A convergent and flexible approach to hydroxylamines, hydrazines and related structures

Article abstract of DOI:10.1055/s-2002-31899

Intermolecular xanthate transfer radical addition to protected allyl hydroxylamine or hydrazine provides a new, flexible, and convergent route to adducts which can be readily elaborated into complex aromatic or heterocyclic hydroxylamine or hydrazine derivatives.

Full text of DOI:10.1055/s-2002-31899

LETTER
903
A Convergent and Flexible Approach to Hydroxylamines, Hydrazines and
Related Structures
A
B
C
onvergent
A
p
é
proach to H
a
ydroxylam
t
ines,
H
r
ydrazin
i
c
elate
d
Str
e
Laboratoire de Synthèse Organique associé au CNRS, Ecole Polytechnique, 91128 Palaiseau, France
Fax +33(169)333851; E-mail: zard@poly.polytechnique.fr
Received 22 March 2002
We have, over the past few years, shown that xanthates
and related dithiocarbonic acid derivatives) readily un-
dergo a group transfer radical addition, allowing the intra-
Abstract: Intermolecular xanthate transfer radical addition to pro-
tected allyl hydroxylamine or hydrazine provides a new, flexible,
and convergent route to adducts which can be readily elaborated
(
into complex aromatic or heterocyclic hydroxylamine or hydrazine and especially inter-molecular creation of new C–C bonds
3
derivatives.
even on unactivated olefins. The superiority of this tech-
nology derives from its generality, mildness, and absence
of heavy metals and other ecologically unacceptable in-
gredients. As part of our ongoing study, we have now
found that complex hydroxylamine and hydrazine struc-
tures can be readily assembled through a radical addition
to Boc protected N-allyl-hydroxylamine 2a or hydrazine
2b.4
Key words: hydrazines, hydroxylamines, xanthates, radical reac-
tions
Hydroxylamine and hydrazine based functions, especially
hydroxamic acids and hydrazides, are present in a number
1
of biologically active natural products. These include si-
1
f
derophores, such as mycobactin J (Figure), matrix met- The general mechanism outlining the principle of the pro-
alloproteinase inhibitors, and some antibiotics and cess is shown in Scheme 1. Radical R , generated from
antifungals, such as compound YM-24074, a peptide an- xanthate 1, has a relatively long effective lifetime in the
tibiotic, which contains both a hydroxamic and a cyclic medium, since it is not consumed by reaction with its pre-
hydrazide subunit (Figure; only two of the three asymmet- cursor (path A is reversible and degenerate), and can
1
g
ric centers have been determined).
therefore add to the unactivated olefinic bond of the trap
path B). Reversible exchange of xanthate finally produc-
(
es the adduct 4 and regenerates R to propagate the chain.
In the present case, we were concerned by the possibility
that intermediate radical 3 might undergo an S 2 substitu-
H
tion on the nitrogen to give an aziridine 5 by cleavage of
relatively weak N–O or N–N bond (path C). Such a be-
haviour has indeed been observed in the case of allylic
peroxides, which readily produce epoxides.5
In the event, our worries about an S 2 side reaction via
H
path C were unfounded. We first tested this approach by
the synthesis of -tetralones 7a–c, as depicted in
Scheme 2. Thus, heating a solution of S-p-bromophenacyl
xanthate 5a and protected allylhydroxylamine 2a in re-
fluxing 1,2-dichloroethane with the periodic addition of a
small amount of lauroyl peroxide, resulted in the forma-
tion of the expected adduct 6a in 43% yield (60% based
on recovered starting material). Exposure of this com-
Figure
Traditional routes to such compounds have relied mostly pound to a stoichiometric amount of the peroxide (added
on the alkylation and acylation of simple hydroxylamine portion-wise) induced a second C–C bond formation
or hydrazine derivatives and on the partial reduction of, or through ring closure onto the aromatic ring to give tetral-
6
addition of organometallic reagents to oximes, nitrones, one 7a in 55% yield. In a similar fashion, protected allyl-
2
and hydrazones. Except for the acylation, where a com- hydrazine 2b was converted first into adducts 6b and 6c in
plex acylating agent may be used, these methods are often 79% and 82% yield respectively, then into the corre-
limited to simple structures and are intolerant of many sponding tetralones 7b and 7c by treatment with stoichio-
functional groups, which have to be protected beforehand. metric amounts of peroxide.
Synlett 2002, No. 6, 04 06 2002. Article Identifier:
1
©
437-2096,E;2002,0,06,0903,0906,ftx,en;D06502ST.pdf.
Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

9
04
B. Quiclet-Sire et al.
LETTER
hyde. A similar sequence starting from lactone 12 and ole-
fin 2a provided first adduct 13, then a cyclic hydroxamic
acid, characterized as its diacetate 15 in reasonable overall
yield.
Scheme 1
Scheme 3 (i) Lauroyl peroxide (10–15 mol%), (CH Cl) , reflux.
2
2
(
(
ii) Bu SnH (AIBN), toluene, reflux. (iii) TFA, (CH Cl) ; TEA,
3
2
2
CH Cl) . (iv) p-Chlorobenzaldehyde, EtOH, reflux. (v) Ac O,
2
2
2
Scheme 2 (i) Lauroyl peroxide (10–15 mol%), (CH Cl) , reflux.
2
2
pyridine.
(
ii) Lauroyl peroxide (1–1.15 equiv), (CH Cl) , reflux. (yield in
2 2
parenthesis is based on recovered starting material).
The versatility of this convergent approach to heterocyclic
ring construction was further demonstrated by varying the
functions present in the xanthate partner. Addition of
compound 16 to olefin 2b occurred with remarkable effi-
ciency, giving the corresponding adduct 17 in almost
quantitative yield. Reductive removal of the xanthate then
treatment with trifluoroacetic acid followed by buffering
with triethylamine gave rise to the seven membered ring
hydrazone 19. As anticipated, the aldehyde reacted in
preference to the ester group to give the relatively rare
This methodology could be easily extended to the synthe-
sis of useful heterocycles, as illustrated by the examples in
Scheme 3. Thus, addition of xanthate 8 to olefin 2b gave
the expected addition product 9, from which the xanthate
group was reductively removed with tri-n-butylstannane
in nearly quantitative yield. Exposure of the resulting
product 10 to the action of trifluoroacetic acid in 1,2-
dichloroethane, followed by triethylamine afforded N-
amino-2-piperidone in 75% yield. To facilitate isolation
and characterization, this was converted into the known
[
1,2] diazepine structure.8
7
hydrazone 11 by condensation with p-chlorobenzalde-
Synlett 2002, No. 6, 903–906 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
A Convergent Approach to Hydroxylamines, Hydrazines and Related Structures
905
The xanthate group, in the preceding examples was re- hydroxylamine 26 in 70% crude yield. Some decomposi-
moved for convenience. More densely functionalized tion occurred upon purification by distillation.
structures may be constructed by omitting the reduction
step. For instance, reaction of xanthate 20 with protected
allyl hydrazine 2b afforded the corresponding addition
In summary, we have described a simple, yet highly effi-
cient and flexible route to a variety of hydroxylamine and
hydrazine derivatives, many of which would be difficult
product 21, which underwent acid mediated deprotection
and double ring closure to furnish bicyclic pyrazolone 22
in a useful overall yield (Scheme 4). It is interesting to
note that the formation of compound 21 represents ulti-
mately an elongation at position 4 of ethyl acetoacetate,
performed under neutral conditions. Using ionic chemis-
try, the creation of new C–C bonds at this position re-
quires the prior formation of either the strongly basic
dianion of the acetoacetate or the bis-(silyl enol ether) un-
10
to obtain by more conventional methods. The reagents
are cheap and readily available, and the reaction condi-
tions sufficiently mild to tolerate many of the functional
groups encountered in modern organic synthesis.
References
(
1) (a) Surnam, M. D.; Miller, M. J. J. Org. Chem. 2001, 66,
2466; and numerous references there cited. (b) Miller, M. J.
Chem. Rev. 1989, 89, 1563. (c) Michaelides, M. R.; Curtin,
M. L. Curr. Pharm. Des. 1999, 5, 787. (d) Nikam, S. S.;
Kornberg, B. E.; Johnson, D. R.; Doherty, A. M.
9
der Lewis acid catalysis. Xanthate 20, trivially made by
displacing the chloride from commercially available ethyl
4
-chloroacetoacetate with potassium O-ethyl xanthate, is
Tetrahedron Lett. 1995, 36, 197. (e) Karunartne, V.;
Hoveyda, H. R.; Orvig, C. Tetrahedron Lett. 1992, 33,
thus a very convenient reagent, which complements by its
reactivity the more common ionic processes.
1827. (f) Schwartz, B. D.; De Voss, J. J. Tetrahedron Lett.
2001, 42, 3653. (g) Sato, T.; Takebayashi, Y.; Tokunaga, T.;
Ozasa, T. J. Antibiot. 1996, 49, 811.
(
2) (a) Wroblonsky, H.-J.; Andree, R.; Kluth, J. F. In Methoden
der Organischen Chemie (Houben-Weyl), Vol. E16a;
Klamann, D., Ed.; Georg Thieme Verlag: Stuttgart, 1990, 1.
(
b) Jensen-Korte, U.; Müller, N. In Methoden der
Organischen Chemie (Houben-Weyl), Vol. E16a; Klamann,
D., Ed.; Georg Thieme Verlag: Stuttgart, 1990, 421.
(
3
c) Chang, Z.-Y.; Coates, R. M. J. Org. Chem. 1990, 55,
464. (d) Merino, P.; Lanaspa, A.; Merchan, F. L.; Tejero, T.
J. Org. Chem. 1996, 61, 9028; and references there cited.
3) (a) Zard, S. Z. Angew.Chem., Int. Ed. Engl. 1997, 36, 672.
(
(
(
b) Quiclet-Sire, B.; Zard, S. Z. Phosphorus, Sulfur, Silicon
1999, 153. (c) Zard, S. Z. Angew.Chem., Int. Ed. Engl. 1997,
36, 137. (d) Zard, S. Z. J. Chin. Chem. Soc. 1999, 46, 139.
(
e) For addition of xanthates to allyl amines, see: Boivin, J.;
Pothier, J.; Zard, S. Z. Tetrahedron Lett. 1999, 40, 3701.
4) (a) Staszak, M. A.; Doecke, C. W. Tetrahedron Lett. 1993,
34, 7043. (b) Mellor, S. L.; Chan, W. C. Chem. Commun.
1997, 2005. (c) Genet, J. P.; Thorimbert, S.; Touzin, A. M.
Tetrahedron Lett. 1993, 34, 1159. (d) Maëorg, U.;
Ragnarsson, U. Tetrahedron Lett. 1998, 39, 681.
5) (a) Ramon, F.; Degueil-Castaing, M.; Maillard, B. J. Org.
Chem. 1996, 61, 2071. (b) Ramon, F.; Degueil-Castaing,
M.; Maillard, B. Tetrahedron 1998, 54, 11489; and
references there cited.
(
(
6) Liard, A.; Quiclet-Sire, B.; Saicic, R. N.; Zard, S. Z.
Tetrahedron Lett. 1997, 38, 1759.
(
(
7) Smith, P. A. S.; Pars, H. G. J. Org. Chem. 1959, 24, 1325.
8) For some examples see: (a) Kane, J. M.; Stewart, K. T. J.
Heterocycl. Chem. 1988, 25, 1471. (b) Kalyanam, K. G.;
Likhate, M. A. Synth. Commun. 1988, 18, 2183.
(
c) Zimmerman, H. E.; Eberbach, W. J. Am. Chem. Soc.
973, 95, 3970.
9) (a) Huckin, S. N.; Weiler, L. J. Am. Chem Soc. 1974, 96,
082. (b) Chan, T.-H.; Brownbridge, P. J. Chem. Soc.,
1
Scheme 4 (i) Lauroyl peroxide (15–40 mol%), (CH Cl) , reflux.
2
2
(
(
ii) TFA, (CH Cl) , reflux.
2 2
1
Chem. Commun. 1979, 578. (c) Hagiwara, H.; Kimura, K.;
Uda, H. J. Chem. Soc., Perkin Trans. 1 1992, 693.
10) Typical Procedure for 19: Lauroyl peroxide (10–15 mol%)
was added portion-wise (in 3–4 portions over several hours)
to a degassed, refluxing solution of 800 mg (2 mmol) of
xanthate 16 and 1.1 g (4.0 mmol) of olefin 2b in 2 mL of
Finally, the expedient generation and capture of a com-
plex nitrone is illustrated by the second example in
Scheme 3. Addition of xanthate 23 to olefin 2a proceeded
efficiently to adduct 24 in 81% yield. Deprotection with
trifluoroacetic acid was followed by spontaneous cyclisa-
tion to nitrone 25, which was not isolated but trapped by
addition of diethyl acetylenedicarboxylate to give bicyclic
(
1,2-dichloroethane under argon. The reaction was regularly
monitored for the disappearance of the starting material by
thin layer chromatography. Upon completion, the solvent
Synlett 2002, No. 6, 903–906 ISSN 0936-5214 © Thieme Stuttgart · New York

9
06
B. Quiclet-Sire et al.
LETTER
was removed under reduced pressure and the residue
purified by chromatography on silica gel (heptane/EtOAc
COOCH ), 3.53–3.34 (m, 2 H, CH N), 3.35 (s, 3 H, OCH ),
3
2
3
3.34 (s, 3 H, OCH ), 2.76–2.72 (m, 1 H, CH), 1.68–1.37 (22
3
1
3
98/2–95/5) to give compound 17 (1.58 g, 98%) as a
H, 2 CH and 6 CH ); C NMR (CDCl , 75 MHz, ppm): =
2 3 3
colourless oil; it consisted of a 3:2 mixture of diastereo-
173.3 (COO), 155.3–155.2 (2 COO), 104.6 (CHO) 80.8–
80.7 (2 Cq), 54.5–54.4 (2 CH ), 52.6 (CH), 51.5 (NCH ),
isomers, which were used without further purification in the
3
2
1
next step. H NMR (CDCl , 250 MHz, ppm): = 6.72 (bs, 1
48.7 (OCH ), 28.1 (CH ), 25.2–25.0 (2 CH ); IR (CCl ):
3
3 3 2 4
H, NH), 4.62 (q, 2 H, OCH , J = 6.5 Hz), 4.52 (d, 1 H, CH,
3329 (broad), 1735(vs), 1454 (m), 1398 (m), 1369 (m), 1253
(m), 1161 (s), 1067 (m)cm .
2
–
1
J = 7.2 Hz), 4.01–3.79 (m, 3 H, CH N, CHS), 3.71 (s, 3 H,
2
COOCH ), 3.35 (s, 3 H, OCH ), 3.31 (s, 3 H, OCH ), 3.08–
A solution of 18 (280 mg, 0.7 mmol) in 1,2-dichloroethane
(2 mL) and trifluoroactic acid (2 mL) was stirred for 1 h at
r.t. under argon. The mixture was then evaporated under
reduced pressure and the residue dissolved in a mixture of
1,2-dichloroethane (2 mL) and triethylamine (2 mL) and
kept at r.t. for 48 h. The solvent was removed and the crude
residue was extracted with dichoromethane and distilled
water. The organic layer was dried over sodium sulfate.
Evaporation under reduced pressure and purification by
chromatography on silica gel (heptane–EtOAc, 1:1)
3
3
3
3
2
.02 (m, 0.6 H, CHCOO), 2.99–2.91 (m, 0.4 H, CHCOO),
.14–1.79 (m, 2 H, CH ), 1.60 (s, 18 H, 6CH ), 1.59 (t, 3 H,
2
3
1
3
CH , J = 6.5 Hz); C NMR (CDCl , 62.5 MHz, ppm):
=
3
3
2
1
11.6 (CS), 172.4 (COO), 154.5–154.4 (2 COO), 104.1/
04.0 (CH), 81.2–80.9 (2 Cq, Boc), 69.9 (OCH ), 54.4–54.2
2
(
2 CH ), 53.0/52.9 (NCH ), 51.8 (CH ), 47.7/46.7 (CHS),
3 2 3
4
5.2 (CHCOO), 46.1 (CH ), 27.9 (CH ), 13.5 (CH ); IR
2 3 3
(
1
CCl ): 3326 (m), 1736(vs), 1479 (m), 1443 (m), 1394 (m),
368 (m), 1220 (s), 1155 (s), 1051 (s)cm .
4
–
1
1
A solution of xanthate 17 (800 mg, 1.5 mmol), Bu SnH
afforded 19 as a colourless oil (50 mg, 48%). H NMR
3
(0.75 mL), and AIBN (22 mg) in benzene (15 mL) was
(CDCl , 250 MHz, ppm): = 6.25 (d, 1 H, CH=, J = 7.3 Hz),
3
heated to reflux for 2 h under an inert atmosphere. The
solvent was then removed under reduced pressure and the
residue was purified by chromatography on silica gel
3.68 (s, 3 H, OOCH ), 3.04 (m, 1 H, CH), 2.52–2.34 (m, 1 H,
3
NH), 2.34–2.25 (m, 2 H, CH N), 2.24–2.12 (m, 2 H, CH ),
2
2
1
3
1.94–1.89 (m, 2 H, CH ); C NMR (CDCl , 62.5 MHz,
2
3
(pentane heptane–EtOAc, 7:3) to give 18 (602 mg, 97%)
ppm): = 173.1 (COO), 153.1 (CH=), 53.9 (CH N), 51.8
2
as a colourless oil. This material was used in the next step
(OOCH ), 46.8 (CH), 27.6 (CH ), 23.8 (CH ); IR (CCl ):
3
2
2
4
1
–1
without further purification. H NMR (CDCl , 300 MHz,
3432, 2947, 1735, 1670, 1322, 1266, 735 cm . Calcd for
C H N O : C, 53.83; H, 7.74%. Found: C, 53.69; H, 7.51%.
3
ppm): = 6.58 (s, 1 H, NH), 4.50 (d, 1 H, CH), 3.69 (s, 3 H,
7
12
2
2
Synlett 2002, No. 6, 903–906 ISSN 0936-5214 © Thieme Stuttgart · New York