A versatile radical based approach to O-alkylated hydroxylamines and oximes

Article abstract of DOI:10.1016/j.tet.2008.08.113

O-Alkylhydroxylamines, often used for the preparation of bioconjugates, can be readily obtained by radical addition to suitable O-alkenylhydroxylamine derivatives. In the case of N-Boc-O-allylhydroxylamine, the addition is unexpectedly followed by elimination resulting in an overall allylation of the radical species.

Full text of DOI:10.1016/j.tet.2008.08.113

Tetrahedron 64 (2008) 11917–11924
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A versatile radical based approach to O-alkylated hydroxylamines and oximes
*
´
Beatrice Quiclet-Sire, Daniel Woollaston, Samir Z. Zard
Laboratoire de Synthe`se Organique associe´ au C. N. R. S., De´partement de Chimie, Ecole Polytechnique, F-91128 Palaiseau, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 17 July 2008
Accepted 21 August 2008
Available online 20 September 2008
O-Alkylhydroxylamines, often used for the preparation of bioconjugates, can be readily obtained by
radical addition to suitable O-alkenylhydroxylamine derivatives. In the case of N-Boc-O-allylhydroxyl-
amine, the addition is unexpectedly followed by elimination resulting in an overall allylation of the
radical species.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
ꢁ78 ꢀC, for the addition reaction of xanthate 2b also led solely to
the elimination product 6b, according to 1H NMR analysis of the
Reactions between aldehydes or ketones and O-alkylated hy-
droxylamines to form oximes are both high-yielding and require
only mild conditions. These reactions have been used for the
chemical ligation of steroids,1 oligonucleotides,2 modified pep-
tides,3 antibodies,4 viruses5 and natural products such as erythro-
mycin.6 The resulting bioconjugates have been shown to exhibit
different biological activities and solubilities. Despite their utility,
there are few established methods to prepare complex O-alkylated
hydroxylamines.
reaction mixtures (Scheme 2). This unexpected elimination process
is surprisingly facile, occurring even at very low temperatures.
In stark contrast, xanthate transfer additions to oximes 1b and
1c proceeded cleanly and in good yields. This observation is again
surprising, since
b-elimination of the more stabilised iminoxyl
would have been expected to occur more readily. It appears that
polar effects are more important than thermodynamic factors in
determining the rate of fragmentation in the present case. The
electron-withdrawing Boc group thus exerts ultimately a greater
We have developed a radical chain process based on the de-
generative exchange of a xanthate group.7 This chemistry has pro-
vided a simple, efficient and reasonably general method for the
intermolecular formation of carbon–carbon bonds on non-activated
alkenes. We herein describe a general approach, applying the xan-
thate transfer radical reaction, to the synthesis of O-alkylated
hydroxylamines and oximes. It was anticipated that N-protected
O-allylated or O-butenylated hydroxylamines 1 would undergo xan-
thate transfer addition reactions with xanthates 2 to form addition
products 3. Subsequent modification, inmostcasesxanthatereduction,
would furnish protected hydroxylamines 4 and deprotection would
provide the required O-alkylated hydroxylamines 5 (Scheme 1).
Alkenes 1a–d were formed by treatment of the oxime or N-Boc-
hydroxylamine with NaH, nBu4NI and allyl bromide or 4-bromo-1-
butene as appropriate. Unfortunately, when allylic hydroxylamine
1a was treated with xanthate 2a and substoichiometric lauroyl
peroxide (DLP) in 1,2-dichloroethane (DCE) at reflux none of the
expected addition product was observed; alkene 6a, resulting from
influence by lowering the energy level of the antibonding
C–O bond and bringing it closer to the level of the SOMO of
the radical. The resulting stronger interaction between the and
s
*
of the
s
*
the SOMO increases the rate of fragmentation of the C–O bond,
even though the ensuing oxygen centred departing radical,
BocNHOꢂ, is less stable than the iminoxyl radical, RR0C]N–Oꢂ, that
would be generated from the O-allyloxime adducts. The use of
a butenyl group, rather than an allyl group, in hydroxylamine 1d
removed the possibility of b-elimination, thus providing access to
Boc-protected substrates. A variety of functionalities are tolerated
S
R1
SCSOEt
S
OEt
2
P
O
P
O
R1
N
P
N
P
n
n
Initiator
3
1
Modification
b
-elimination of the first-formed radical, was obtained in 69%.
Using BEt3/O2 radical initiation conditions,8 both at 0 ꢀC and
R2
O
R2
Deprotection
P
O
H2N
N
n
n
P
4
5
* Corresponding author. Tel.: þ33 169335971; fax: þ33 169335972.
E-mail address: zard@poly.polytechnique.fr (S.Z. Zard).
Scheme 1.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.08.113

11918
B. Quiclet-Sire et al. / Tetrahedron 64 (2008) 11917–11924
NHBoc
O
both the solvent and hydrogen source, with DLP as the radical
initiator.9 Under these conditions, however, substrates 3i and 3j
gave mixture of products, indicating that the hydrogen
abstraction from 2-propanol was slow compared to other possible
pathways, such as the -elimination already discussed. Instead,
reduction of a range of substrates was achieved in good yields using
the triethyl ammonium salt of hypophosphorous acid as a faster
hydrogen source and AIBN as the initiator (Table 2).10
OEt
Cl
Cl
S
S
1a
a
DLP,
DCE, Δ
3a
b
O
O
O
S
BocHN
S
1a
Cl
DLP
OEt
2a
(40 mol%)
DCE, Δ
Liberation of the Boc protecting groups was effected using
trifluoroacetic acid; hydroxylammonium salts 6a and 6b were
formed in near quantitative yields from their respective Boc-pro-
tected compounds 4i and 4j. Upon treatment with K2CO3 in MeOH/
H2O, 6a furnished the expected hydroxylamine 5a. Under the same
conditions, however, 6b formed hydroxylamine 5b, in which the
oxazolidinone functionality has been replaced by methanol. When
ketone 4h was treated with trifluoroacetic acid, the liberated
hydroxylamine condensed with the ketone functionality to form
oxazocine 6c as a mixture of oxime geometric isomers (Scheme 4).
Only one example of such [1,2]-oxazocines has been reported in the
literature according to the Beilstein database.11 The present route
should expand considerably the access to this very rare family of
heterocycles.
While neither unanticipated nor unwelcome, the formation of
heterocycle 6c exemplifies the lack of compatibility between
O-alkylated hydroxylamines and certain common functional
groups. The creation, via the formation of an oxime, of a bio-
conjugate containing a ketone constituent would be difficult to
achieve without the use of protecting groups. If, however, an oxime
incorporating an alkene was synthesised, a subsequent xanthate
transfer radical reaction could insert the required ketone
functionality.
As an example, glucose pentaacetate was treated with the tri-
fluoroacetic acid salt of O-allylhydroxylamine to furnish a complex
mixture of products arising from acetate migration onto the first-
formed alcohol. Acetylation of this mixture using acetic anhydride
gave alkene 1e as a 5:1 mixture of geometrical isomers. Addition of
xanthate 2g, followed by reduction furnished oxime 4k in 49%
overall yield over four steps. In a further example, treatment of
alkene 1f, derived from epiandrosterone and O-butenylhydroxyl-
amine, furnished oxime 4l in 54% overall yield. The radical addition
and subsequent cyclisation reaction were conducted in a single pot,
with the reaction being diluted once TLC analysis showed that the
addition reaction was complete (Scheme 5).
To conclude, the xanthate transfer radical reaction can provide
access to complex hydroxylamines and oximes, which would
otherwise prove difficult to synthesise. It allows the preparation
of compounds containing functional groups that would be in-
compatible with usual methods of forming oxime-linked
bioconjugates.
6a, 69%
O
Me
N
Me
N
1a
S
BEt3, O2
DCM
O
O
EtO
S
F
F
2b
6b
Scheme 2.
in the xanthate: ketones (2a,c,d,f,j); amides (2b,e,g); lactones (2i).
In the case of the bis-xanthate 2k, a mixture of the mono- (3m) and
bis-addition products (3n) were obtained. The bis-addition product
(3n) is not trivial to prepare otherwise and would be interesting in
cross-linking processes. When using acetophenone derived xan-
thates 2a and 2d, small quantities of the products (4a and 4b)
arising from cyclisation onto the aromatic ring were obtained
(Fig. 1, Table 1).
By using stoichiometric amounts of DLP it is possible to induce
complete radical cyclisation onto aromatic rings. This allowed the
conversion of adduct 3e into the respective tetralone 4a in 56%
yield. A more difficult cyclisation to form a seven-membered
tetracycle 4d also proved possible, although competitive
elimination and xanthate reduction lowered the effective yield to
40% (Scheme 3).
Before the hydroxylamine functionality could be liberated it was
necessary to remove the xanthate groups. The standard conditions
for the reductive elimination of xanthate groups use 2-propanol as
Me
Cl
BocHN
O
O
Me
N
1c
1d
F
O
O
N
S
S
N
2b
1b
Cl
EtO
OEt
S
EtO
S
O
O
Me
EtO
S
Me
Me
O
S
S
N
H
S
Me
Me
2a, R = Cl
2. Experimental
R
2c, R = OMe
2d, R = F
2f
2e
2.1. General conditions
EtO
EtO
S
S
EtO
S
O
All reactions were carried out under an inert atmosphere.
Commercial reagents were used as-received without further puri-
fication. All products were purified by using silica gel (SDS, Silice 60
A. C. C. 40–63 mm) or by crystallisation. Analytical TLC was carried
out on Merck silica gel plates using short wave (254 nm) UV light,
1% aq KMnO4 solution to visualise components. NMR spectra were
recorded in CDCl3 using a Bruker AMX400 operating at 400 MHz for
1H and 100 MHz for 13C. The chemical shifts are expressed in parts
per million (ppm) referenced to residual chloroform. 1H NMR data
are reported as follows: d, chemical shift; multiplicity (recorded as:
s, singlet; br s, broad singlet; d, doublet; t, triplet; q, quadruplet; qt,
quintuplet; ht, heptuplet; dd, double doublet; ddd, double double
O
S
S
S
NHAc
CF3
S
N
O
2i
2h
2g
EtO
EtO
S
S
S
OEt
EtO
S
O
O
O
O
S
S
S
N
O
2l
2j
2k
N
Ts
Figure 1.

B. Quiclet-Sire et al. / Tetrahedron 64 (2008) 11917–11924
11919
Table 1
Addition of xanthates to O-allyl and O-homoallyl hydroxylamine derivatives (Ar¼p-ClC6H4–)
Alkene 1
Xanthate 2
Adduct 3
Alkene 1
Xanthate 2
Adduct 3
O
AcHN
N
O
CF3 SCSOEt Me
Me
N
Ar
O
1b
2c
3b, 91%
3c, 68%
3d, 85%
1c
2h
3i, 69%
EtOCSS
Ar
MeO
Me
Ts
N
Me
O
SCSOEt
O
Me
Me
N
Ar
1b
1b
2e
2f
1c
2j
3j, 93%
3k, 79%
N
O
Me
H
N
Ar
Me SCSOEt
O
F
O
SCSOEt
N
O
Ar
NHBoc
Me
O
Ar
N
EtOCSS
O
O
BocHN
1d
1d
2d
2i
Me
Me
O
O
F
EtOCSS
3e, 64%
4a, 7%
4b, 13%
3l, 79%
Cl
1c
2a
Me
Me
O
O
N
SCSOEt
Cl
O
NHBoc
O
O
O
F
SCSOEt
EtOCSS
O
NHBoc
N
Me
Me
1c
1c
2b
2f
3f, 58%
3g, 87%
3m, 24%
3n, 56%
O
N
O
O
Me
SCSOEt
1d
1d
2k
O
SCSOEt
SCSOEt
N
O
Me
Me
O
O
Me
NHBoc
BocHN
2
2
O
EtOCSS
O
SCSOEt
N
Me
Me
O
O
N
N
NHBoc
1c
2g
3h, 84%
2l
3o, 81%
O
EtOCSS
O
O
Spectrophotometer. Mass spectra were recorded with an HP 5989B
mass spectrometer via direct introduction for chemical positive
ionisation (CI) using ammonia as the reagent gas. Melting points
were determined by Reichert microscope apparatus and were un-
corrected. HRMS was performed on JEOL JMS-GcMate II, GC/MS
system spectrometer. Xa represents the xanthate group,
–SC(]S)OEt.
Me
Me
N
O
S
DLP
Cl
Me
S
OEt
(120 mol%)
Cl
O
PhCl, Δ
Me
N
O
O
3e
4a, 56%
2.2. General procedure A. Xanthate transfer radical addition
Me
Me
N
O
S
Alkene and xanthate were dissolved in dichloroethane (1 M
concentration) and the mixture was heated at reflux for 15 min
under nitrogen. 5 mol % DLP was added every hour until TLC
analysis showed the reaction had gone to completion. The mixture
was concentrated in vacuo. Column chromatography furnished the
product.
DLP
(200 mol%)
OEt
Me
S
O
N
Me
N
PhCl, Δ
N
O
4c, 40%
3h
O
Scheme 3.
2.2.1. S-1-(Bis(4-chlorophenyl)methyleneaminooxy)-5-(4-
methoxyphenyl)-5-oxopentan-2-yl O-ethyl carbonodithioate (3b)
General procedure A. Alkene 1b (305 mg; 1 mmol); xanthate
2c (405 mg; 1.5 mmol); solvent: DCE (1 mL); DLP: 4ꢃ20 mg
(0.2 mmol); column: petrol/EtOAc (10:1). Yield of 3b: 523 mg
(91%); nmax (thin film)/cmꢁ1 2928m, 1680s, 1599m; dH (CDCl3,
400 MHz) 1.39 (3H, t, J 7.2, Xa-CH3), 1.95–2.02 (1H, m, CHH0),
2.26–2.30 (1H, m, CHH0), 3.09 (2H, app t, J 7.4, CH2), 3.87 (3H, s,
doublet; dddd, double double double doublet; dt, double triplet;
ddt, double double triplet; dq, double quadruplet; tt, triple triplet;
td; triple doublet; tdd, triple double doublet; m, multiplet),
coupling constants (J are given in hertz, Hz) and integration.
Infrared Absorption spectra were recorded as thin films or as
solutions in CCl4 with a Perkin–Elmer 1600 Fourier Transform
OMe), 4.20–4.24 (1H, m, CHXa), 4.34 (1H, dd,
J 11.6, 6.4,

11920
B. Quiclet-Sire et al. / Tetrahedron 64 (2008) 11917–11924
Table 2
Reduction of xanthates adducts 3 (Ar¼p-ClC6H4–)
O
N
O
OAc
H
OAc
OAc
N
Xanthate 3
Reduced product 4
1) 2g
O
N
H
AcO
H
3
DLP (25 mol%)
H
AcO
H
OAc
H
OAc
Me
O
DCE, Δ
N
Ar
Me
Me
3c
4d, 73%
4e, 75%
4f, 85%
4g, 88%
N
O
2) H2PO3, NEt3
AIBN
H2O, dioxane, Δ
H
H
Ar
Ar
Me
H
OAc
CH2OAc
O
CH2OAc
N
3d
3i
4k, 49%
1e
Me
O
O
Ar
AcHN
N
Me
O
O
CF3
Me
N
N
O
Ts
N
2d
Me
Me
3j
F
O
DLP
(210 mol%)
DCE, Δ
N
O
F
H
H
3k
3l
4h, 74%
4i, 88%
NHBoc
O
4l, 54%
1f
HO
Scheme 5.
HO
O
O
O
NHBoc
O
O
13.8, 25.7, 35.4, 49.8, 55.5, 70.2, 76.2, 128.6, 128.6, 128.6, 129.2,
129.8, 130.3, 130.7, 130.7, 130.8, 130.9, 134.4, 135.1, 135.7, 155.4,
163.5, 197.6; m/z (CIþ) 457 (MHþ, 55%), 459 (30), 516 (12), 575
(Mþ, 100), 576 (35), 577 (75), 578 (20).
N
NHBoc
3o
4j, 87%
O
O
O
CHH0ON), 4.46 (1H, dd, J 11.6, 5.2, CHH0ON), 4.67 (2H, m, Xa-
CH2), 6.91 (2H, d, J 8.8, 2ꢃAr-H), 7.29 (2H, d, J 8.4, 2ꢃAr-H), 7.31
(2H, d, J 8.4, 2ꢃAr-H), 7.40 (2H, d, J 8.4, 2ꢃAr-H), 7.42 (2H, d, J
8.4, 2ꢃAr-H), 7.89 (2H, d, J 8.8, 2ꢃAr-H). dC (CDCl3, 100 MHz)
2.2.2. S-1-(Bis(4-chlorophenyl)methyleneaminooxy)-5-(tert-
butylamino)-4-methyl-5-oxopentan-2-yl O-ethyl
carbonodithioate (3c)
General procedure A. Alkene 1b (307 mg, 1 mmol); xanthate 2e
(355 mg, 1.5 mmol); solvent: DCE (1 mL); DLP: 8ꢃ20 mg
(0.40 mmol); column: petrol/DCM (1:1). Yield of 3c: 378 mg (68%).
The product was obtained as a mixture of diastereoisomers, which
was characterised as the monoisomeric xanthate reduction product
4d.
CF3CO2
O
O
CF3CO2H
DCM
O
O
NHBoc
NH3
4
4
O
O
6a, 99%
4i
K2CO3
MeOH, H2O
2.2.3. S-1-(Bis(4-Chlorophenyl)methyleneaminooxy)-5-oxohexan-
2-yl O-ethyl carbonodithioate (3d)
General procedure A. Alkene 1b 307 mg (1 mmol); xanthate
2f (267 mg, 1.5 mmol); Solvent: DCE (1 mL); DLP: 5ꢃ20 mg
(0.25 mmol); column: petrol/ether (20:1). Yield of 3d: 412 mg
(85%); nmax (thin film)/cmꢁ1 2928m, 1714s, 1598w; dH (CDCl3,
400 MHz) 1.45 (3H, t, J 7.2, Xa-CH3), 1.76–1.87 (1H, m, CHH0),
2.10–2.22 (2H, m, CHH0), 2.14 (3H, s, Me), 2.63 (2H, app t, J 7.4,
CH2), 4.11–4.18 (1H, m, CHXa), 4.34 (1H, dd, J 11.6, 6.4, CHH0ON),
4.46 (1H, dd, J 11.6, 5.6, CHH0ON), 4.67 (2H, q, J 7.2, Xa-CH2),
7.33 (2H, d, J 8.4, 2ꢃAr-H), 7.35 (2H, d, J 8.4, 2ꢃAr-H), 7.45 (2H,
d, J 8.4, 2ꢃAr-H), 7.45 (2H, d, J 8.4, 2ꢃAr-H). dC (CDCl3, 100 MHz)
13.9, 24.9, 30.1, 40.6, 49.6, 70.3, 76.1, 128.6, 128.6, 129.2, 130.7,
130.9, 134.3, 135.1, 135.8, 155.4, 207.5, 213.4; m/z (CIþ) 484 (MHþ,
100%), 485 (32), 486 (83), 487 (21), 488 (18); HRMS found
363.0796; C22H23O3NCl2S2 (Mþ) requires 363.0793.
O
O
O
NH2
4
5a, 75%
NHBoc
O
N
O
O
CF3CO2H
DCM
O
O
N
NH3
4
4
O
O
O
CF3CO2
6b, 99%
4j
K2CO3
MeOH, H2O
O
MeO
O
NH2
5b, 73%
4
2.2.4. S-5-(4-Chlorophenyl)-5-oxo-1-(propan-2-ylidene-
aminooxy)pentan-2-yl O-ethyl carbonodithioate (3e)
General procedure A. Alkene 1c (113 mg,1 mmol); xanthate
2a (275 mg, 1 mmol); Solvent: DCE (1 mL); DLP: 10ꢃ20 mg
(0.50 mmol); column: petrol/ether (10:1). Yield of 3e: 249 mg
(64%); nmax (thin film)/cmꢁ1 2922m, 1687s, 1588w; dH (CDCl3,
400 MHz) 1.41 (3H, m, Xa-CH3), 1.60–1.66 (1H, m, CHH0), 1.85
(3H, s, Me), 1.87 (3H, s, Me) 2.01–2.12 (1H, m, CHH0), 2.32–
2.37 (2H, m, CH2), 4.10–4.16 (1H, m, CHXa), 4.21 (1H, dd, J
O
O
N
O
CF3CO2H
DCM
NHBoc
4
F
F
4h
6c, 59%
Scheme 4.

B. Quiclet-Sire et al. / Tetrahedron 64 (2008) 11917–11924
11921
10.8, 6.4, CHH0ON), 4.25 (1H, dd, J 10.8, 4.8, CHH0ON), 4.58–
2.2.9. O-Ethyl S-2-methyl-11-oxo-8-(trifluoromethyl)-4,10-dioxa-
4.66 (2H, m, Xa-CH2), 7.43 (2H, d, J 8.6, 2ꢃAr-H), 7.91 (2H, d, J
8.6, 2ꢃAr-H). dC (CDCl3, 100 MHz), 13.8, 15.7, 21.9, 25.6, 35.9,
49.8, 70.2, 74.5, 129.0, 129.5, 135.1, 139.6, 155.8, 197.9, 213.7;
m/z (CIþ) 315 (15%), 388 (MHþ, 100), 389 (22), 390 (42); HRMS
(EIþ) found 314.0192; C14H15O2ClS2 (MþꢁHON]CMe2) requires
314.0202.
3,9-diazadodec-2-en-6-yl carbonodithioate (3i)
General procedure A. Alkene 1c (113 mg, 1 mmol); xanthate 2h
(277 mg, 1 mmol); solvent: DCE (1 mL); DLP: 12ꢃ20 mg
(0.60 mmol); column: petrol/ether (4:1). Yield of 3i: 271 mg (69%).
This product was obtained as a mixture of diastereoisomers and
was characterised as the monoisomeric reduction product 4f below.
2.2.5. 6-Chloro-4-((propan-2-ylideneaminooxy)methyl)-3,4-
dihydronaphthalen-1(2H)-one (4a)
2.2.10. O-Ethyl S-1-(4-oxo-1-tosylpiperidin-3-yl)-3-(propan-2-
ylideneaminooxy)propan-2-yl carbonodithioate (3j)
Further elution yielded 4a as a viscous oil (19 mg, 7%). nmax (thin
film)/cmꢁ1 2925m, 1687s, 1590m; dH (CDCl3, 400 MHz) 1.91 (3H, s,
Me), 1.94 (3H, s, Me), 2.16–2.35 (2H, m, CHH0), 2.66 (1H, dt, J 17.7,
5.3, CHH0), 2.84 (1H, ddd, J 17.7, 11.6, 5.2, CHH0), 3.36–3.42 (1H, m,
CHAr), 4.25–4.35 (2H, m, CHH0ON), 7.36, (1H, dd, J 8.5, 1.8, Ar-H),
7.44 (1H, d, J 1.8, Ar-H), 8.02 (1H, d, J 8.5); dC (CDCl3, 100 MHz) 15.8,
21.9, 24.8, 35.2, 37.7, 75.3, 127.6, 128.8, 129.0, 131.0, 139.8, 146.3,
155.7, 197.0; m/z (CIþ) 266 (MHþ, 100%), 268 (36); HRMS could not
be obtained.
General procedure A. Alkene 1c 113 mg (1 mmol); xanthate 2j
(370 mg, 1 mmol); solvent: DCE (1 mL); DLP: 7ꢃ20 mg
(0.35 mmol); column: petrol/ethyl acetate (10:1). Yield of 3j:
447 mg (93%). This product was obtained as a 1:1 mixture of di-
astereoisomers, which was characterised as the monoisomeric re-
duction product 4g below.
2.2.11. tert-Butyl 3-(ethoxycarbonothioylthio)-6-(4-fluorophenyl)-
6-oxohexyloxycarbamate (3k)
General procedure A. Alkene 1d (186 mg, 1 mmol); xan-
thate: 2d (258 mg, 1 mmol); solvent: DCE (1 mL); DLP:
8ꢃ20 mg (0.40 mmol); column: petrol/ether (5:1). Yield of 3k:
349 mg (79%); nmax (thin film)/cmꢁ1 3299br m, 1732s, 1684s,
1597 m; dH (CDCl3, 400 MHz) 1.41 (3H, m, Xa-CH3), 1.50 (9H,
m, (CH3)3), 2.00–2.32 (4H, m, 2ꢃCHH0), 3.07–3.23 (2H, m,
CHH0), 3.95–4.07 (3H, m, CHXa and CHH0ON), 4.58–4.66 (2H,
m, Xa-CH2), 7.14 (2H, t, J 8.8, 2ꢃAr-H), 7.43 (1H, s, NH), 8.00
2.2.6. O-Ethyl S-5-((4-fluorophenyl)(methyl)amino)-5-oxo-1-
(propan-2-ylideneaminooxy)pentan-2-yl carbonodithioate (3f)
This compound was obtained in the same manner from alkene
1c and xanthate 2b in 58% yield; nmax (thin film)/cmꢁ1 2925 m,
1653s, 1508 m; dH (CDCl3, 400 MHz) 1.37 (3H, t, J 7.2, Xa-CH3), 1.77
(3H, s, Me), 1.0–1.81–1.90 (1H, m, CHH0), 1.82 (3H, s, Me), 2.10–2.25
(1H, m, CHH0), 3.21 (3H, s, NMe), 3.89–3.92 (1H, m, CHXa), 4.05 (1H,
dd, J 11.0, 6.2, CHH0ON), 4.16 (1H, dd, J 11.0, 5.0, CHH0ON), 4.54–4.61
(2H, m, Xa-CH2), 7.05–7.20 (4H, m, 4ꢃAr-H); dC (CDCl3, 100 MHz)
(major rotamer) 13.7,15.6, 21.7, 26.9, 31.5, 37.4, 49.7, 69.9, 74.4,116.7
(d, J 22), 129.1 (d, J 9), 139.9 (d, J 3), 155.5, 161.7 (d, J 246), 172.1,
213.7; m/z (CIþ) 328 (12%), 401 (MHþ, 100), 402 (21); HRMS could
not be obtained.
(2H, dd,
J
8.8, 5.2, 2ꢃAr-H), dC (CDCl3, 100 MHz) (major
rotamer) 13.8, 28.2, 28.7, 33.1, 35.8, 47.9, 70.1, 73.9, 81.7, 115.7
(d, J 21.7), 130.7 (d, J 9.3), 133.2 (d, J 3.0), 157.0, 165.8 (d, J
253.0), 197.6, 213.9; HRMS found 445.1381; C20H28O5NS2F (Mþ)
requires 445.1393.
2.2.12. tert-Butyl 2-(7-fluoro-4-oxo-1,2,3,4-tetrahydronaphthalen-
1-yl)ethoxycarbamate (4b)
2.2.7. O-Ethyl S-5-oxo-1-(propan-2-ylideneaminooxy)hexan-2-yl
carbonodithioate (3g)
Further elution yielded 4b (41 mg, 13%). nmax (thin film)/
cmꢁ1 3378br m, 1740 m, 1681s, 1606w; dH (CDCl3, 400 MHz)
1.55 (9H, m, (CH3)3), 1.97–2.20 (3H, m, CHH0 and CHH0), 2.31–
2.41 (1H, m, CHH0), 2.65 (1H, dt, J 18.2, 5.2CHH0C]O), 2.80 (1H,
ddd, J 18.2, 11. 6, 4.8 CHH0C]O), 3.25–3.31 (1H, m, CHAr), 3.99–
4.06 (2H, m, CHH0ON), 7.05 (1H, td, J 8.4, 2.4, Ar-H), 7.12 (1H,
dd, J 9.4, 2.6 Ar-H), 7.22 (1H, s, NH), 8.11 (1H, dd, J 8.4, 6.0, Ar-
H); HRMS found 267.0906; C13H14O4NF (MþꢁH2]Me2) requires
267.0907.
General procedure A. Alkene 1c (113 mg,1 mmol); xanthate 2f
(178 mg,1 mmol); solvent: DCE (1 mL); DLP: 7ꢃ20 mg (0.35 mmol);
column: petrol/ether (10:1). Yield of 3g: 254 mg (87%); nmax (thin
film)/cmꢁ1 2923 m, 1715s, 1643w; dH (CDCl3, 400 MHz) 1.41 (3H, t, J
7.0, Xa-CH3), 1.83–1.91 (1H, m, CHH0), 1.84 (3H, s, Me), 1.86 (3H, s,
Me), 2.12–2.21 (1H, m, CHH0), 2.15 (3H, s, Me), 2.56–2.71 (2H, m,
CH2), 3.98–4.05 (1H, m, CHXa), 4.13 (1H, dd, J 11.2, 6.4, CHH0ON),
4.25 (1H, dd, J 11.2, 4.8, CHH0ON), 4.67 (2H, q, J 6.9, Xa-CH2). dC
(CDCl3, 100 MHz) 13.8, 15.7, 12.8, 24.9, 30.0, 40.7, 49.7, 70.1, 74.4,
155.6, 207.6, 213.7; m/z (CIþ), 292 (MHþ, 100%), 293 (17); HRMS
(EIþ) found 218.0436; C9H14O2S2 (MþꢁHON]CMe2) requires
218.0435.
2.2.13. tert-Butyl 3-(ethoxycarbonothioylthio)-4-(2-
oxotetrahydrofuran-3-yl)butoxycarbamate (3l)
General procedure A. Alkene 1d (345 mg, 1.68 mmol); xanthate
2i (316 mg, 1.68 mmol); solvent: DCE (1.7 mL); DLP: 7ꢃ34 mg
(0.60 mmol); column: petrol/ethyl acetate (3:2). Yield of 3l: 522 mg
2.2.8. S-5-(9H-Carbazol-9-yl)-5-oxo-1-(propan-2-
ylideneaminooxy)pentan-2-yl O-ethyl carbonodithioate (3h)
General procedure A. Alkene 1c (113 mg,1 mmol); xanthate, 2g
(329 mg, 1 mmol); solvent: DCE (1 mL); DLP: 8ꢃ20 mg
(0.40 mmol); column: petrol/ether (20:1). Yield of 3h: 371 mg
(84%); mp 249 ꢀC decomp.; nmax (thin film)/cmꢁ1 2923 m, 1694s,
1597w; dH (CDCl3, 400 MHz) 1.45 (3H, t, J 7.0, Xa-CH3), 1.88 (3H, s,
Me), 1.90 (3H, s, Me), 2.27–2.37 (1H, m, CHH0), 2.53–2.63 (1H, m,
CHH0), 3.31–3.45 (2H, m, CH2), 4.29–4.37 (2H, m, CHXa and
CHH0ON), 4.45 (1H, dd, J 9.6, 3.6, CHH0ON), 4.67 (2H, q, J 7.2, Xa-
CH2, with doubling due to xanthate rotamers), 7.42 (2H, t, J 7.4,
2ꢃAr-H), 7.50 (2H, td, J 7.4, 1.2, 2ꢃAr-H), 8.02 (2H, d, 7.4, 2ꢃAr-H),
8.25 (2H, d, 7.4, 2ꢃAr-H). dC (CDCl3, 100 MHz) 13.8, 15.7, 21.9, 26.8,
36.7, 49.8, 70.3, 74.9, 116.6, 119.8, 123.7, 126.5, 127.4, 138.5, 155.9,
172.4, 213.8; m/z (CIþ) 365 (22%), 443 (MHþ, 100), 444 (28);
HRMS found 370.0946; C20H20O2NS2 (MHþꢁHON]CMe2) requires
370.0936.
(93%). This product was obtained as a 1:1 mixture of di-
astereoisomers, which was characterised as the monoisomeric re-
duction product 4i below.
2.2.14. tert-Butyl 3,7-bis(ethoxycarbonothioylthio)-6-
oxoheptyloxycarbamate (3m)
General procedure A. Alkene 1d (155 mg, 0.83 mmol); xanthate
2k (124 mg, 0.42 mmol); solvent: DCE (1 mL); DLP: 13ꢃ18 mg
(0.54 mmol); column: petrol/ether (4:1). Yield of 3m: 396 mg
(24%); nmax (thin film)/cmꢁ1 3300br m, 1721s; dH (CDCl3, 400 MHz)
1.43–1.48 (3H, m, Xa-CH3), 1.50 (9H, m, (CH3)3), 1.91–2.25 (4H, m,
2ꢃCHH0), 2.76–2.90 (2H, m, CHH0), 3.86–3.94 (1H, m, CHXa), 3.96–
4.06 (2H, m, CHH0ON), 4.02 (2H, CH2Xa), 4.63–4.71 (4H, m, 2ꢃXa-
CH2), 7.30 (1H, s, NH). dH (CDCl3, 400 MHz) 13.8, 13.8, 28.2, 28.3,
33.1, 39.1, 45.4, 47.7, 70.2, 70.9, 73.8, 81.8, 156.9, 202.5, 213.3, 213.9;
m/z (CIþ) 380 (24%), 430 (MHþꢁH2]CMe2, 100), 431 (19%).

11922
B. Quiclet-Sire et al. / Tetrahedron 64 (2008) 11917–11924
2.2.15. tert-Butyl (3,9-bis(ethoxycarbonothioylthio)-6-
oxoundecane-1,11-diyl)bis(oxy)dicarbamate (3n)
1.52–1.96 (4H, m, CHH0CHH0), 1.86 (3H, s, Me), 1.88 (3H, s, Me),
2.06 (3H, s, Me), 4.03 (1H, t, J 6.0CHH0ON), 4.55–4.70 (1H, CHCF3),
6.36 (1H, br s, NHOAc). dH (CDCl3, 400 MHz) 15.5, 21.8, 22.9, 24.7,
25.0, 50.3 (q, J 30), 71.9, 125.2 (q, J, 280), 155.1, 170.6; m/z (CIþ) 255
(MHþ, 100%); HRMS found 255.1312; C10H18O2N2F3 (MHþ) requires
255.1320.
Further elution yields compound 3n as a viscous oil (300 mg,
56%); nmax (thin film)/cmꢁ1 3292br m, 1714s; dH (CDCl3, 400 MHz)
1.45 (6H, t, J 7.2, 2ꢃXa-CH3), 1.50 (18H, m, 2ꢃ(CH3)3), 1.86–2.18 (8H,
m, 2ꢃCHH0), 2.55–2.67 (4H, m, 2ꢃCHH0), 3.82–3.90 (2H, m,
2ꢃCH3a), 3.96–4.06 (4H, m, 2ꢃCHH0ON), 4.66 (4H, q, J 7.2, 2ꢃXa-
CH2), 7.36 (2H, s, 2ꢃNH). dH (CDCl3, 400 MHz) 13.8, 28.1, 28.3, 33.0,
39.9, 47.9, 70.2, 73.8, 81.7, 156.9, 208.8, 214.0. HRMS could not be
obtained.
2.3.4. 3-(3-(Propan-2-ylideneaminooxy)propyl)-1-tosylpiperidin-
4-one (4g)
This compound was obtained from xanthate 3j in 88% yield.
nmax (thin film)/cmꢁ1 2925s, 1719s, 1598w; dH (CDCl3, 400 MHz)
1.30–1.42 (3H, m, CHH0 and CHH0), 1.64–1.74 (2H, m, CHH0),
1.85–1.90 (1H, m, CHC]O), 1.89 (3H, s, ON]CMeMe0), 1.91 (3H,
s, ON]CMeMe0), 2.48 (3H, s, ArMe), 2.60–2.72 (3H, m,
CHH0C]O and TsNCHH0), 3.00 (1H, td, J 11.0, 4.4, TsNCHH0),
3.75–3.87 (2H, m, CHH0NTsCHH0), 4.03 (2H, t, J 6.4, CH2ON), 7.48
(2H, d, J 8.0, 2ꢃAr-H), 7.71 (2H, d, J 8.0, 2ꢃAr-H); dC (CDCl3,
100 MHz) 14.6, 20.5, 20.9, 22.8, 25.4, 39.1, 45.6, 48.2, 49.9, 71.7,
126.5, 128.9, 132.3, 143.1, 153.7, 206.6; HRMS could not be
obtained.
2.2.16. tert-Butyl 3-(ethoxycarbonothioylthio)-6-oxo-6-(2-
oxooxazolidin-3-yl)hexyloxycarbamate (3o)
General procedure A. Alkene 1d (144 mg, 0.7 mmol); xanthate
2l (193 mg, 0.7 mmol); solvent: DCE (0.7 mL); DLP: 4ꢃ15 mg
(0.14 mmol); column: petrol/ethyl acetate (2:1).
Yield of 3o: 273 mg (81%); nmax (thin film)/cmꢁ1 3287br m,
1784s,1711s dH (CDCl3, 400 MHz) 1.47 (3H, t, J 7.2, Xa-CH3),1.52 (9H,
m, (CH3)3), 2.00–2.32 (4H, m, 2ꢃCHH0), 3.02–3.10 (1H, m, CHH0),
3.15–3.25 (1H, m, CHH0), 3.95–4.09 (5H, m, CHXa and CHH0ON and
oxazolidine CH2), 4.46 (2H, t, J 8.4, oxazolidine CH2), 4.58–4.66 (2H,
m, Xa-CH2), 7.43 (1H, s, NH). dC (CDCl3, 100 MHz) (major rotamer)
13.8, 28.3, 29.0, 32.6, 32.6, 42.6, 47.4, 62.2, 70.2, 73.7, 81.7, 153.5,
156.9, 172.6, 214.0; HRMS found 380.0704; C13H19O7S2N2
(MþꢁH2]Me2) requires 380.0707.
2.3.5. tert-Butyl 6-(4-fluorophenyl)-6-oxohexyloxycarbamate (4h)
General procedure B. Xanthate 3k (258 mg, 0.58 mmol); col-
umn: petrol/ether (5:1). Yield of 4h: 139 mg (74%); nmax (thin film)/
cmꢁ1 3299br m, 1726s, 1686s; dH (CDCl3, 400 MHz) 1.47–1.55 (2H,
m, CH2), 1.51 (9H, m, (CH3)3), 1.66–1.84 (4H, m, CH2CH2), 2.99 (2H, t,
J 7.4, CH2), 3.90 (2H, t, J 6.6, CH2ON), 7.15 (2H, t, J 8.6, 2ꢃAr-H), 7.25
(1H, s, NH), 8.01 (2H, dd, J 8.6, 5.4, 2ꢃAr-H). dC (CDCl3, 100 MHz)
24.0, 25.7, 27.9, 28.3, 38.4, 76.6, 81.6, 115.6 (d, J 22), 130.7 (d, J 9),
133.4 (d, J 3), 156.9, 165.9 (d, J 253), 198.7; HRMS found 257.1058;
C12H16O4NF (MþꢁH2C]CMe2) requires 257.1059.
2.3. General procedure B. Xanthate reduction
A solution of xanthate (1 equiv), hyposphosphorous acid (50%
solution in water, 5 equiv), and triethylamine (5.5 equiv) in dioxane
(1 mmol xanthate in 12 mL) was heated at reflux for 15 min. AIBN
(10 mol %) was added and the reaction mixture was refluxed for
30–60 min. The reaction mixture was cooled and poured onto
water. Extraction with ether and column chromatography provided
the reduced product.
2.3.6. tert-Butyl 4-(2-oxotetrahydrofuran-3-yl)
butoxycarbamate (4i)
General procedure B. Xanthate 3l (456 mg, 1.2 mmol); column:
petrol/ether (3:2). Yield of 4i: 288 mg (88%); nmax (thin film)/cmꢁ1
3296br m, 1760s, 1720s; dH (CDCl3, 400 MHz) 1.46 (9H, m, (CH3)3),
1.46–1.53 (3H, m, CHH0 and CHH0), 1.60–1.69 (2H, m, CHH0), 1.84–
1.99 (2H, m, CHH0 and CHH0), 2.35–2.55 (2H, m, CHH0 and CH), 3.84
(2H, t, J 6.4, CH2ON), 4.17 (1H, dt, J 9.0, 6.8, CHH0O), 4.32 (1H, td, J
9.0, 2.8, CHH0O), 7.43 (1H, s, NH). dC (CDCl3, 100 MHz) 23.8, 27.8,
28.2, 28.6, 30.1, 39.2, 66.6, 76.2, 81.5, 156.9, 179.5; HRMS found
141.0920; C8H13O2 (MþꢁONHBoc) requires 141.0916.
2.3.1. 5-(Bis(4-Chlorophenyl)methyleneaminooxy)-N-tert-butyl-2-
methylpentanamide (4d)
General procedure B. Xanthate 3c (0.2 mmol); column: petrol/
DCM. Yield of 4d 73%; nmax (thin film)/cmꢁ1 2967 m, 1667s, 1599w;
dH (CDCl3, 400 MHz) 1.14 (3H, d, J 6.6, CHMe), 1.37 (9H, s, C(CH3)3),
1.39–1.41 (1H, m, CHH0),1.65–1.76 (3H, m, CHH0CHH0), 2.07 (1H, app
q, J 6.6, CHMe), 4.17–4.24 (2H, m, CHH0ON), 5.21 (1H, s, NH), 7.32
(2H, d, J 8.4, 2ꢃAr-H), 7.34 (2H, d, J 8.4, 2ꢃAr-H), 7.43 (2H, d, J 8.4,
2ꢃAr-H), 7.45 (2H, d, J 8.4, 2ꢃAr-H). dC (CDCl3, 100 MHz) 18.1, 27.0,
28.9, 30.9, 42.0, 51.1, 74.8, 128.5, 128.6, 129.0, 130.8, 131.3, 134.7,
135.0, 135.5, 154.4, 175.6. HRMS found 435.1603; C23H29O2N2Cl2
(MHþ) requires 435.1606.
2.3.7. tert-Butyl 6-oxo-6-(2-oxooxazolidin-3-
yl)hexyloxycarbamate (4j)
General procedure B. Xanthate 3o 81 mg (0.19 mmol); column:
petrol/ethyl acetate (1:1). Yield of 4j: 52 mg (87%); nmax (thin film)/
cmꢁ1 3301br m, 1779s, 1701s; dH (CDCl3, 400 MHz) 1.42–1.51 (2H,
m, CH2), 1.51 (9H, m, (CH3)3), 1.65–1.76 (4H, m, CH2CH2), 2.96 (2H, t,
J 7.4, CH2), 3.87 (2H, t, J 6.6, CH2ON), 4.05 (2H, t, J 8.2, oxazolidine
CH2), 4.44 (2H, t, J 8.2, oxazolidine CH2), 7.25 (1H, s, NH). dC (CDCl3,
100 MHz) 24.0, 25.4, 27.8, 28.3, 35.0, 42.6, 62.1, 76.5, 81.6, 153.6,
157.0, 173.4; m/z (CIþ), 202 (15%), 217 (MHþꢁBoc, 100), 261 (62),
278 (36); HRMS found 216.1114; C9H16N2O4 (MþꢁBoc) requires
216.1110.
2.3.2. 6-(Bis(4-Chlorophenyl)methyleneaminooxy)
hexan-2-one (4e)
General procedure B. Xanthate 3d; column: petrol/DCM (3:1).
Yield of 4e: 75%. nmax (thin film)/cmꢁ1 1718s, 1601 m; dH (CDCl3,
400 MHz), 1.63–1.78 (2H, m, CH2CH2), 2.15 (3H, s, Me), 2.48 (2H, t, J
6.6, CH2), 4.22 (2H, t, J 6.2, CH2ON), 7.32 (2H, d, J 8.4, 2ꢃAr-H), 7.34
(2H, d, J 8.4, 2ꢃAr-H), 7.44 (2H, d, J 8.4, 2ꢃAr-H), 7.45 (2H, d, J 8.4,
2ꢃAr-H). dC (CDCl3, 100 MHz) 20.3, 28.6, 29.9, 43.3, 74.6, 128.5,
128.6, 129.1, 130.8, 131.3, 134.7, 135.0, 135.5, 154.4, 208.8; m/z (CIþ)
248 (22), 364 (MHþ, 100%), 365 (24), 366 (65); HRMS found
363.0791; C19H19O2NCl2 (Mþ) requires 363.0789.
2.3.8. 6-Chloro-4-((propan-2-ylideneaminooxy)methyl)-3,4-
dihydronaphthalen-1(2H)-one (4a)
Xanthate 3e (80 mg, 0.21 mmol) was dissolved in chloroben-
zene (1.5 mL) and the mixture was heated at reflux for 15 min. DLP
(17 mg, 0.042 mmol, 20 mol %) was added every 20 min for 2 h
(totald102 mg, 0.252 mmol, 120 mol %). The mixture was con-
centrated in vacuo. Column chromatography (20:1 petrol/ethyl
acetate) furnished the product 4a (28 mg, 56%). Spectroscopic data
as above.
2.3.3. Propan-2-one O-4-(acetoxyamino)-5,5,5-trifluoropentyl
oxime (4f)
General procedure B. Xanthate 3i (140 mg; 0.36 mmol); col-
umn: petrol/ether (1:1). Yield of 4f: 77 mg (85%); mp 61–63 ꢀC;
nmax (thin film)/cmꢁ1 3277br s, 1667s, 1551 m; dH (CDCl3, 400 MHz)

B. Quiclet-Sire et al. / Tetrahedron 64 (2008) 11917–11924
11923
2.3.9. 4-((Propan-2-ylideneaminooxy)methyl)-5,6-
dihydroazepino[3,2,1-jk]carbazol-7(4H)-one (4c)
mixture was stirred for 1 h before being poured onto H2O (5 mL)
and extracted with EtOAc (3ꢃ10 mL). The combined organic layers
were dried over MgSO4 and concentrated in vacuo. Column chro-
matography (EtOAc) yielded the product 5b as a colourless oil
(25 mg, 68%); nmax (thin film)/cmꢁ1 3444br m, 1733s; dH (CDCl3,
400 MHz) 1.35–1.45 (2H, m, CH2), 1.58–1.73 (4H, m, CH2 and CH2),
2.35 (2H, t, J 7.4, CH2), 3.68 (2H, t, J 6.6, CH2ON), 3.69 (3H, s, Me),
4.50 (2H, br s, NH2); dC (CDCl3, 100 MHz) 24.8, 25.6, 28.1, 34.0, 51.5,
75.8, 174.2; m/z (CIþ) 162 (MHþ, 100%); HRMS (EIþ) found 162.1122;
C7H16NO3 (MHþ) requires 162.1130.
Xanthate 3h (230 mg, 0.52 mmol) was dissolved in chloroben-
zene (1.5 mL) and the mixture was heated at reflux for 15 min. DLP
(40 mg, 0.104 mmol, 20 mol %) was added every 20 min for 3 h
(totald400 mg, 1.04 mmol, 200 mol %). The mixture was concen-
trated in vacuo. Column chromatography (20:1 petrol/ethyl ace-
tate) furnished the product 4c (67 mg, 40%) as a viscous oil; nmax
(thin film)/cmꢁ1 2925m, 1690s; dH (CDCl3, 400 MHz) 1.88 (3H, s,
Me), 1.93 (3H, s, Me) 2.31–2.43 (2H, m, CHH0), 3.14 (1H, ddd, J 16.6,
7.2, 2.9, CHH0), 3.25 (1H, ddd, J 16.6, 10.8, 3.6, CHH0), 3.70–3.77 (1H,
m, CHAr), 4.24 (1H, dd, J 11.0, 9.0,CHH0ON), 4.24 (1H, dd, J 11.0, 5.6,
CHH0ON), 7.36–7.48 (3H, m, 3ꢃAr-H), 7.53 (1H, ddd, J 8.4, 7.2,1.2, Ar-
H), 7.95 (1H, dd, J 7.2, 1.2, Ar-H), 8.01 (1H, d, 7.6, Ar-H), 8.71 (1H, d, J
8.4, Ar-H). dC (CDCl3, 100 MHz) 15.7, 21.9, 23.2, 35.6, 41.8, 76.2, 118.4,
118.4, 119.1,123.6, 124.1, 126.2, 127.8,127.9, 128.0, 129.4, 136.4, 139.6,
155.5, 173.8; HRMS found 247.0999; C17H13NO (MþꢁHON]Me2)
requires 247.0997.
2.3.14. 3-(4-Fluorophenyl)-5,6,7,8-tetrahydro-4H-[1,2]
oxazocine (6c)
To a solution of Boc-protected amine 4h (85 mg, 0.27 mmol) in
DCM (1 mL) trifluoroacetic acid (1 mL) was added dropwise over
5 min. The mixture was stirred for a further 30 min before being
concentrated in vacuo to yield oxime 6c (trans) as a white solid
(10 mg, 62%); mp 105–106 ꢀC; nmax (thin film)/cmꢁ1 2930 m,
1608w; dH (CDCl3, 400 MHz) 1.26–1.40 (4H, m, 2ꢃCH2), 1.72–1.79
(2H, m, CH2), 2.85 (2H, t, J 7.4, CH2C]NO), 4.21 (2H, t, J 5.6, CH2ON),
7.10 (2H, t, J 8.8, 2ꢃAr-H), 7.69 (2H, dd, J 8.8, 5.2, 2ꢃAr-H); dC (CDCl3,
100 MHz) 26.5, 26.6, 26.6, 28.7, 73.2, 115.4 (d, J 21), 128.0 (d, J 8),
132.0 (d, J 0.3), 157.2, 163.2 (d, J 124); m/z (CIþ) 208 (MHþ, 100%);
HRMS found 207.1067; C12H14ONF (Mþ) requires 207.1059.
Further elution yielded oxime 6c (cis) as a white solid (2 mg,
12%); mp 115–118 ꢀC; nmax (thin film)/cmꢁ1 2923 m, 1607w; dH
(CDCl3, 400 MHz) 1.51–1.69 (4H, m, 2ꢃCH2), 1.73–1.83 (2H, m, CH2),
2.80 (2H, t, J 7.4, CH2C]NO), 4.22 (2H, t, J 5.6, CH2ON), 7.09 (2H, t, J
8.8, 2ꢃAr-H), 7.65 (2H, dd, J 8.8, 5.2, 2ꢃAr-H); dC (CDCl3, 100 MHz)
26.1, 26.5, 26.5, 28.8, 34.2, 73.8, 115.4 (d, J 21), 128.0 (d, J 8), 132.1 (d,
J 0.3), 157.3, 163.3 (d, J 123); m/z (CIþ) 208 (MHþ, 100%); HRMS
found 208.1139; C12H15ONF (MHþ) requires 208.1138.
2.3.10. O-(4-(2-Oxotetrahydrofuran-3-yl)butyl)hydroxyl-
ammonium trifluoroacetate (6a)
To a solution of Boc-protected amine 4i (55 mg, 0.20 mmol) in
DCM (1 mL) trifluoroacetic acid (1 mL) was added dropwise over
5 min. The mixture was stirred for a further 30 min before being
concentrated in vacuo to yield the product 6a as a colourless oil
(57 mg, 99%); nmax (thin film)/cmꢁ1 1756s, 1685s; dH (d4-MeOD,
400 MHz) 1.17–1.30 (3H, m, CHH0 and CHH0), 1.42–1.60 (3H, m,
CHH0 and CHH0), 1.70–1.82 (2H, m, CHH0), 2.15–2.26 (1H, m, CHH0),
2.45–2.54 (1H, m, CH), 3.85 (2H, t, J 6.4, CH2ON), 4.06 (1H, dt, J 9.0,
6.8, CHH0O), 4.19 (1H, td, J 9.0, 2.8, CHH0O). dC (CDCl3, 100 MHz)
24.4, 28.5, 29.6, 30.9, 40.4, 68.3, 76.1, 182.2; m/z (CIþ) 174 (MHþ,
100%); HRMS found 141.0918; C8H13O2 (MþꢁONH2) requires
141.0916.
2.3.15. (2R,3R,4R,5S)-6-(Allyloxyimino)hexane-1,2,3,4,5-pentayl
pentaacetate (1e)
2.3.11. 3-(4-(Aminooxy)butyl)dihydrofuran-2(3H)-one (5a)
To a solution of triflate salt 6a (55 mg 0.19 mmol) in MeOH/H2O
(1 mL, 1:1 v/v) was added K2CO3 (83 mg, 0.6 mmol) and the mix-
ture was stirred for 1 h before being poured onto H2O (5 mL) and
extracted with EtOAc (3ꢃ10 mL). The combined organic layers were
dried over MgSO4 and concentrated in vacuo. Column chromatog-
raphy (EtOAc) yielded the product 5a as an oil (24 mg, 74%); nmax
(thin film)/cmꢁ1 3418br m, 1762s; dH (CDCl3, 400 MHz) 1.45–1.56
(3H, m, CHH0 and CHH0), 1.62–1.70 (3H, m, CHH0 and CHH0), 1.88–
2.03 (2H, m, CHH0), 2.40–2.48 (1H, m, CHH0), 2.52–2.61 (1H, m, CH),
3.71 (2H, t, J 6.4, CH2ON), 4.23 (1H, dt, J 9.0, 6.8, CHH0O), 4.37 (1H, td,
J 9.0, 2.8, CHH0O). dC (CDCl3, 100 MHz) 24.0, 28.2, 28.6, 30.2, 39.2,
39.3, 66.5, 75.6, 179.5; m/z (CIþ) 174 (MHþ, 100%); HRMS found
141.0921; C8H13O2 (MþꢁONH2) requires 141.0916.
To a solution of protected hydroxylamine 1a (258 mg, 1.5 mmol)
in DCM (1 mL), trifluoroacetic acid (1 mL) was added dropwise over
5 min. The mixture was stirred for a further 30 min before being
concentrated in vacuo. The resultant oil was dissolved in pyridine
(5 mL), glucose pentaacetate 7a (390 mg, 1 mmol) was added and
the mixture was heated at 60 ꢀC for 150 min before being allowed
to cool to room temperature. The mixture was diluted with ethyl
acetate (20 mL), poured onto 1 M aqueous HCl solution (20 mL) and
the layers were separated. The aqueous layer was extracted with
ethyl acetate (2ꢃ20 mL) and the combined organics were dried
over MgSO4 and concentrated in vacuo to furnish a mixture of
oxime diastereoisomers and acetate regioisomers. The mixture was
dissolved in acetic anhydride (5 mL), pyridine (1 drop) and DMF (1
drop) were added and the mixture was stirred for 16 h before being
concentrated in vacuo. Column chromatography (4:1 petrol/ethyl
acetate) furnished alkene 1e as a 5:1 mixture of diastereoisomers as
2.3.12. O-(6-Oxo-6-(2-oxooxazolidin-3-yl)hexyl)
hydroxylammonium (6b)
To a solution of Boc-protected amine 4j (85 mg, 0.27 mmol) in
DCM (1 mL) trifluoroacetic acid (1 mL) was added dropwise over
5 min. The mixture was stirred for a further 30 min before being
concentrated in vacuo to yield the product 6b as a colourless oil
(89 mg, 99%); nmax (MeOH)/cmꢁ1 3409br m, 1781s, 1679s; dH (d4-
MeOD, 400 MHz) 1.44–1.52 (2H, m, CH2), 1.65–1.77 (4H, m, CH2 and
CH2), 2.90 (2H, t, J 7.4, CH2), 3.97 (2H, t, J 8.2, oxazolidine CH2), 4.07
(2H, t, J 6.6, CH2ON), 4.41 (2H, t, J 8.2, oxazolidine CH2). dC (d4-
MeOD, 100 MHz) 24.9, 26.2, 28.5, 35.8, 43.8, 63.8, 76.2, 155.8, 174.9;
m/z (CIþ) 217 (Mþ, 100%); HRMS found 217.1184; C9H17N2O4 (Mþ)
requires 217.1188.
a white solid (295 mg, 66%); mp 66–72 ꢀC; (thin film)/cmꢁ1
n
2966m, 1751s, 1644w; dH (CDCl3, 400 MHz) 2.07 (3H, s, Me, minor
diastereoisomer), 2.08 (6H, app s, 2ꢃMe, major diastereoisomer),
2.09 (3H, s, Me, minor), 2.09 (3H, s, Me, minor), 2.10 (3H, s, Me,
major), 2.10 (3H, s, Me, major), 2.11 (3H, s, Me, minor), 2.15 (3H, s,
Me, major), 2.16 (3H, s, Me, minor), 4.09 (1H, dd, J 12.4, 5.4,
CHH0OAc, major), 4.15 (1H, dd, J 12.2, 6.4, CHH0OAc, minor), 4.27
(1H, dd, J 12.4, 3.4, CHH0OAc, major), 4.15 (1H, dd, J 12.2, 3.6,
CHH0OAc, minor), 4.57, (1H, dt, J 4.8, 1.4, CH2CH], major), 4.63 (1H,
dt, J 4.8, 1.2, CH2CH], minor), 5.10 (1H, m, CHOAc, minor), 5.12 (1H,
ddd, J 8.0, 5.4, 3.4, CHOAc, major), 5.24 (1H, dq, J 10.4, 1.4,]CHH0,
major), 5.25 (1H, dq, J 10.4, 1.2,]CHH0, minor), 5.31 (1H, dq, J 17.2,
1.4,]CHH0, major), 5.34 (1H, dq, J 17.2, 1.2,]CHH0, minor), 5.41 (1H,
dd, J 8.0, 2.4, CHOAc, major), 5.44 (1H, dd, J 6.4, 4.8, CHOAc, minor),
5.50–5.54 (2H, m, CHOAcCHOAc, major), 5.51–5.56 (1H, m, CHOAc,
2.3.13. Methyl 6-(aminooxy)hexanoate (5b)
To a solution of triflate salt 6b (75 mg 0.23 mmol) in MeOH/H2O
(1 mL, 1:1 v/v) was added K2CO3 (94 mg, 0.6 mmol) and the

11924
B. Quiclet-Sire et al. / Tetrahedron 64 (2008) 11917–11924
minor), 5.62 (1H, t, J 5.2, CHOAc, minor), 5.93–6.04 (1H, m,
CH2CH], major), 5.97–6.07 (1H, m, CH2CH], minor), 6.59 (1H, d, J
5.6, CH]NO, minor), 7.33 (1H, d, J 5.6, CH]NO, major); dC (CDCl3,
100 MHz) major diastreoisomer 20.6, 20.7, 20.7, 20.8, 20.8, 61.8,
68.2, 68.4, 69.3, 69.5, 75.5, 118.3, 133.5, 143.8, 169.5, 169.5, 169.8,
169.8, 170.5dminor diastereoisomer 20.5, 20.6, 20.7, 20.8, 20.8,
61.5, 66.1, 68.9, 68.9, 75.8, 118.0, 133.6, 145.6, 169.5, 169.5, 169.6,
169.8, 170.5; m/z (CIþ) 381 (75%), 382 (15), 446 (MHþ, 100%), 447
(22), 463 (18); HRMS found 445.1586; C19H27NO11 (Mþ) requires
445.1584.
diastereoisomer), 4.08 (1H, t, J 6.8, CH2CH]CH2, major di-
astereoisomer), 5.05 (1H, d, J 10.0,]CHH0), 5.10 (1H, dq, J 17.2,
1.6,]CHH0), 5.80–5.90 (1H, m, CH]CHH0). dC (CDCl3, 100 MHz)
12.4, 17.3, 20.8, 23.2, 25.8, 28.6, 31.5, 31.6, 33.9, 34.3, 35.0, 35.7, 37.0,
38.1, 44.0, 44.9, 53.9, 54.6, 71.2, 72.4, 116.3, 135.3, 170.8.
2.3.19. 6-Fluoro-4-(2-((E)-((3S,5S,10S,13S)-3-hydroxy-10,13-
dimethyldodecahydro-1H-cyclopenta[a]phenanthren-
17(2H,10H,14H)-ylidene)aminooxy)ethyl)-3,4-dihydro-
naphthalen-1(2H)-one (4l)
Alkene 1f (300 mg, 0.81 mmol) and xanthate 2d (315 mg,
1.2 mmol) were dissolved in dichloroethane (1.2 mmol) and the
mixture was heated at reflux for 15 min. DLP (16 mg, 5 mol %) was
added every hour for 10 h (160 mg, 50 mol % in total). The mixture
was diluted with dichloroethane (4 mL) and DLP (74 mg, 20 mol %)
was added every 30 min for 4 h (592 mg, 160 mol % in total). The
mixture was concentrated in vacuo and column chromatography
(2:1 petrol/ether) furnished oxime 4l (215 mg, 54%) as a 1:1 mix-
2.3.16. (11S,12R,13R,14R)-6-(3-(9H-Carbazol-9-yl)-3-oxopropyl)-4-
thioxo-3,8-dioxa-5-thia-9-azapentadec-9-ene-11,12,13,14,15-
pentayl pentaacetate
Alkene 1e (90 mg, 0.2 mmol) and xanthate 2g (100 mg,
0.3 mmol) were dissolved in dichloroethane (0.3 mL) and the
mixture was heated at reflux for 15 min. DLP (4 mg, 5 mol %) was
added every hour for 5 h (20 mg, 25 mol %). The mixture was
concentrated in vacuo and column chromatography (4:1 petrol/
ethyl acetate) furnished the product (120 mg, 76%) as a mixture of
diastereoisomers, which was characterised as the monoisomeric
reduction product 4k below.
ture of diastereoisomers; mp 208–210 ꢀC;
n
(thin film)/cmꢁ1 3408
br s, 2928s, 1682s, 1606m; dH (CDCl3, 400 MHz) 83 (3H, s, steroid-
Me), 0.92 (3H, s, steroid-Me), 0.70–2.52 (20H, m, 20ꢃsteroid-H and
2ꢃCHH0), 2.62 (1H, dt, 17.6, 4.8, CHH0C]O), 2.80 (1H, ddd, J 17.6,
11.6, 4.8, CHH0C]O), 3.12–3.17 (1H, m, ArCH), 3.59–3.67 (1H, m,
CHOH), 7.00–7.05 (2H, m, 2ꢃAr-H), 8.10 (1H, dd, J 9.6, 7.4, Ar-H); dC
(CDCl3, 100 MHz) peaks which exhibit doubling due to di-
astereoisomeric mixture are labelled d 12.4, 17.4d, 20.9, 23.3, 25.9,
27.0d, 28.6, 31.5, 31.6, 33.7d, 34.3d, 34.8, 35.0, 35.3, 35.7, 37.0, 38.2,
44.2, 44.9, 54.0d, 54.6, 70.8, 71.2, 114.4 (d, J 22), 114.9 (d, J 21), 128.7
(d, J 1), 130.6 (d, 10), 151.2d, 165.8 (d, J 253), 171.0, 196.8; m/z (CIþ)
496 (MHþ, 100%), 497 (37); HRMS found 495.3146; C31H41O3NF
(Mþ) requires 495.3149.
2.3.17. (2R,3R,4R,5S)-6-(5-(9H-Carbazol-9-yl)-5-
oxopentyloxyimino)hexane-1,2,3,4,5-pentayl pentaacetate (4k)
The above xanthate (120 mg, 0.15 mmol) was subjected to re-
duction according to General procedure B and the product purified
by column chromatography (petrol/ethyl acetate 1:1). Yield of 4k:
63 mg (64%) as a mixture from which the major trans oxime isomer
could be isolated (24 mg, 24%).
Major isomer: mp 212 ꢀC decomp.; nmax (thin film)/cmꢁ1 2938m,
1750s, 1693m; dH (CDCl3, 400 MHz) 1.88–1.95 (2H, m, CH2), 2.03–
2.08 (2H, m, CH2), 2.07 (3H, s, Me), 2.10 (3H, s, Me), 2.11 (3H, s, Me),
2.12 (3H, s, Me), 2.15 (3H, s, Me), 3.25 (2H, t, J 7.6, CH2C]O), 4.09
(1H, dd, J 12.4, 5.6, CHH0OAc), 4.21 (2H, t, J 6.4, CH2ON), 4.27 (1H, dd,
J 12.4, 3.2, CHH0OAc), 5.12–5.17 (1H, ddd, J 8.0, 5.6, 3.2CHOAc), 5.43
(1H, dd, J 8.0, 2.8, CHOAc), 7.31 (1H, d, J 6.0, CH]NO), 7.44 (2H, t, J
7.4, 2ꢃAr-H), 7.53 (2H, td, J 7.4, 1.2, 2ꢃAr-H), 8.05 (2H, d, J 7.4, 2ꢃAr-
H), 8.28 (2H, d, J 7.4, 2ꢃAr-H). dC (CDCl3, 100 MHz) 19.4, 20.6, 20.7,
20.8, 21.3, 27.3, 28.2, 38.8, 61.8, 68.3, 68.4, 69.3, 69.6, 74.3, 116.5,
119.9, 123.6, 126.5, 127.4, 169.4, 169.5, 169.8, 170.5, 173.0; m/z (CIþ),
656 (MHþ, 100), 659 (25), 673 (18); HRMS found 655.2535;
C33H39N2O12 (MHþ) requires 655.2503.
Acknowledgements
One of us (D.W.) thanks Ecole Polytechnique for a post-doctoral
grant.
References and notes
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Serra, F.; Zappavigna, M. P.; Melloni, P. J. Med. Chem. 2000, 43, 2332–2349; (b)
Mikola, H.; Ha¨nninen, E. Bioconjugate Chem. 1992, 3, 182–186.
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Renaudet, O.; Defrancq, E.; Duny, P. J. Org. Chem. 2006, 71, 2402–2410; (c)
Gilmore, J. M.; Scheck, R. A.; Esser-Kahn, A. P.; Joshi, N. S.; Francis, M. B. Angew.
Chem., Int. Ed. 2006, 45, 5307–5311.
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2.3.18. (5aS,7S,9aS,11aS)-3-Hydroxy-10,13-dimethyltetra-
decahydro-1H-cyclopenta[a]phenanthren-17(2H)-
one O-but-3-enyl oxime (1f)
To a solution of protected hydroxylamine 1d (279 mg, 1.5 mmol)
in DCM (1 mL) trifluoroacetic acid (1 mL) was added dropwise over
5 min. The mixture was stirred for a further 30 min before being
concentrated in vacuo. The resultant oil was dissolved in pyridine
(5 mL), epiandrosterone (306 mg, 1 mmol) was added and the
mixture was heated at 60 ꢀC for 150 min before being allowed to
cool to room temperature. The mixture was diluted with ethyl ac-
etate (20 mL), poured onto 1 M aqueous HCl solution (20 mL) and
the layers were separated. The aqueous layer was extracted with
ethyl acetate (2ꢃ20 mL) and the combined organics were dried
over MgSO4 and concentrated in vacuo. Column chromatography
(3:2 petrol/ether) furnished the oxime 1f as a 15:1 mixture of di-
astereoisomers (318 mg, 86%); mp 157–160 ꢀC;
n
(thin film)/cmꢁ1
3414br m, 2929m, 1671s; dH (CDCl3, 400 MHz) 0.85 (3H, s, steroid-
Me), 0.91 (3H, s, steroid-Me), 0.7–2.0 (20H, m, 20ꢃsteroid-H), 2.03
(1H, br s, OH), 2.36–2.52 (4H, m, CHH0C]NO and CH2CH2CH]CH2),
3.57–3.65 (1H, m, CHOH), 4.99 (1H, t, J 6.8, CH2CH]CH2, minor
11. Saiki, H.; Mukai, T. Chem. Lett. 1981, 1561–1564.