Tertiary alcohols react with stoichiometric BF3·Et2O and N-hydroxyphthalimide to yield N-alkoxyphthalimides. Subsequent hydrazinolyses afford the title compounds

Bocian, Chris M.

McCombs, Michelle R.

Nantz, Michael H.

Palandoken, Hasan

English

DigitalCommons@CalPoly

A facile synthesis of (tert-alkoxy)amines Hasan Palandoken, Chris M. Bocian, Michelle R. McCombs and Michael H. Nantz Abstract—Tertiary alcohols react with stoichiometric BF3ÆEt2O and N-hydroxyphthalimide to yield N-alkoxyphthalimides. Sub­sequent hydrazinolyses aﬀord the title compounds. 1. Introduction The condensation of a ketone or aldehyde with an alk­oxyamine (aka aminooxy) has emerged as a powerful means for labelling liposome, bacterial and mammalian cell surfaces as well as for chemoselectively ligating small molecule recognition elements onto polyfunc­tional substrates.1 The robust oxime ether linkage formed in near quantitative yields in these reactions is ideal for applications in aqueous media; consequently, much eﬀort has been devoted toward developing new, more eﬃcient methods for the synthesis of alkoxy­amines.2–4 The existing methods for the preparation of alkoxyamines of the type RONH2 can be divided into two principal approaches:5 (i) hydroxyl group displace­ment and (ii) hydroxyl group amination. The former approach generally is performed using N-hydroxyph­thalimide under Mitsunobu-like conditions2 or by using O base R  OH  + HN Rt-Bu t-Bu alkox2R1R O 1R BF3•Et2O R  OH  + HO N R CH2Cl2 0 ˚C to rt O1N-protected hydroxylamine derivatives in nucleophilic substitution reactions.3 The amination approach, which has the advantage of retention of alcohol stereochemis­try, requires an electrophilic reagent, such as an appro­priately substituted oxaziridine (Eq. 1).4 As might be expected, both the displacement and amina­tion strategies suﬀer when the starting hydroxyl sub­strate is a tertiary alcohol. Indeed, most of the few reported syntheses of (tert-alkoxy)amines are character­ized by modest to low yields.4,6–8 We recently required access to sterically hindered alkoxyamines and, as a con­sequence, we developed an alternative method for their preparation. Herein, we describe the straightforward conversion of tertiary alcohols 1 (Table 1) to the corre­sponding (tert-alkoxy)amines 3 as well as conditions for isolation of low-molecular weight, water soluble mem­bers of this class of compounds. O  ONH2 + ð1Þt-Bu t-Bu yamine 1R 2R O2RH2NNH2 O N R  ONH2CH2Cl2 EtOH O 3 2 Table 1. Synthesis of (tert-alkoxy)aminesa Entry Alcohol (1) (13C NMR: R3C–OH)b Yield of 2c (%) Alkoxyamine (3) (13C NMR: R3C–ONH2)b Yield of 3d (%) a Ph OH 74 ONH2 A: 85 (δ 71.8) (δ 78.3) b Ph OH 22e ONH2 A: 95 (δ 70.9) (δ 79.7) c Ph OH 0 Me Me d Me OH (δ 69.0) 74 Me ONH2 (δ 83.6)f A: 0 B: 96 e 80 A: 87 (δ 68.0) (δ 76.1) f (δ 70.0) 52 (δ 83.3)f A: 0 B: 80 g HO OH 45 ONH2 A: 75 (C(1) δ 63.1, C(6) δ 71.3) (C(1) δ 63.0, C(6) δ 79.2) MeMe Ph MeMe MeMe Ph MeMe MeMe MeMe OH ONH2 OHMe ONH2Me MeMe HO MeMe a All reactions were performed on P1 mmol scale. b Taken in CDCl3. c Isolated yield from 1. d Isolated yield from 2 using either Method A (aqueous work-up) or Method B (anhydrous conditions). e Major product is b,b-dimethylstyrene (69%). f HCl salt. 2. Results The simple treatment of tertiary alcohols with stoichio­metric BF3ÆEt2O and  N-hydroxy-phthalimide in CH2Cl2 proceeds to give the corresponding O-alkyl phthalimides 2 in fair to good yields (Table 1, entries a, d–f). The use of TMSOTf or other Lewis acids to facilitate this trans­formation was less eﬀective. In cases where alcohol elim­ination would provide a conjugated alkene (e.g., entries b and c), formation of the desired substitution product was minimal to nonexistent. We reasoned that N­hydroxyphthalimide did not competitively intercept the putative carbenium ion formed on alcohol reaction with BF3 due, in part, to its poor solubility in CH2Cl2. How­ever, our attempts at solubilizing N-hydroxyphthalimide using several polar and mixed solvent systems did not improve product yields in these facile elimination cases. We also noted that secondary alcohols do not aﬀord N­hydroxyphthalimide substitution products under the BF3 conditions. The reactions of cyclohexanol and 2­dodecanol resulted only in recovered starting alcohol. These results suggested the possibility for a chemoselec­tive alcohol to alkoxyamine transformation. We exam­ined this event using 6-methylheptane-1,6-diol (entry g) and found that only its tertiary alcohol reacted to give alkoxyamine 3g. Cleavage of the phthalimide groups of 2a–b,e,g using standard hydrazinolysis conditions (Method A: excess hydrazine hydrate, 1:5 CH2Cl2–EtOH, rt, 12 h)9 gave the (tert-alkoxy)amine products in good yields.10 The consistent, slight 13C NMR downﬁeld shift of the alk­oxyamine ONH2-bearing carbon relative to starting alcohol is a convenient means for analyzing the transfor­mation (see Table 1). The cleavage products of phthal­imides 2d and 2f had appreciable solubility in water and this precluded their straightforward isolation. How­ever, by adopting a non-aqueous method for phthali­mide cleavage (Method B: methylhydrazine, CH2Cl2; HCl),11 we were gratiﬁed to isolate alkoxyamines 3d and 3f as their hydrochloride salts in good yields.10 In our experience, application of this method to other low-molecular weight phthalimides also dramatically improved product isolation (e.g., Eq. 2; Method A: 7%, Method B: 98%).  a. N-hydroxyphthalimide   PPh3, DIAD, THF OH b. MeNHNH2, CH2Cl2 ONH2 •HCl c. HCl (anhydr.) ð2Þ 3. Representative anhydrous hydrazinolysis (Method B) To a solution of N-(tert-butoxy)phthalimide 2d (1.0 g, 4.6 mmol) in CH2Cl2 (15 mL) at 0 �C was added meth­ylhydrazine (0.32 mL, 6.0 mmol) dropwise. The reaction was gradually warmed to room temperature and stirred for 12 h. After re-cooling to 0 �C, the reaction mixture was ﬁltered to remove precipitated solids. HCl(g) then was bubbled through the ﬁltrate at 0 �C for 15 min. The resulting slurry was stirred at 0 �C for an additional 30 min and subsequently ﬁltered. Concentration of the ﬁltrate in vacuo aﬀorded 3d as an oﬀ-white solid (0.55 g, 96%). Mp 154.0–155.4 �C; 1H NMR (CDCl3): d 1.43 (s, 9H), 10.57 (br s, 3H); 13C NMR (CDCl3): d 26.6, 83.6. In conclusion, we have presented a straightforward two-step method for the transformation of tertiary alcohols to (tert-alkoxy)amines. The method uses inexpensive reagents and is amenable to large scale synthesis. Acknowledgements This work was supported by the National Institutes of Health (NS-046591). References and notes 1. For recent examples, see: (a) Lemieux, G. A.; Yarema, K. J.; Jacobs, C. L.; Bertozzi, C. R. J. Am. Chem. Soc. 1999, 121, 4278–4279; (b) Perouzel, E.; Jorgensen, M. R.; Keller, M.; Miller, A. D. Bioconjug. Chem. 2003, 14, 884–898; (c) Sadamoto, R.; Niikura, K.; Ueda, T.; Monde, K.; Fukuhara, N.; Nishimura, S.-I. J. Am. Chem. Soc. 2004, 126, 3755–3761. 2. (a) Grochowski, E.; Jurczak, J. Synthesis 1976, 682–684; (b) Nicolaou, K. C.; Groneberg, R. D. J. Am. Chem. Soc. 1990, 112, 4085–4086; (c) Su, S.; Giguere, J. R.; Schaus, S. E., Jr.; Porco, J. A., Jr. Tetrahedron 2004, 60, 8645–8657. 3. (a) Kim, J. N.; Kim, K. M.; Ryu, E. K. Synth. Commun. 1992, 22, 1427–1432; (b) Jones, D. S.; Hammaker, J. R.; Tedder, M. E. Tetrahedron Lett. 2000, 41, 1531–1533; (b) Marcaurelle, L. A.; Shin, Y.; Goon, S.; Bertozzi, C. R. Org. Lett. 2001, 3, 3691–3694; (c) Carrasco, M. R.; Brown, R. T.; Seraﬁmova, I. M.; Silva, O. J. Org. Chem. 2003, 68, 195–197. 4. (a) Choong, I. C.; Ellman, J. C. J. Org. Chem. 1999, 64, 6528–6529; (b) Foot, O. F.; Knight, D. W. Chem. Commun. 2000, 11, 975–976. 5. For recent syntheses of N-substituted alkoxylamines, see: (a) Braslau, R.; Tsimelzon, A.; Gewandter, J. Org. Lett. 2004, 6, 2233–2235; (b) Grubbs, R. B.; Wegrzyn, J. K.; Xia, Q. Chem. Commun. 2005, 80–82, and references cited therein. 6. Mavunkel,	 B. J.; Rzeszotarski, W. J.; Kaplita, P. V.; DeHaven-Hudkins, D. L. Eur. J. Med. Chem. 1994, 29, 659–666. 7. Bicknell, A. J.; Gasson, B. C.; Hardy, K. D. EP-386940, 1990. 8. (a) Chimiak, A.; Kolasa, T. Bull. Acad. Pol. Sci. 1974, 12, 195–198; (b) Labeeuw, O.; Phansavath, P.; Geneˆt, J.-P. Tetrahedron Lett. 2004, 45, 7107–7110. 9.	 Sasaki, T.; Minamoto, K.; Itoh, H. J. Org. Chem. 1978, 43, 2320–2325. 10.	 Alkoxyamines 3b,d–f have been previously described. Characterization data for the new compounds is as follows: Compound 2a: mp 78.6–80.1 �C; 1H NMR (CDCl3): d 1.42 (s, 6H), 1.98 (m, 2H), 2.86 (m, 2H), 7.15 (m, 1H), 7.27 (m, 4H), 7.63 (m, 2H), 7.74 (m, 2H); 13C NMR (CDCl3): d 25.2, 30.5, 42.3, 88.0, 123.1, 123.2, 125.7, 128.3, 129.1, 134.3, 142.2, 165.5; HRMS [M+Na+] Calcd for C19H19NO3: 332.1257, found: 332.1262. Compound 3a: 1H NMR (CDCl3): d 1.36 (s, 6H), 1.99 (m, 2H), 2.76 (m, 2H), 4.93 (br s, 2H), 7.35 (m, 5H); 13C NMR (CDCl3): d 24.4, 30.5, 40.8, 78.3, 125.6, 128.3, 142.9; HRMS [M+Na+] Calcd for C11H17NO: 202.1202, found: 202.1206. Compound 2g: mp 55.5–56.6 �C; 1H NMR (CDCl3): d 1.36 (s, 6H), 1.59 (m, 8H), 3.68 (t, J = 6.6 Hz, 2H), 7.76 (m, 2H), 7.84 (m, 2H); 13C NMR (CDCl3): d 24.3, 25.4, 26.4, 32.9, 40.6, 63.0, 89.1, 123.7, 129.5, 134.7, 166.1; HRMS [M+Na+] Calcd for C16H21NO4: 314.1363, found: 314.1362. Compound 3g: 1H NMR (CDCl3): d 1.09 (s, 6H), 1.29 (m, 4H), 1.50 (m, 4H), 3.58 (t, J = 6.6 Hz, 2H), 3.81 (br s, 2H); 13C NMR (CDCl3): d 24.1, 24.6, 26.6, 33.0, 39.1, 63.0, 79.2; HRMS [M+Na+] Calcd for C8H19NO2: 184.1308, found: 184.1306. 11. We modiﬁed the procedure	 described in the following reference to obviate column chromatography: Bailey, S.; Harnden, M. R.; Jarvest, R. L.; Parkin, A.; Boyd, M. R. J. Med. Chem. 1991, 34, 57–65. 

A Facile Synthesis of (\u3cem\u3etert\u3c/em\u3e-alkoxy)amines

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A Facile Synthesis of (\u3cem\u3etert\u3c/em\u3e-alkoxy)amines

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