4 Et3B –5–0 ºC CH2Cl2 EtI b)
5 Et3B –40 ºC CH2Cl2 EtI 2a 71
6 Et3B –40 ºC CH2Cl2 i-PrI 2b 82
7 Et3B –40 ºC CH2Cl2 t-BuI 2c 89
8 Et3B –40 ºC CH2Cl2 Iodocyclohex-
ane
2d 79
9 Et3B –40 ºC CH2Cl2 4-Chloroiodo-
benzene
2a 53
10 Et3B –40 ºC CH2Cl2 (2-Iodoethyl)
benzene
2a 45
11 Et3B –40 ºC CH2Cl2 1-Iodooctane 2a 7
12 Et3B –40 ºC CH2Cl2 1-Iodohexane 2a 38
13 Et3B –40 ºC CH2Cl2 Allyl iodide
c) 2a d)
14 Et3B r.t. CH2Cl2 Allyl iodide b)
15 Et3B –5 ºC CH2Cl2 Allyl iodide b)
16 Et3B –20 ºC CH2Cl2 Allyl iodide
e) 2a d)
17 Et3B –40 ºC CH2Cl2 MeOCH2I b)
18 Et3B –70 ºC CH2Cl2 MeOCH2I b)
19 Et3B –100 ºC CH2Cl2 MeOCH2I b)
20 Et3B –40ºC CH2Cl2 None d)
21 Et3B/
nBu3SnH
–40 ºC CH2Cl2 EtI 2a 37
22 Et3B –40 ºC Toluene Iodocyclohex-
ane
2d 45
23 ZnEt2 –40 ºC CH2Cl2 i-PrI –
24 ZnMe2 –40 ºC CH2Cl2 i-PrI –
a Complex mixture without isolable product.
b Polymer like product.
c 3 h Reaction.
d Complex mixture from which 2a was isolated in very low yield.
e Reaction time: 1.5 h.
LETTER Intermolecular Alkyl Radical Addition to Methyl 2-(2,6-Dichlorophenyl)-2H-azirine-3-carboxylate 1405
Synlett 2003, No. 10, 1403–1406 © Thieme Stuttgart · New York
as solvent (entry 22) did not bring advantages. The use of
diethyl2h or dimethyl zinc,7 which have been successfully
applied to intermolecular radical additions to imines,
proved to be a complete failure as only degradation prod-
ucts were identified (entries 23, 24).
In summary, we have found that intermolecular radical
addition of secondary and tertiary alkyl radicals to methyl
2-(2,6-dichlorophenyl)-2H-azirine-3-carboxylate pro-
ceeded in good yields and with high regio- and diastereo-
selectivity. When the conjugation of high reactivity of
azirine and radical (e.g. methoxymethyl) is observed the
reaction is (under the conditions used) incontrollable. For
iodides where the rate of iodine atom transfer is not so
fast, a proper balance must be reached in order to avoid
polymerization (high reactivity of azirine) or the ethyl ad-
dition from Et3B. The scope (generality) of the intermo-
lecular radical additions as well the reactivity of other
activated and unactivated 2H-azirines are under investiga-
tion.
Scheme 3 Plausible mechanism for the alkyl addition to 1.10
Acknowledgment
The present work has been supported by Fundação para a Ciência e
a Tecnologia, Ministério da Ciência e do Ensino Superior, projecto
POCTI/32723/QUI/2000. Thanks are also expressed to Dr. T. L.
Gilchrist for helpful discussions.
References
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5461. (b) Naito, T. Heterocycles 1999, 50, 505. (c) Fallis, 
A. G.; Brinza, I. M. Tetrahedron 1997, 53, 17543.
(2) For some examples see: (a) Miyabe, H.; Ueda, M.; 
Nishimura, A.; Naito, T. Org. Lett. 2002, 4, 131. (b) Kim, 
S.; Kavali, R. Tetrahedron Lett. 2002, 43, 7189. 
(c) Halland, N.; Jorgensen, K. A. J. Chem. Soc., Perkin 
Trans. 1 2001, 1290. (d) Miyabe, H.; Ueda, M.; Naito, T. J. 
Org. Chem. 2000, 65, 5043. (e) Bertrand, M. P.; Stephanie, 
C.; Feray, L.; Nouguier, R.; Perfetti, P. Tetrahedron 2000, 
56, 3951. (f) Miyabe, H.; Ueda, M.; Yoshioka, N.; 
Yamakawa, K.; Naito, T. Tetrahedron 2000, 56, 2413. 
(g) Miyabe, H.; Fujishima, Y.; Naito, T. J. Org. Chem. 1999, 
64, 2174. (h) Bertrand, M. P.; Feray, L.; Nouguier, R.; 
Perfetti, P. J. Org. Chem. 1999, 64, 9189. (i) Miyabe, H.; 
Ueda, M.; Yoshioka, N.; Naito, T. Synlett 1999, 465. 
(j) Miyabe, H.; Yamakawa, K.; Yoshioka, N.; Naito, T. 
Tetrahedron 1999, 55, 11209. (k) Miyabe, H.; Shibata, R.; 
Sangawa, M.; Ushiro, C.; Naito, T. Tetrahedron 1998, 54, 
11431. (l) Miyabe, H.; Shibata, R.; Ushiro, C.; Naito, T. 
Tetrahedron Lett. 1998, 39, 631. (m) Miyabe, H.; Ushiro, 
C.; Naito, T. Chem. Commun. 1997, 1789.
(3) (a) Miyabe, H.; Fujii, K.; Naito, T. Org. Biomol. Chem. 
2003, 1, 381. (b) Friestad, G. K.; Qin, J. J. Am. Chem. Soc. 
2001, 123, 9922. (c) Friestad, G. K.; Qin, J. J. Am. Chem. 
Soc. 2000, 122, 8329. (d) Bertrand, M. P.; Feray, L.; 
Nouguier, R.; Perfetti, P. Synlett 1999, 1148. (e) Miyabe, 
H.; Fujii, K.; Naito, T. Org. Lett. 1999, 1, 569. (f) Bertrand, 
M. P.; Feray, L.; Nouguier, R.; Stella, L. Synlett 1998, 780.
(4) (a) Gilchrist, T. L. Aldrichimica Acta 2001, 34, 51. 
(b) Alves, M. J.; Azoia, N. G.; Bickley, J. F.; Fortes, A. G.; 
Gilchrist, T. L.; Mendonca, R. J. Chem. Soc., Perkin Trans. 
1 2001, 2969. (c) Alves, M. J.; Gilchrist, T. L.; Sousa, J. H. 
J. Chem. Soc., Perkin Trans. 1 1999, 1305.
(5) Review: Ollivier, C.; Renaud, P. Chem. Rev. 2001, 101, 
3415.
(6) CCDC 207633 contains the supplementary crystallographic 
data for this paper. These data can be obtained free of charge 
via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the 
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; 
fax:+44(1223)336033; e-mail: deposit@ccdc.cam.ac.uk.).
(7) Yamada, K.; Fujihara, H.; Yamamoto, Y.; Miwa, Y.; Taga, 
T.; Tomioka, K. Org. Lett. 2002, 4, 3509.
(8) Typical Procedure: A solution of triethylborane (15% in 
hexane) (0.4 mL, 6.12 mmol) was added to a mixture of 
methyl 2-(2,6-dichlorophenyl)-2H-azirine-3-carboxylate 
(0.3g, 1.23 mmol) and the alkyl iodide (12.4 mmol) in 
CH2Cl2 (20 mL) at –40 °C. The reaction was maintained at 
this temperature for 30 min and the mixture was then washed 
with a 10% aq solution of NaHCO3 the organic layer dried 
(Na2SO4) and evaporated. Flash chromatography (hexanes/
EtOAc: 80/20) afforded the product.
With iodoethane: Methyl 3-(2,6-dichlorophenyl)-2-
ethylaziridine-2-carboxylate 2a, 0.24 g (71%), mp 53.0–
54.5 °C (from toluene/CH2Cl2). (Found: C, 52.28; H, 4,92; 
N, 5,07. C12H13Cl2NO2 requires C, 52.57; H, 4.78; N, 
5.11%). IR nmax = 1724, 1433, 1207, 777 cm–1. 1H NMR (300 
MHz): d = 1.11 (3 H, t, J = 7.5 Hz), 1.52–1.64 (1 H, m, 
CH3HCH), 2.41–2.53 (2 H, m, CH3HCH and NH, 
integration became one after D2O shake), 3.12 (1 H, br s, H-
3, turns into a sharp singlet after D2O shake), 3.57 (3 H, s,) 
7.12–7.17 (1 H, m), 7.27–7.29 (2 H, m). MS (CI): m/z (%) = 
274 (100), 276 (66), 278 (12) [(M + H)+].
With 2-iodopropane: Methyl 3-(2,6-dichlorophenyl)-2-(1-
methylethyl) aziridine-2-carboxylate 2b, 0.29 g (82%); mp 
81.7–82.9 (from hexanes/EtOAc). (Found: C, 53.96; H, 
5.47; N, 5.03; C13H15Cl2NO2 requires C, 54.18; H, 5.25; N, 
4.86%). IR nmax = 3209, 2968, 1724, 1433, 1207, 775 cm–1. 
1H NMR (300 Mz): d = 1.2 (9 H, s), 2.66 (1 H, br d, J = 7.3 
Hz, aziridine NH), 3.28 (1 H, br d, J = 7.1 Hz, H-3), 3.47 (3 
H, s) 7.10–7.16 (1 H, m), 7.25–7.28 (2 H, m). MS (CI): m/z 
(%) = 288 (100), 290 (66), 292 (12) [(M + H)+].
BEt3
O2
N
O
O
Cl
Cl
R
BEt2
Et
R I
BEt3
Et I
N
O
O
Cl
Cl
R
R
N
O
O
Cl
Cl
1406 M. J. Alves et al. LETTER
Synlett 2003, No. 10, 1403–1406 © Thieme Stuttgart · New York
With 2-iodo-2-methylpropane: Methyl 3-(2,6-dichloro-
phenyl)-2-(1,1-dimethylethyl)aziridine-2-carboxy-late 2c 
(0.33 g, 89%), as a low melting point solid. IR nmax = 3406, 
2959, 1714, 1431, 1242, 774 cm–1. 1H NMR (300 Mz): d = 
1.2 (9 H, s), 2.66 (1 H, bd, J = 7.3 Hz, aziridine NH), 3.28 (1 
H, bd, J = 7.1 Hz, H-3), 3.47 (3 H, s) 7.10–7.16 (1 H, m), 
7.25–7.28 (2 H, m).
With iodocyclohexane: Methyl 3-(2,6-dichlorophenyl)-2-
cyclohexylaziridine-2-carboxylate 2d, (0.32 g, 79%), mp 
105.6–107.2 °C (from toluene/CH2Cl2), IR nmax = 3209, 
2967, 1724, 1433, 1207, 775 cm–1. 1H NMR (300 Mz): d = 
1.08–1.9 (10 H, multiplet), 2.29 (1 H, br t, J = 4.2 Hz), 2.54 
(1 H, br s, NH), 3.28 (1 H, br s), 7.10–7.16 (1 H, m), 7.26–
7.29 (2 H, m).
(9) Giese, B. In Radicals in Organic Synthesis: Formation of 
Carbon-Carbon Bonds; Pergamon Press: Oxford, 1986.
(10) Similar mechanisms, for borane mediated reactions, have 
been proposed, see references: 1a) p. 5488; 2c); 2i); 2j); 5) p. 
3429; 9) p. 86.


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Intermolecular alkyl radical addition to methyl 2-(2,6-Dichlorophenyl)-2H-azirine-3-carboxylate

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