Synthesis of N,O-heterocycles by intramolecular conjugate addition of a hydroxylamine

Article abstract of DOI:10.1055/s-2008-1072650

Isoxazolidines and tetrahydro-1,2-oxazines were produced by a tandem deprotection-intramolecular Michael addition of hydroxylamines. For tetrahydrooxazine formation, high stereoselectivity was observed, even when a quaternary centre was formed. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1072650

1042
LETTER
Synthesis of N,O-Heterocycles by Intramolecular Conjugate Addition of a
Hydroxylamine
Synthesis of
N,
O
o
d
s
erick W. Bates,*a Robert H. Snell,a SusAnn Winbushb
a
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
21 Nanyang Link, Singapore 637371, Singapore
E-mail: roderick@ntu.edu.sg
Laboratory of Medicinal Chemistry, Chulabhorn Research Institute, Laksi, Bangkok 10210, Thailand
b
Received 20 August 2007
CO2Me
NHBoc
NHBoc
Abstract: Isoxazolidines and tetrahydro-1,2-oxazines were pro-
duced by a tandem deprotection–intramolecular Michael addition of
hydroxylamines. For tetrahydrooxazine formation, high stereose-
lectivity was observed, even when a quaternary centre was formed.
O
O
IMes(Cy3P)RuCl2CHPh
CO2Me
Ph
Ph
n
n
2a n = 1
2b n = 2
1a n = 1
1b n = 2
Keywords: Michael addition, hydroxylamine, oxazine
O
Ph
CO2Me
Intramolecular conjugate (Michael) addition of oxygen or
nitrogen nucleophiles has proven to be a useful method
3
for the formation of heterocycles and can proceed with Scheme 1
both useful and predictable stereochemistry, especially
during the formation of six-membered rings.1
(Scheme 2) on the grounds that the phthaloyl group would
be a worse donor and would not coordinate with rutheni-
um and bring it into the proximity of the N–O bond. In this
case, cross-metathesis proceeded smoothly, delivering the
desired alkenes, 6 and 7, in good to excellent yield as the
E-isomers. The reactions, which were complete within
three hours, were carried out in refluxing dichloromethane
and the amount of catalyst could be reduced to as little as
2 mol% without any significant adverse impact on the
yield.8,9 Even with 0.5 mol% of catalyst, a product yield
of 78% could be obtained (for 7a).
Cyclic hydroxylamine derivatives, such as isoxazolidines
and 1,2-oxazines, have been widely used in organic syn-
thesis.2 Access to these classes of heterocycles is typically
by cycloaddition. Recently we reported an alternative
route to isoxazolidines by a palladium-catalysed cyclisa-
tion of an O-substituted hydroxylamine.3 Other electro-
phile-induced cyclisations have also been reported.4
We wish to report our recent results on the use of the in-
tramolecular conjugate addition of the nitrogen of an O-
substituted hydroxylamine, with introduction of the
Michael acceptor by cross-metathesis.5,6
NRR
NRR
Z
Our preliminary experiments (Scheme 1) involved the
tert-butoxycarbonyl-protected hydroxylamine (R = t-Boc,
R¢ = H). In the case of n = 1, the same substrate was em-
ployed in our palladium methodology. Surprisingly, ex-
posure of 1a or 1b to excess methyl acrylate and up to 10
mol% Grubbs’ II catalyst in refluxing dichloromethane
overnight led to a poor yield (20–25%) of the desired met-
athesis products 2a, 2b as an E/Z mixture, accompanied
by unreacted starting material. Upon increasing the reac-
tion temperature (for 1b) by employing dichloroethane
(bp 83 °C) at reflux, the yield of 2b was not increased, but
a by-product, ketone 3, was also isolated. The implication
is that ruthenium-mediated N–O bond cleavage took
place, which led to catalyst deactivation.
O
O
IMes(Cy3P)RuCl2CHPh
Z
Ph
Ph
n
n
4 n = 1
6 n = 1
5 n = 2
7 n = 2
RR = phthaloyl
RR = phthaloyl
Z = CO2Me
a
CO2t-Bu b
CO2Me
Ph3P
Z = CHO
SO2Ph
COMe
CHO
c
d
e
NRR
O
CO2Me
Ph
8a
Scheme 2 Cross-metathesis
The corresponding N-phthaloyl derivatives, 4 and 5, easi-
ly prepared from the corresponding alcohols by a Mit-
sunobu reaction,7 were selected for further experiments
Exposure of the cross-metathesis products 6 and 7 to hy-
drazine hydrate at room temperature or at 0 °C resulted in
rapid deprotection and formation of a copious precipitate
of phthaloyl hydrazide. There was no evidence of any re-
action between hydrazine and the Michael acceptor. In
most cases, the only isolable product after filtration was
SYNLETT 2008, No. 7, pp 1042–1044
x
x.
x
x.
2
0
0
8
Advanced online publication: 28.03.2008
DOI: 10.1055/s-2008-1072650; Art ID: D25707ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of N,O-Heterocycles
1043
that of tandem deprotection–conjugate addition corresponding a,b-unsaturated isomer was detected. The
(Scheme 3, Table 1). In the case of n = 1, the isoxazoli- product is clearly formed by kinetic protonation of the in-
dine 9 was isolated as an inseparable 2:1 mixture of ste- termediate enolate produced by the intramolecular Micha-
reoisomers. On the other hand, in the case of n = 2, the el addition. As the cyclisation occurs in the absence of any
tetrahydro-1,2-oxazines 10 were formed as the trans iso- acids or bases, alkene migration does not occur.
1
mers.10 The stereochemistry was apparent from the H
Alkene 12,11 isomeric to 4, underwent cross-metathesis
NMR spectra. Each methine proton displayed a typical
with more difficulty (Scheme 4). To obtain a useful yield
axial-axial coupling.
(55%), it was necessary to add 5 mol% of Grubbs’ II cat-
alyst as a solution in dichloromethane in five equal por-
O
NH
NH
tions over a five hour period. Deprotection of 13 resulted
in immediate cyclisation to yield the isoxazolidine 14 as
an inseparable 4.5:1 mixture of isomers in 99% yield. The
major isomer was shown to be trans by nOe experiments.
Z
Z
H2NNH2
H2NNH2
Ph
Ph
NRR
O
9
Z
Ph
O
n
6 n = 1
7 n = 2
NPhth
NPhth
O
O
CO2Me
Grubbs' II
10
Z = CO2Me
CO2t-Bu
SO2Ph
a
CO2Me
CO2Me
b
c
d
55%
Ph
Ph
COMe
13
NH
12
NRR
O
O
O
NH
H2NNH2
99%
CO2Me
+
Ph
H2NNH2
CO2Me
O
NH
Ph
cis-14
8a RR = Phth
8b RR = H, H
Ph
trans-14
Ph
Scheme 4
11
CO2Me
Scheme 3 Intramolecular Michael addition
The same metathesis procedure, but using methyl croto-
nate in place of methyl acrylate, worked for disubstituted
alkene 15 to give the trisubstituted metathesis product 16
in 80% yield as a 1:1 mixture of double bond isomers
Table 1 Reaction of the Cross-Metathesis Products 6 and 7 with
Hydrazine Hydrate
Entry
n
Z
Cross-metathesis Intramolecular (Scheme 5).12 Deprotection did not result in immediate
product, yield
addition
product, yield
cyclisation. Complete formation of the tetrahydrooxazine
17 occurred when the crude product was left standing (re-
frigerator, 4 d). Tetrahydrooxazine 17 was obtained as a
single isomer in 96% yield. The stereochemistry was de-
termined by N–O bond cleavage with excess zinc and ace-
tic acid, followed by sulfonylation–cyclisation to the N-o-
nosylpyrrolidine 18. The structure of 18 was determined
by X-ray crystallography (Figure 1). Inversion during
ring closure is assumed.
1
2
3
4
5
6
1
2
2
2
2
2
CO2Me
CO2Me
CO2t-Bu
SO2Ph
6a, 92%
7a, 97%
7b, 97%
7c, 70%
7d, 77%
8a, 82%d
9a, 88%
10a, 98%
10b, 99%a
10c, 95%
ndb
COMe
CHO →
11, 90%e
NPhth
NPhth
CO2Me
Grubbs' II
80%
CH=CHCO2Mec
O
O
a Yield after the crude product was left standing for 3 d.
b Not determined; a complex mixture was formed due to competing
condensation reactions.
Ph
CO2Me
CO2Me
Ph
Me
Me
Ph
16
15
c Cross-metathesis with crotonaldehyde, followed by reaction with
Ph3P=CHCO2Me.
CO2Me
O
NH
Me
H2NNH2
96%
d Yield over two steps.
Ph
NH2
O
e Yield after heating (THF, reflux, 2 h).
Me
17
Curiously, the tert-butyl ester 7b cyclised slowly, but did
give the tetrahydro-1,2-oxazine 10b as a single isomer.
The dienoate 8a, formed by a combination of cross-met-
athesis and Wittig olefination, yielded only the deprotec-
tion product 8b. Cyclisation could be achieved by heating
in THF. Oxazine 11 was then obtained as the trans isomer
with the remaining double bond in the b,g-position. No
o-Ns
1. Zn (10 equiv), AcOH, THF
2. o-NsCl (2 equiv),
Et3N, DMAP
CO2Me
Me
N
Ph
46% (two steps)
18
Scheme 5
Synlett 2008, No. 7, 1042–1044 © Thieme Stuttgart · New York

1044
R. W. Bates et al.
LETTER
thanks the NSF for support as an REU student at CRI (grant number
NSF INT-0123857).
It may be noted that, in tetrahydrooxazine 17, the phenyl
group and the ester substituent were trans, as in tetrahy-
drooxazines 10 and 11. It may be postulated that the
Michael acceptor in each case adopts a pseudoequatorial
position during cyclisation, regardless of the orientation
of the ester group. It is, however, interesting that a single
isomer of 17 was formed from a mixture of two geometri-
cal isomers of alkene. For tetrahydropyran and piperidine
formation by intramolecular Michael addition, Banwell
has shown that the stereochemistry of the product is de-
pendent on the starting alkene geometry, although only
with disubstituted alkenes.13
References and Notes
(1) Perlmutter, P. Conjugate Addition Reactions in Organic
Synthesis; Pergamon Press: Oxford, 1992.
(2) For some examples of isoxazolidines, see: Bates, R. W.; Sa-
Ei, K. Tetrahedron 2002, 58, 5957.
(3) Bates, R. W.; Sa-Ei, K. Org. Lett. 2002, 4, 4225.
(4) (a) Janza, B.; Studer, A. Synthesis 2002, 2117. (b) Tiecco,
M.; Testaferri, L.; Marini, F.; Sternativo, S.; Santi, C.;
Bagnoli, L.; Temperini, A. Tetrahedron: Asymmetry 2001,
12, 3053.
(5) (a) Connon, S. J.; Blechert, S. Angew Chem. Int. Ed. 2003,
42, 1900. (b) Vernall, A. J.; Abell, A. D. Aldrichimica Acta
2003, 36, 93.
(6) For applications of this combination of reactions to the
synthesis of tetrahydropyrans, see: (a) Bressy, C.; Allais, F.;
Cossy, J. Synlett 2006, 3455. (b) Bates, R. W.; Song, P.
Tetrahedron 2007, 63, 4497.
(7) Grochowski, E.; Jurczak, J. Synthesis 1976, 682.
(8) This is considered to be much lower than typical loadings:
Namba, K.; Wang, J.; Cui, S.; Kishi, Y. Org. Lett. 2005, 7,
5421.
(9) Typical Procedure: A solution of alkene 5 (207 mg, 0.67
mmol), Grubbs second generation catalyst (11 mg, 2 mol%)
and methyl acrylate (182 mL, 2.02 mmol) in CH2Cl2 (2 mL)
was heated at reflux under nitrogen for 3 h. The mixture was
then cooled and the volatiles were removed under reduced
pressure. The mixture was purified by column
Figure 1 Pyrrolidine 18
chromatography on silica gel eluting with 10–20% EtOAc in
hexane to give the ester 7a as a solid (237 mg, 97%). 1H
NMR (300 MHz, CDCl3): d = 7.65 (m, 4 H, Ar), 7.39 (m, 2
H, Ar), 7.26 (m, 3 H, Ar), 6.99 (dt, J = 6.5, 15.5 Hz, 1 H, H3),
5.87 (d, J = 15.5 Hz, 1 H, H2), 5.31 (t, J = 6.5 Hz, 1 H, H6),
3.72 (s, 3 H, OMe), 2.32 (m, 3 H, H4, H5), 2.00 (m, 1 H, H5).
(10) Typical Procedure: Hydrazine hydrate (78 mL, 1.6 mmol)
was added to a solution of phthalimide 7a (195 mg, 0.53
mmol) in CH2Cl2 (2 mL). The mixture was stirred for 15
min, and then filtered through a pad of celite to remove the
copious colourless precipitate. The filtrate was evaporated to
give the oxazine 10a as an oil (122 mg, 98%). 1H NMR (300
MHz, CDCl3): d = 7.23 (m, 5 H, Ph), 5.30 (br s, 1 H, NH),
4.55 (dd, J = 11.2 Hz, 1 H, H6), 3.70 (s, 3 H, OMe), 3.44 (m,
1 H, H3), 2.45 (dd, J = 16.8, 4.7 Hz, 1 H, CHHCO2Me), 2.37
(dd, J = 16.8, 8.5 Hz, 1 H, CHHCO2Me), 1.50–2.00 (m, 4 H,
H4, H5). Compound 10c was prepared analogously. 1H
NMR (300 MHz, CDCl3): d = 7.80 (m, 2 H, Ar), 7.50 (m, 3
H, Ar), 7.20 (m, 5 H, Ar), 6.40 (br s, 1 H, NH), 4.59 (dd, J =
10.7, 2.3 Hz, 1 H, H6), 3.59 (ddt, J = 10.9, 8.8, 2.8 Hz, 1 H,
H3), 3.14 (dd, J = 14.5, 9.0 Hz, 1 H, CHHSO2Ph), 3.03 (dd,
J = 14.5, 3.0 Hz, 1 H, CHHSO2Ph), 1.50–1.90 (m, 4 H, H4,
H5).
The final example reported here involves the ene-yne sub-
strate 19, easily prepared by Sonogashira chemistry (83%
yield from the corresponding terminal alkyne). Exposure
of 19 to hydrazine yielded the isoxazine 20 in 87% yield
(Scheme 6) with the double bond shown to be a,b to the
imine (rather than to the ester) by an HMBC experiment.
Thus, this chemistry might be readily adapted to more
complex Michael acceptors, and to the formation of N,O-
heterocycles in different oxidation states.
NPhth
O
O
N
H2NNH2
89%
CO2Me
Ph
CO2Me
Ph
19
20
Scheme 6
The combination of cross-metathesis and intramolecular
conjugate addition represents a useful method to generate
N,O-heterocycles. In the case of tetrahydro-1,2-oxazines,
stereoselectivity is excellent, even for the formation of a
quaternary centre. This may be considered an example of
1,4-induction of stereochemistry.
(11) The corresponding alcohol is prepared by the reaction
between styrene oxide and vinyl magnesium bromide in
Et2O. We thank Professor David Knight, University of
Cardiff, for this procedure.
(12) For a discussion of cross-metathesis of different classes of
alkenes, see: Chatterjee, A. K.; Choi, T. L.; Sanders, D. P.;
Grubbs, R. H. J. Am. Chem. Soc. 2003, 125, 11360.
(13) Banwell, M. G.; Bui, C. T.; Pham, H. T. T.; Simpson, G. W.
J. Chem. Soc., Perkin Trans. 1 1996, 967.
Acknowledgment
We thank the Nanyang Technological University for support of this
work. Generous support from the Chulabhorn Research Institute du-
ring the early part of this work is gratefully acknowledged. SW
Synlett 2008, No. 7, 1042–1044 © Thieme Stuttgart · New York

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