Tandem oxidation processes: The direct conversion of activated alcohols into oximes; synthesis of citaldoxime

Article abstract of DOI:10.1055/s-2002-32949

The direct conversion of primary alcohols into oximes is reported using manganese dioxide and alkoxylamines/hydroxylamine as their hydrochloride salts or supported on Amberlyst 15. This transformation has been applied to a range of benzylic, allylic and propargylic alcohols and utilised to prepare the natural product citaldoxime.

Full text of DOI:10.1055/s-2002-32949

LETTER
1287
Tandem Oxidation Processes: The Direct Conversion of Activated Alcohols
into Oximes; Synthesis of Citaldoxime
Tandem
O
xidation
i
Proces
s
ses ashi Kanno, Richard J. K. Taylor*
Department of Chemistry, University of York, Heslington, York YO10 5DD, UK
Fax +44(1904)434523; E-mail: rjkt1@york.ac.uk
Received 19 April 2002
Initial studies were carried out using benzyl alcohol, man-
Abstract: The direct conversion of primary alcohols into oximes is
reported using manganese dioxide and alkoxylamines/hydroxyl-
amine as their hydrochloride salts or supported on Amberlyst 15.
This transformation has been applied to a range of benzylic, allylic
ganese dioxide, molecular sieves and methoxylamine hy-
drochloride in dichloromethane as shown in Equation 3.
To our delight the procedure gave the corresponding O-
and propargylic alcohols and utilised to prepare the natural product methyl oxime 1 in 62% isolated yield with NMR data in
accord with the literature.5 It should be noted that when
citaldoxime.
amine bases were added to this mixture in an attempt to in-
crease the rate of reaction by releasing free methoxy-
lamine, the yield of adduct 1 decreased dramatically. We
assume that the hydrochloride salt is stable to the oxida-
tive conditions, whereas free methoxylamine is probably
oxidised by manganese dioxide.6
Key words: oxidation, O-alkyl oximes, oximes, citaldoxime, one-
pot
We have recently designed a range of transformations
based on the manganese dioxide-mediated oxidation of
primary alcohols followed by in situ trapping of the result-
ing aldehydes.1–4 This one-pot, tandem methodology
avoids the need to isolate the intermediate aldehydes,
which is particularly useful in the case of volatile, toxic or
highly reactive examples. We first employed stabilised
phosphoranes,1 non-stabilised phosphoranes2 and stabi-
lised phosphonate anions as trapping agents.2 We then
went on to extend this concept by incorporating amines as
the nucleophilic trapping agent (Equation 1).3 In this way
alcohols can be converted into imines in a one-pot pro-
cess.3,4 In this paper we report that O-alkoxylamines (and
in certain cases, hydroxylamine itself) can also be em-
ployed as trapping agents in a similar sequence (Equation
2). We also describe the use of this methodology for the
preparation of the antifungal natural product citaldoxime.
OMe
MnO2
OH
N
MeONH2 HCl
4Å mol. sieves
CH2Cl2, ∆
1, 62%
(E:Z = 12:1)
Equation 3
We went on to investigate the in situ oxidation-oxime for-
mation reaction with a range of benzylic alcohols under
these conditions (Table 1).7,8 They all underwent smooth
transformation to give the corresponding O-methyl
oximes in good yields. The reaction was compatible with
electron withdrawing or donating substituents (entries ii
and iii), and 1,4-benzenedimethanol was efficiently con-
verted into the corresponding di-oxime (entry iv). Other
alkoxylamines were tried with less success (entries v–vii).
Thus, treatment of benzyl alcohol under the standard con-
ditions with O-tert-butoxylamine hydrochloride or O-al-
loxylamine hydrochloride gave only trace amounts of the
desired oximes (entry v). With benzoxylamine hydrochlo-
ride and 4-methoxybenzyl alcohol a reasonable yield of
the corresponding O-benzyl oxime was obtained (entry vi,
68%), but all attempts to utilise hydroxylamine hydro-
chloride in this sequence to produce the parent oximes
were disappointing, the best result being shown in entry
vii (ca. 16% with benzyl alcohol).
MnO2
R1NH2
RCH NR1
RCH2OH
RCHO
CH2Cl2
AcOH
4Å mol. sieves
R = aryl, alkenyl, alkynyl; R1 = alkyl
Equation 1
MnO2
RCH NOR1
RCHO
RCH2OH
R1ONH2 HX
We next looked at similar reactions with allylic, propar-
gylic and related alcohols (Table 2). Cinnamyl alcohol, E-
non-2-en-1-ol and non-2-yn-1-ol reacted smoothly under
the standard conditions to give the corresponding O-me-
thyl oximes (Table 2 entries i, ii and iv). With Z-non-2-en-
1-ol, however, there was a significant amount of alkene
isomerisation (entry iii, Z:E = 2.4:1). This procedure
was also successful with an -hydroxy ketone,9 hydroxy-
acetophenone giving the corresponding O-methyl oxime
Equation 2
Synlett 2002, No. 8, Print: 30 07 2002.
Art Id.1437-2096,E;2002,0,08,1287,1290,ftx,en;D08702ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1288
H. Kanno, R. J. K. Taylor
LETTER
Table 1 In Situ Oxidation-Oxime Formation:a Benzylic Examples
Entry
(i)
Alcohol
Alkoxylamine
MeONH2 HCl
Product (isolated yield)
OMe
N
OH
62% (E:Z=12:1)
(ii)
MeONH2 HCl
MeONH2 HCl
MeONH2 HCl
OMe
N
OH
OH
O2N
O2N
85% (E:Z=13:1)
(iii)
(iv)
OMe
N
MeO
HO
MeO
88% (E:Z=8:1)
OMe
OH
N
N
MeO
84%b
(v)
tBuONH2 HCl
OBut
OH
N
tracec
(vi)
PhCH2ONH2 HCl
OCH2Ph
OH
N
MeO
MeO
68% (E:Z=7:1)
(vii)
HONH2 HCl
OH
NOH
ca. 16%d
a Using manganese dioxide (5–20 equiv.) and 4Å molecular sieves in CH2Cl2 at reflux for overnight.8
b 30 equiv of manganese dioxide were used in this example; the product was obtained as a separable mixture of isomers (E,Z:E,E:Z,Z =
2.7:1.7:1).
c AllylONH2 HCl also gave only trace amounts of the expected product.
d Crude yield based on NMR integration.
and parent oxime in just over 40% yield for each (entries droxyacetophenone can be employed with supported hy-
v and vi).
droxylamine (entry vi).
The disappointing yields with oximes other than methox- We next went on to apply this new methodology. Cital-
ylamine encouraged us to look at alternative systems. The doxime 5 is an antifungal natural product first obtained as
earlier discovery that hydrochloride salts were preferable a radiation-induced stress metabolite of Citrus sinensis,11
to the free amines, and the presumption that this was due and later isolated from the roots of several different citrus
to their low solubility preventing oxidative degradation, plants.12 Citaldoxime was conveniently prepared using
prompted us to look at other heterogeneous systems. Suc- the in situ oxidation-oxime formation procedure as shown
cess was achieved when the oximes were supported on in Scheme 1. Bromination-acetoxylation-hydrolysis of
Amberlyst 15 resin (Table 3).10 Thus, benzyl alcohol re- methyl ketone 2 gave alcohol 313 which on alkylation with
acted with supported methoxylamine in 59% yield (entry prenyl bromide produced the key -hydroxy ketone pre-
i), which was about the same as using MeONH2 HCl. cursor 4. Oxidation-oxime formation using Amberlyst-
However, with benzyl alcohol and supported alloxyl- supported hydroxylamine proceeded in 43% yield in di-
amine and tert-butoxylamine, fair yields of the corre- ethyl ether14 producing citaldoxime 5 in a one step process
sponding O-alkyl oxime adducts were obtained (entries ii (mp 104–105 °C; lit.11 mp 104–105 °C).
and iii); this contrasts to the reactions using the hydro-
chloride salts which failed. We have also shown that sup-
ported benzoxylamine is compatible with this procedure
(entry iv), that 4-nitrobenzyl alcohol gives a good yield
We also prepared the novel citaldoxime analogue 6 as
shown in Scheme 1. Thus, oxidation-oxime formation
of -hydroxy ketone 4 using Amberlyst-supported meth-
oxylamine gave a 49% yield of O-methyl citaldoxime 6
with supported allyloxylamine (entry v), and that hy-
which was fully characterised.
Synlett 2002, No. 8, 1287–1290 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Tandem Oxidation Processes: Direct Conversion of Alcohols into Oximes
1289
Table 2 In Situ Oxidation-Oxime Formation:a Allylic, Propargylic and Related Examples
Entry
(i)
Alcohol
Alkoxylamine
MeONH2 HCl
Product (isolated yield)
OMe
Ph
N
Ph
OH
91% (E,E:E,Z=5:4)
(ii)
MeONH2 HCl
MeONH2 HCl
MeONH2 HCl
OMe
C6H13
OH
C6H13
N
61% (E,E:E,Z=1:1.4)
(iii)
(iv)
N
OH
C6H13
OMe
C6H13
(iii)
87% (Z,E:Z,Z:E,E:E,Z=2.9:2.4:1:1.2)
OH
N
OMe
C6H13
C6H13
71% (E:Z=3:10)
(v)
MeONH2 HCl
O
O
O
OH
N
OMe
45% (E:Z=2:1)
(vi)
HONH2 HCl
O
NOH
OH
44%c
a Using manganese dioxide (5–20 equiv.) and 4Å molecular sieves in CH2Cl2 at reflux for overnight.
b E,E and E,Z indicates the configuration of the alkene followed by the configuration of the oxime.
c This reaction was only successful when THF was used as solvent (no product observed in dichloromethane).
O
the parent hydroxylamines. This latter procedure has been
used as the cornerstone of an efficient synthesis of the
antifungal natural product citaldoxime.
O
i. Br2
ii. AcOH, Et3N
OH
iv. NaH
Br
iii. aq. NaOH
MeOH
HO
HO
2
Acknowledgement
3
We are grateful to the Kureha Chemical Industry for studentship
support (H. K.).
O
O
MnO2
OH
NOH
Et2O, r.t., 26 h
References
O
O
P SO3H NH2OH
(1) (a) Wei, X.; Taylor, R. J. K. Tetrahedron Lett. 1998, 39,
3815. (b) Blackburn, L.; Wei, X.; Taylor, R. J. K. Chem.
Commun. 1999, 1337. (c) Wei, X.; Taylor, R. J. K. J. Org.
Chem. 2000, 65, 617.
4, 22% over 4 steps
Citaldoxime 5 (43%)
O
O
(2) Blackburn, L.; Pei, X.; Taylor, R. J. K. Synlett 2002, 215.
(3) Blackburn, L.; Taylor, R. J. K. Org. Lett. 2001, 3, 1637.
(4) For other tandem oxidation processes see the following two
papers.
MnO2
OH
P
N
THF, ∆, 24 h
OMe
O
O
SO3H NH2OMe
(5) (a) Gordon, M. S.; Sojka, S. A.; Krause, J. G. J. Org. Chem.
1984, 49, 97. (b) Tanimoto, S.; Yamadera, T.; Sugimoto, T.;
Okano, M. Bull. Chem. Soc. Jpn. 1979, 52, 4897.
(c) Mauleon, D.; Granados, R.; Minguilon, C. J. Org. Chem.
1983, 48, 3105.
4
6, O-Methyl citaldoxime
(49%; E:Z = 11:1)
Scheme 1
(6) Carey, F. A.; Hayes, L. J. J. Org. Chem. 1973, 38, 3107.
(7) Known products gave consistent spectroscopic data (and
mps if solids); novel products were fully characterised.
(8) Representative Procedure: Activated manganese dioxide
(Aldrich, 21764-6; 0.87 g, 10 mmol) was added to a stirred
solution of 4-nitrobenzyl alcohol (0.153 g, 1 mmol),
methoxylamine hydrochloride (0.251 g, 3 mmol) and 4 Å
molecular sieves (ca. 0.2 g) in dichloromethane (15 mL) and
the mixture was heated to reflux for 22 h. After cooling, the
In conclusion, we have successfully developed a simple
one-pot procedure using MnO2–NH2OMe HCl for the
conversion of activated primary alcohols into O-methyl
oximes. We have also developed a variant using Am-
berlyst 15-supported alkoxylamines, which can be em-
ployed to prepare other types of O-alkyl oximes as well as
Synlett 2002, No. 8, 1287–1290 ISSN 0936-5214 © Thieme Stuttgart · New York

1290
H. Kanno, R. J. K. Taylor
LETTER
Table 3 In Situ Oxidation-Oxime Formation Using Amberlyst 15-Supported Alkoxylaminesa
MnO2
P– SO3H NH2OR1
OR1
R
R
OH
N
4Å mol. sieves
CH2Cl2, ∆
Entry
(i)
Alcohol
Alkoxylamine
Product (isolated yield)
OMe
N
P SO3H NH2OMe
OH
OH
OH
59% (E:Z=11:1)
(ii)
Oallyl
N
P SO3H NH2Oallyl
P SO3H NH2OBut
P SO3H NH2OCH2Ph
69% (E:Z=13:1)
OBut
N
(iii)
(iv)
44% (E:Z=17:1)
OCH2Ph
OH
OH
N
MeO
O2N
MeO
83% (E:Z=9:1)
(v)
Oallyl
P SO3H NH2Oallyl
P SO3H NH2OH
N
O2N
87% (>97% E)
(vi)
O
O
NOH
OH
60%b
a Using manganese dioxide (5–10 equiv), supported oxime (2–5 equiv.), and 4Å molecular sieves in CH2Cl2 at reflux overnight.
b Using THF as solvent (32% in dichloromethane).
reaction mixture was filtered through Celite®, washing well
with dichloromethane. The combined organic fractions were
concentrated in vacuo and the resulting product purified by
column chromatography on silica. Elution with petroleum
ether–ethyl acetate (4:1) gave 4-nitrobenzaldehyde O-
methyl oxime (0.154 g, 85%; E:Z = 13.1) as a yellow solid,
mp 97.6–98.0 °C (lit.15 mp for E-isomer, 102–104 °C) which
displayed spectroscopic data consistent with those
the resulting mixture was stirred for 1 h. The resin was
removed by filtration, washed with methanol (50 mL) and
dichloromethane (3 20 mL), and then used in the
manganese dioxide reaction without further purification.
(11) (a) Dubery, I. A.; Holzhapfel, C. W.; Kruger, G. J.; Schabort,
J. C.; Van Dyk, M. Phytochemistry 1988, 27, 2769.
(b) Dubery, I. A.; Louw, A. E.; van Heerden, F. R.
Phytochemistry 1999, 50, 983.
(12) Ito, C.; Tanahashi, S.; Tani, Y.; Ju-ichi, M.; Omura, M.;
Furukawa, H. Chem. Pharm. Bull. 1990, 38, 2586.
(13) Zhang, K.; Corrie, J. E. T.; Munasinghe, V. R. N.; Wan, P.
J. Am. Chem. Soc. 1999, 121, 5625; and references therein.
(14) The yield was only 9% in dichloromethane at r.t. and 30% in
refluxing THF.
published.5
(9) Runcie, K. A.; Taylor, R. J. K. Chem. Commun. 2002, 974.
(10) Representative procedure for the preparation of Amberlyst-
supported alkoxylamine: A solution of sodium methoxide in
methanol (4.37 M, 0.75 mL, 3.3 mmol) was added to a
stirred solution of methoxylamine hydrochloride (0.251 g, 3
mmol) in methanol (10 mL) and the mixture was stirred at
r.t. for 0.5 h. Amberlyst 15 (1.06 g, 5 mmol) was added and
(15) Hegarty, A. F.; Tuohey, P. J. J. Chem. Soc., Perkin Trans. 2
1980, 1313.
Synlett 2002, No. 8, 1287–1290 ISSN 0936-5214 © Thieme Stuttgart · New York