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S. Onogi et al. / Tetrahedron Letters 53 (2012) 3710–3712
Boc group of 4 by CF3CO2H and evaporation of CF3CO2H, the result-
ing trifluorocarboxylate salt 7 was subjected to microwave-as-
sisted cycloamination reaction at 60 °C for 30 min, followed by
hydroxylation at 140 °C for 90 min. After treatment with Boc2O,
endo-3 was obtained in 30% yield from 4. It should be noted
endo-3 was not obtained when the microwave irradiation was re-
placed by oil bath heating. The observation strongly suggests that
microwave irradiation is crucial to the hydroxylation reaction.
Endo-3 was oxidized by 1-Me-AZADO catalyzed reaction to give
ketone 16.10
In summary, the intramolecular cycloamination of methyl
(1R,2S,4R,5R)-2-amino-4,5-dibromocyclohexanetrifluorocarboxy-
late (7) was improved to give methyl (1S,2R,4S,5R)-7-aza-5-bromo-
bicyclo[2.2.1]heptan-2-carboxylate (8) in high yield in short time
by employing microwave-assisted conditions. Substitution reac-
tion of 8 by carboxylate anion was also achieved to afford alcohol
endo-3. In the substitution reaction, unusual endo-stereoselectivity
was observed owing to the participation of the nitrogen atom of 7-
azabicyclo[2.2.1]heptane skeleton. The prepared endo-3 and 16
could be amenable synthetic intermediates for chiral 7-aza-
bicyco[2.2.1]heptane derivatives with multi-functional groups.
0
Scheme 4. Hydroxylation of 12 and 14.
References and notes
1. Carroll, F. I. Bioorg. Med. Chem. Lett. 1889, 2004, 14.
2. (a) Chen, Z. M.; Trudell, M. L. Chem. Rev. 1996, 96, 1179; (b) Olivo, H. F.;
Hemenway, M. S. Org. Prep. Proc. Int. 2002, 34, 1.
3. Kapferer, P.; Vasella, A. Helv. Chim. Acta 2004, 87, 2764.
4. Other cycloamination condition of 3,4-dibromocyclohexanamine derivatives
with NaH was reported in the following literature, and we applied the
condition to cycloamination of 4. But desired product 8 was not formed. See the
following reference; Gomez-Sanchez, E.; Soriano, E.; Marco-Contelles, J. J. Org.
Chem. 2007, 72, 8656.
5. Identical data of methyl (1S,2R,4S,5S)-7-aza-5-hydroxybicyclo[2.2.1]heptane-
2-carboxylate (endo-3): ½a D26
ꢀ
: 22.9 (c = 1.0, CHCl3). IR (neat) m 3439, 2977, 1739,
1703, 1681 cmꢁ1. HRMS (EI): m/z Calcd for C13H21N1O5 [M+]: 271.1420. Found:
271.1412. 1H NMR (CDCl3): d 4.40 (1H, brs), 4.30 (1H, ddd, J = 3.2, 4.0, 10.0 Hz),
4.20 (1H, brs), 3.68 (3H, s), 2.65 (1H, dd, J = 5.2, 9.2 Hz), 2.62 (1H, brs), 2.35 (1H,
dd, J = 9.2, 12.8 Hz), 2.24 (1H, ddd, J = 5.2, 10.0, 12.8 Hz), 2.14 (1H, ddd, J = 4.0,
5.2, 12.8 Hz), 1.39 (9H, s), 1.12 (1H, dd, J = 3.2, 10.0 Hz) ppm. 13C NMR (CDCl3):
d 173.7, 154.6, 80.1, 69.7, 60.2, 59.6, 52.1, 47.4, 39.3, 28.1, 24.4 ppm. The
relative configuration of hydroxyl group was determined by NOESY spectrum.
6. Abad, A.; Agulló, C.; Cuñat, A. C.; Navarro, I. Synthesis 2005, 19, 3355.
7. endo-Selective substitution reaction of Boc-protected 7-aza-2-bromo-
bicyclo[2.2.1]heptane by azido anion was reported; Gomez-Sanchez, E.;
Marco-Contelles, J. Lett. Org. Chem. 2006, 3, 827.
Scheme 5. One-pot synthesis of endo-3 under microwave-assisted conditions.
under microwave-assisted heating proceeded very slowly to give a
mixture of exo-13 (12%) and endo-13 (7%) in low yield, exo-13 was
still observed as a major isomer (Scheme 4-(2)). In contrast, only
endo-15 was obtained in the hydroxylation of 14 under similar
conditions (Scheme 4-(3)), which proves that the endo-stereoselec-
tivity derives from the existence of unprotected amino group at 7-
position of bicyclo[2.2.1]heptane skeleton. In the case of 12, the
carbocation, generated by elimination of bromide, can be stabilized
by a non-classical carbocation mechanism, which causes a struc-
tural change to open the exo-face of cationic center.8 In contrast,
the generated carbocation of 14 could be stabilized by an interac-
tion with the lone pair of non-bonding electrons of nitrogen. The
endo-face of the cationic center can be opened to facilitate the
endo-substitution.
8. (a) Olah, G. A.; Prakash, G. K. S.; Saunders, M. Acc. Chem. Res. 1983, 16, 440; (b)
Olah, G. A. Angew. Chem. Int. Ed. Engl. 1995, 34, 1393.
9. Experimental procedure of one-pot synthesis of endo-3 from 4: 4 (83.0 mg,
0.2 mmol) was placed and dissolved in CH2Cl2 (0.8 mL) in a microwave reactor
vessel under Ar atmosphere. Trifluoroacetic acid (0.2 mL) was added and
stirred for 30 min. The reaction solvent and excess amount of reagent were
removed under reduced pressure. The trifluoroacetate salt 7 was mixed with
Me2NAc (1.4 mL) and K2CO3 (99.5 mg, 0.72 mmol), and then sealed after
purging with Ar. Initially the cycloamination reaction was carried out for
30 min at 60 °C, and then the hydroxylation reaction was carried out for 90 min
at 140 °C. After the reaction mixture cooled down to room temperature, Boc2O
(44 lL, 0.24 mmol) and NEt3 (83 lL, 0.6 mmol) were added and the reaction
mixture was stirred overnight. The reaction mixture was quenched by 1 M HCl,
extracted by tert-butylmethylether (5 mL ꢂ 3), and washed by water and brine.
The combined organic layer was dried over Na2SO4, filtered and concentrated.
Purification by using PTLC (hexane:AcOEt = 1:1) gave endo-3 (16.5 mg, 30%) as
pale yellow oil.
By applying the optimized reaction conditions for the cycloam-
ination and hydroxylation under microwave-assisted conditions,
endo-3 was prepared in one-pot from 4 in slightly better yield than
that of the stepwise procedure (Scheme 5).9 After deprotection of
10. Shibuya, M.; Tomizawa, M.; Suzuki, I.; Iwabuchi, Y. J. Am. Chem. Soc. 2006, 128,
84.