A facile synthesis of (tert-alkoxy)amines

Article abstract of DOI:10.1016/j.tetlet.2005.07.149

Tertiary alcohols react with stoichiometric BF₃?Et ₂O and N-hydroxyphthalimide to yield N-alkoxyphthalimides. Subsequent hydrazinolyses afford the title compounds.

Full text of DOI:10.1016/j.tetlet.2005.07.149

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6667–6669
A facile synthesis of (tert-alkoxy)amines
Hasan Palandoken, Chris M. Bocian, Michelle R. McCombs and Michael H. Nantz*
Department of Chemistry, University of California, Davis, CA 95616, USA
Received 30 June 2005; revised 28 July 2005; accepted 28 July 2005
Available online 16 August 2005
Abstract—Tertiary alcohols react with stoichiometric BF3ÆEt2O and N-hydroxyphthalimide to yield N-alkoxyphthalimides. Sub-
sequent hydrazinolyses afford the title compounds.
Ó 2005 Published by Elsevier Ltd.
1. Introduction
N-protected hydroxylamine derivatives in nucleophilic
substitution reactions.3 The amination approach, which
has the advantage of retention of alcohol stereochemis-
try, requires an electrophilic reagent, such as an appro-
priately substituted oxaziridine (Eq. 1).4
The condensation of a ketone or aldehyde with an alk-
oxyamine (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 elementsꢁ onto polyfunc-
tional 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 alkoxy-
amines.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 displace-
ment and (ii) hydroxyl group amination. The former
approach generally is performed using N-hydroxyph-
thalimide under Mitsunobu-like conditions2 or by using
As might be expected, both the displacement and amina-
tion strategies suffer when the starting hydroxyl sub-
strate is a tertiary alcohol. Indeed, most of the few
reported syntheses of (tert-alkoxy)amines are character-
ized by modest to low yields.4,6–8 We recently required
access to sterically hindered alkoxyamines and, as a con-
sequence, we developed an alternative method for their
preparation. Herein, we describe the straightforward
conversion of tertiary alcohols 1 (Table 1) to the corre-
sponding (tert-alkoxy)amines 3 as well as conditions for
isolation of low-molecular weight, water soluble mem-
bers of this class of compounds.
O
base
O
+
+
R
OH
HN
R
ONH
2
ð1Þ
t-Bu
t-Bu
t-Bu
t-Bu
alkoxyamine
O
O
1
2
1
2
R
R
R
R
1
2
R
R
BF •Et O
H NNH
2 2
3
2
+
R
OH
HO N
R
O N
R
ONH
2
CH Cl
CH Cl
2
2
2
2
0 ˚C to rt
EtOH
O
O
1
3
2
Keywords: Alkoxyamine; Aminooxy; N-Hydroxyphthalimide; Boron trifluoride; Chemoselective.
*
Corresponding author. Tel.: +1 530 752 6357; fax: +1 530 752 8995; e-mail: mhnantz@ucdavis.edu
0040-4039/$ - see front matter Ó 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2005.07.149

6668
H. Palandoken et al. / Tetrahedron Letters 46 (2005) 6667–6669
Table 1. Synthesis of (tert-alkoxy)aminesa
Entry
Alcohol (1) (13C NMR: R3C–OH)b
Me Me
OH
Yield of 2c (%)
Alkoxyamine (3) (13C NMR: R3C–ONH2)b
Me Me
ONH
Yield of 3d (%)
a
74
Ph
A: 85
Ph
2
(δ 71.8)
(δ 78.3)
Me Me
Me Me
OH
Ph
Ph
b
c
22e
ONH
A: 95
2
(δ 70.9)
(δ 79.7)
Me Me
0
Ph
OH
Me Me
Me Me
Me OH
d
e
74
80
Me
ONH
A: 0
B: 96
2
(δ 83.6)f
(δ 69.0)
OH
ONH
2
A: 87
(δ 68.0)
(δ 76.1)
Me OH
Me ONH
2
f
52
45
A: 0
B: 80
(δ 70.0)
(δ 83.3)f
Me Me
Me Me
OH
HO
HO
g
ONH
A: 75
2
(C(1) δ 63.1, C(6) δ 71.3)
(C(1) δ 63.0, C(6) δ 79.2)
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
dodecanol resulted only in recovered starting alcohol.
These results suggested the possibility for a chemoselec-
tive alcohol to alkoxyamine transformation. We exam-
ined this event using 6-methylheptane-1,6-diol (entry g)
and found that only its tertiary alcohol reacted to give
alkoxyamine 3g.
The simple treatment of tertiary alcohols with stoichio-
metric 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 trans-
formation was less effective. In cases where alcohol elim-
ination would provide a conjugated alkene (e.g., entries
b and c), formation of the desired substitution product
was minimal to nonexistent. We reasoned that N-
hydroxyphthalimide did not competitively intercept the
putative carbenium ion formed on alcohol reaction with
BF3 due, in part, to its poor solubility in CH2Cl2. How-
ever, 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 N-
hydroxyphthalimide substitution products under the
BF3 conditions. The reactions of cyclohexanol and 2-
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 alk-
oxyamine ONH2-bearing carbon relative to starting
alcohol is a convenient means for analyzing the transfor-
mation (see Table 1). The cleavage products of phthal-
imides 2d and 2f had appreciable solubility in water
and this precluded their straightforward isolation. How-
ever, by adopting a non-aqueous method for phthali-
mide cleavage (Method B: methylhydrazine, CH2Cl2;
HCl),11 we were gratified to isolate alkoxyamines 3d

H. Palandoken et al. / Tetrahedron Letters 46 (2005) 6667–6669
6669
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%).
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.
a. N-hydroxyphthalimide
PPh , DIAD, THF
3
OH
ONH •HCl
2
b. MeNHNH , CH Cl
2
2
2
c. HCl (anhydr.)
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.
ð2Þ
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.
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 meth-
ylhydrazine (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
9. Sasaki, T.; Minamoto, K.; Itoh, H. J. Org. Chem. 1978,
43, 2320–2325.
1
(0.55 g, 96%). Mp 154.0–155.4 °C; H NMR (CDCl3):
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
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.
1
3a: H 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.
Acknowledgements
This work was supported by the National Institutes of
Health (NS-046591).
References and notes
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