Asymmetric radical additions of trialkylboranes to 2H-azirine-3- carboxylates

Article abstract of DOI:10.1039/b408532a

Asymmetric additions of alkyl radicals, generated from R₃B, to chiral 2H-azirine-3-carboxylates offer a new entry to enantio-enriched aziridines, and proceed with high diastereo-selectivity when using 8-phenylmenthol as chiral auxiliary.

Full text of DOI:10.1039/b408532a

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Asymmetric radical additions of trialkylboranes to 2H-azirine-3-
carboxylates
Erik Risberg,a Andreas Fischerb and Peter Somfai*a
a KTH Chemistry, Organic Chemistry, KTH, S-100 44 Stockholm, Sweden. E-mail: Somfai@kth.se;
Fax: 146 8 791 2333; Tel: 146 8 790 6960
b KTH Chemistry, Inorganic Chemistry, KTH, S-100 44 Stockholm, Sweden
Received (in Cambridge, UK) 7th June 2004, Accepted 13th July 2004
First published as an Advance Article on the web 20th August 2004
Table 1 Solvent optimisation in alkyl radical addition to 1 and 4a
Asymmetric additions of alkyl radicals, generated from R3B,
to chiral 2H-azirine-3-carboxylates offer a new entry to
enantio-enriched aziridines, and proceed with high diastereo-
selectivity when using 8-phenylmenthol as chiral auxiliary.
Entry
Azirine
Solvent
Yieldb (%)
Drc
1
2
3
4
5
1
1
1
1
4
CH2Cl2
Et2O
PhMe
THF
CH2Cl2
77
73
64
58
95
91 : 9
91 : 9
86 : 14
68 : 32
79 : 21
2H-Azirines are highly reactive, nitrogen-containing, 3-membered
heterocycles and represent interesting starting materials for the
preparation of amino acids and alkaloids.1 The pronounced
reactivity of these compounds is due to their ring strain, the
electron-rich nature of the CLN-bond and the nitrogen lone pair.2
Asymmetric nucleophilic addition to azirines is a potentially
attractive entry to enantio-enriched aziridines, a class of com-
pounds that has received much recent interest.3 In principle the
stereochemical outcome of such additions can be controlled by
employing a chiral auxiliary or, more efficiently, by the use of a
chiral catalyst. In a previous study we showed that the asymmetric
alkylation of 2H-azirines using organolithium reagents in the
presence of various chiral ligands gave the corresponding aziridine
in low to modest ee.4 Consequently, an alternative stereoselective
alkylation protocol was required and herein is detailed a stereo-
selective addition of alkyl radicals to azirines.5 We have previously
shown that enantiomerically pure 2H-azirine-3-carboxylates 1 and
4 are excellent dienophiles in Lewis acid-mediated hetero Diels–
Alder reactions,6 and consequently, these compounds were selected
as substrates for the initial screening in the Et3B–O2 mediated
addition of nucleophilic radicals (Scheme 1).7
For the 8-phenylmenthol derived azirine 1 CH2Cl2 and Et2O
gave the best results affording aziridine 2a in good yield and
excellent diastereoselectivity (Table 1, entries 1, 2). Other solvents,
such as PhMe and THF, gave inferior results (entries 3, 4). Azirine
4, incorporating Oppolzer’s sultam as auxiliary, gave aziridine 5 in
good yield, although with poor dr (entry 5); other solvents did not
improve the outcome. Satisfied with these results we turned our
attention towards the addition of other alkyl radicals to azirine 1.
For the addition of radical fragments other than ethyl, a corres-
ponding alkyl iodide (R–I) can be used together with the initiator
(Et3B–O2) and the substrate.8,9 Not surprisingly, mixtures derived
from incorporation of both the R moiety and the ethyl radical are
often obtained. When using this protocol for the addition of a
cyclohexyl radical to azirine 1 only the formation of 2a and 3a
could be detected (Table 2, entry 1), presumably due to a slow
a Reaction conditions: azirine (1 equiv.), solvent (2 mL), EtI
(10 equiv.), Et3B (5 equiv.) and O2 (5 mL) at 2105 uC, 5 minutes.
b Isolated yield. c Ratio of 2 : 3 in entry 1–4 and of 5 : 6 in entry 5,
determined by HPLC.
iodine atom transfer process from cyclohexyl iodide (c-C6H11I) to
the ethyl radical under these reaction conditions.5,9 Somewhat
puzzlingly, the dr obtained in this reaction was higher than that
achieved in the absence of c-C6H11I (Table 1, entry 1). When
repeating the reaction with freshly distilled c-C6H11I the dr
decreased (Table 2, entry 2), suggesting that the copper added to
stabilize the commercial c-C6H11I might play a pivotal role. Indeed,
when the reaction was repeated in the presence of CuCl (cat.), and
excluding c-C6H11I, 2a : 3a was obtained in excellent diastereo-
selectivity.{ Other Lewis acids tested proved less efficient.10
Since no radical transfer was observed in the presence of
cyclohexyl iodide at low temperatures, an alternative approach
would be to use other trialkylboranes to generate a reacting
radical.11 To test this several trialkylboranes were investigated and
the results are summarized in Table 3. The addition of Et3B went
smoothly and gave 2a in high yields and excellent ds (entry 1).
Addition of butyl radical also proceeded in good yield with high ds
(entry 3). With trialkylboranes forming more stable radicals, yields
were moderate to good but ds dropped dramatically (entries 5, 7,
9). In addition, two trialkylboranes were prepared and used in the
reaction giving aziridines 2f and 2g in moderate to good yield with
moderate dr (entries 11, 13). In order to further investigate the
importance of an additional Lewis acid in these reactions all alkyl
radical additions were repeated in the presence of 0.1 equiv. CuCl
(entries 2, 4, 6, 8, 10, 12, 14). Activation of azirine 1 with CuCl gave
a low increase of the dr and varying effect on the yield. The simple
preparation of R3B, via transmetallation or hydroboration,11,12
offers an attractive approach for the stereoselective addition of
functionalized alkyl radicals to 2H-azirines.
In order to determine the stereochemical outcome of the radical
Table 2 Additions to azirine 1 activated by Lewis acids to give 2a : 3aa
Entry Lewis acidb Et3B equiv. c-C6H11I equiv. Yield (%)e Drf
1
2
3
—
—
CuCl
5
5
3
10c
10d
—
71
82
69
94 : 6
89 : 11
96 : 4
a Reaction run in CH2Cl2 at 2105 uC under conditions given in
Table 1above. b 0.1 equiv. c Stabilized with metallic copper. d Dis-
tilled prior to use. e Isolated yield. f Determined by HPLC.
Scheme 1 Reaction conditions: (a) RI, R3B, O2, CH2Cl2, 2105 uC.
2 0 8 8
C h e m . C o m m u n . , 2 0 0 4 , 2 0 8 8 – 2 0 8 9
T h i s j o u r n a l i s ß T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

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Table 3 Addition of various alkyl groups to 1a
Entry
R3B/equiv.
Lewis acid/equiv.
Product/yield (%)b
Ratioc
1
2
3
4
5
6
7
8
Et3B/3
Et3B/3
n-Bu3B/3
—
CuCl/0.1
—
CuCl/0.1
—
CuCl/0.1
—
CuCl/0.1
—
CuCl/0.1
—
CuCl/0.1
—
CuCl/0.1
2a : 3a/81
2a : 3a/69
2b : 3b/69
2b : 3b/81
2c : 3c/72
2c : 3c/85
2d : 3d/51
2d : 3d/63
2e : 3e/43
2e : 3e/63
2f : 3f/56
2f : 3f/28
2g : 3g/71
2g : 3g/71
91 : 9
96 : 4
87 : 13
88 : 12
59 : 41
66 : 34
49 : 51
61 : 39
50 : 50
55 : 45
72 : 28
83 : 17
78 : 22
83 : 17
n-Bu3B/3
(allyl)3B/w3d
(allyl)3B/w3d
i-Pr3B/w3d
i-Pr3B/w3d
9
s-Bu3B/3
10
11
12
13
14
s-Bu3B/3
(C6H11CH2CH2)3B/w3d
(C6H11CH2CH2)3B/w3d
(2-methylallyl)3B/w3d
(2-methylallyl)3B/w3d
a Azirine (1 equiv.) in CH2Cl2, R3B, O2 (5 mL), 2105 uC, 5 min. b Isolated yield. c Determined by HPLC. d R3B was not isolated and excess
was used.
addition of O2 (5 mL, bubbled through the reaction mixture). After
5 minutes at 2105 uC the reaction was quenched by addition of NaHCO3
(1 mL), filtered through an Extrelut1 NT3 tube eluting with CH2Cl2
(15 mL), EtOAc (15 mL) and CH2Cl2 (15 mL) and concentrated to give a
yellow oil. Flash chromatography (pentane–EtOAc 1 : 0A4 : 1) gave 2a :
3a as a pale yellow oil.
{ Crystal data: C15H23N2O3S, M ~ 311.43, monoclinic, a ~ 10.7254(6),
3
˚
˚
b ~ 11.9768(9), c ~ 24.980(2) A, b ~ 91.273(4)u, V ~ 3208.1(3) A , T ~
299 K, space group P21 (No. 4), Z ~ 8, m(Mo–Ka) ~ 0.21 mm21, 26285
reflections measured, 8908 unique reflections (Rint ~ 0.0490) used in all
calculations. Friedel pairs were not merged before refinement. Hydrogen
atoms were placed at calculated positions and refined using a riding model.
The final wR(F2) was 0.126 (all reflections). Flack parameter x ~ 20.05(8).
One of the four molecules in the asymmetric unit exhibited severe disorder.
A structure model with split positions for some of the atoms was applied.
CCDC 241323. See http://www.rsc.org/suppdata/cc/b4/b408532a/ for
crystallographic data in .cif format.
Fig. 1 One of the four molecules of 5 in the asymmetric unit. Thermal
ellipsoids are drawn at a 50% probability level.
1 (a) B. Zwanenburg and P. ten Holte, Top. Curr. Chem., 2001, 216, 93;
(b) F. Palacios, A. M. Ochoa de Retana, E. Mart´ınez de Marigorta and
J. M. de los Santos, Org. Prep. Proced. Int., 2002, 34, 219;
(c) T. L. Gilchrist, Aldrichimica Acta, 2001, 34, 51.
2 W. H. Pearson and B. W. Lian, in Comprehensive Heterocyclic
Chemistry II, eds. A. R. Katritzky, C. W. Rees and E. F. V. Scriven,
Pergamon, Oxford, 1996, Vol. 1a, p. 1.
Scheme 2 Reaction conditions: (a) BnBr, K2CO3, MeCN, reflux, 67%;
(b) LAH, Et2O, 278 uC to rt; (c) Ac2O, DMAP, CH2Cl2; combined yield
over two steps 86%.
3 (a) W. McCoull and F. A. Davis, Synthesis, 2000, 1347; (b) D. Tanner,
Angew. Chem., Int. Ed. Engl., 1994, 33, 599.
4 E. Risberg and P. Somfai, Tetrahedron: Asymmetry, 2002, 13, 1957.
5 M. J. Alves, G. Fortes, E. Guimara˜es and A. Lemos, Synlett, 2003, 1403.
˚
6 (a) A. Sjo¨holm Time´n, A. Fischer and P. Somfai, Chem. Commun., 2003,
˚
1150; (b) A. Sjo¨holm Time´n and P. Somfai, J. Org. Chem., 2003, 68,
9958.
additions compound 5 was subjected to an X-ray crystallographic
analysis (Fig. 1).{
Using standard reaction conditions aziridine 5 was converted
into aziridine 7 (Scheme 2). Applying the same reaction conditions,
2a was transformed into ent-7.
We have shown that azirine 1 is an excellent radical acceptor in
diastereoselective intermolecular alkyl radical additions, forming
the corresponding aziridine carboxylates in good to excellent
selectivity, substrates that are valuable intermediates in organic
synthesis.3b,13 Applying CuCl as a Lewis acid can further increase
the diastereoselectivity in the addition reaction. By using various
trialkylboranes to generate the reacting radical, the desired radical
was added and chemoselectivity problems avoided. Further studies
regarding the scope of this reaction are currently ongoing in our
laboratory.
7 Electrophilic radicals are not compatible with reagents and substrates
applied in these reactions. See reference: D. P. Curran, in Comprehensive
Organic Synthesis, eds. B. M. Trost and I. Fleming, Pergamon Press,
Oxford, 1991, Vol. 4, p. 715.
8 (a) H. Miyabe, C. Ushiro, M. Ueda, K. Yamakawa and T. Naito, J. Org.
Chem., 2000, 65, 176; (b) P. Renaud and M. Gerster, Angew. Chem., Int.
Ed. Engl., 1998, 37, 2562.
9 N. Halland and K. A. Jørgensen, J. Chem. Soc., Perkin Trans. 1, 2001,
1290.
10 Examples of other Lewis acids that proved less efficient were Cu(OTf)2,
InCl3, YbCl3 and AgPF6.
11 A. Suzuki, A. Arase, H. Matsumoto, M. Itoh, H. C. Brown, M. M. Rogic
and M. W. Rathke, J. Am. Chem. Soc., 1967, 89, 5708.
12 (a) A. V. Topchiev, A. A. Prokhorova, Y. M. Paushkin and
M. V. Kurashev, Izv. Akad. Nauk SSSR, Ser. Khim., 1958, 370;
(b) H. C. Brown and U. S. Racherla, J. Org. Chem., 1986, 51, 427;
(c) G. W. Kabalka, J. T. Maddox, E. Bogas and S. W. Kelley, J. Org.
Chem., 1997, 62, 3688.
The authors thank the Swedish Foundation for Strategic
Research (SELCHEM) and the Swedish Research Council for
financial support.
Notes and references
{ A typical procedure: to the azirine 1 (60 mmol) in CH2Cl2 was added
CuCl (6 mmol) under argon at 2105 uC. The reaction was stirred for
10 minutes before Et3B (180 ml, 1 M in hexanes) was added, followed by
13 (a) G. Cardillo, L. Gentilucci and A. Tolomelli, Aldrichimica Acta, 2003,
36, 39; (b) W. K. Lee and H.-J. Ha, Aldrichimica Acta, 2003, 36, 57.
C h e m . C o m m u n . , 2 0 0 4 , 2 0 8 8 – 2 0 8 9
2 0 8 9