Allylation reactions of N,O-heterocycles

Article abstract of DOI:10.1055/s-0031-1290458

Iminium ions generated from isoxazolidines and tetrahydro-1,2-oxazines undergo allylation under Sakurai conditions. Allylated isoxazolidines are formed predominantly as the trans isomer, while oxazines are formed exclusively as the cis isomer. Georg Thiem

Full text of DOI:10.1055/s-0031-1290458

2266▌
LETTER
lAettlerlylation Reactions of N,O-Heterocycles
Allylation Reactions of N,O-Heterocycles
Roderick W. Bates,* Chi H. Tang, Yuting Tan, Siti Nurhayati binte Buang
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
21 Nanyang Link, 637371 Singapore, Singapore
Fax +6567911961; E-mail: roderick@ntu.edu.sg
Received: 31.05.2012; Accepted after revision: 01.07.2012
The 3-methoxy-substituted heterocycles,11 intended as
Abstract: Iminium ions generated from isoxazolidines and tetra-
iminium ion precursors, were prepared by adapting the
hydro-1,2-oxazines undergo allylation under Sakurai conditions.
chemistry that we had used for the preparation of earlier
Allylated isoxazolidines are formed predominantly as the trans iso-
mer, while oxazines are formed exclusively as the cis isomer.
starting materials (Scheme 2).3 N-Alkoxyphthalimides 2
were prepared by the Mitsunobu reaction between unsat-
Key words: heterocycles, allylation, stereoselectivity
urated secondary alcohols 1 and N-hydroxyphthalimide.12
The phthaloyl group was then removed by hydrazinolysis,
and the nitrogen was reprotected as a carbamate. Initially,
We have had a longstanding interest in the synthesis of
using the five-membered ring series, ozonolysis in di-
heterocycles containing an N–O bond, namely cyclic
chloromethane yielded the 3-hydroxyisoxazolidines,13
hydroxylamines, by methods that do not involve the well-
which were converted into the 3-methoxy derivatives 6a–
known cycloaddition reactions, and the use of these het-
c by treatment with methanol in the presence of polymer-
erocycles for the synthesis of alkaloids through cleavage
supported PPTS.14 We subsequently found that it was
of the N–O bond to reveal an amino alcohol.1,2 In the five-
more efficient to carry out the ozonolysis in methanol in
membered-ring series – isoxazolidines – we have em-
the presence of the acidic polymer to give the 3-methoxy
ployed both cyclocarbonylation3 and the Claesson allene
derivatives after Me2S work-up in a one-pot process. The
cyclisation.4,5 Both processes favour the formation of the
3-methoxyisoxazolidines 6a–c were obtained as diaste-
3,5-cis isomer.6 We have also employed the intramolecu-
reoisomeric mixtures; the 3-methoxytetrahydrooxazines
lar aza-Michael addition of a hydroxylamine.7 Again, in
7a–c were obtained exclusively as the cis isomers, as
the five-membered-ring series, the 3,5-cis isomers are fa-
demonstrated by X-ray crystallographic analysis of com-
voured, while in the six-membered ring series – tetra-
pound 7b (Figure 1).15,16
hydro-1,2-oxazines – the 3,6-trans products are formed
exclusively. We reasoned that, if one substituent were
1. PhthNOH, Ph3P, DIAD
2. H2NNH2•nH2O
3. see ref. 3
X
ONHPG
added after ring formation, rather than before, we might
be able to access the alternative stereochemical series, that
is, 3,5-trans isoxazolidines and 3,6-cis-tetrahydro-1,2-ox-
azines. Given our interest in iminium ion chemistry,4b,c,8
the use of a Sakurai reaction suggested itself (Scheme 1).
Zhao has reported the allylation of isoxazolidines at C5
with modest stereoselectivity,9 while Jenkins has reported
the stereoselective addition of allyl zinc reagents to
4,5-dihydroisoxazoles.10
R
R
n
n
1 X = OH
2 X = ONPhth
3 X = ONH2
4 n = 1 X = ONHPG
5 n = 2 X = ONHPG
a: PG = t-Boc; b: PG = Cbz;
c: PG = CO2Me
1. O3; Me2S
PG
N
2. MeOH, PS-PPTS
or O3, MeOH, PS-PPTS; Me2S
O
R
OMe
n
6 n = 1
7 n = 2
R = Ph, Me
PG
PG
+
O
N
O
N
2
1
Scheme 2 Synthesis of 3-methoxy heterocycles
3
R
OMe
R
n
n
n = 1, 2
Allylation of the 3-methoxy derivatives was achieved by
treatment with allyl trimethylsilane and BF3·OEt2 at –60 °C
in anhydrous dichloromethane (Scheme 3). Good yields
were obtained in all cases (Table 1) except for those com-
pounds with a t-Boc protecting group, due to acid sensi-
tivity. The isoxazolidines 8a–c were formed as an
inseparable mixture of isomers.17 The stereochemistry
was demonstrated by cleavage18 of the N–O bond of isox-
azolidine 8a to give the diastereoisomeric amino alcohol
derivatives which were separable. The major isomer 9
proved to be crystalline. X-ray crystallographic analysis
PG
SiMe3
O
N
R
n
Scheme 1 N,O-Heterocycle allylation
SYNLETT 2012, 23, 2266–2268
Advanced online publication: 17.08.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0031-1290458; Art ID: ST-2012-D0469-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
Allylation Reactions of N,O-Heterocycles
2267
PG
PG
SiMe3
BF3•OEt2
O
N
O
N
Ph
OMe
Ph
6a–c
8a–c
Mo(CO)6, MeCN, H2O
(R = Ph, PG = t-Boc)
63%
OH NHt-Boc
Ph
9
SiMe3
BF3•OEt2
PG
PG
O
N
O
N
R
OMe
7a–d
R
Figure 1 X-ray crystal structure of compound 7b
10a–d
CF3CO2H
R = Ph, Me
86%
(R = Ph, PG = t-Boc)
(Figure 2)15 revealed it to be the anti isomer, indicating
that the major isoxazolidine was the trans isomer. In con-
trast, the tetrahydro-1,2-oxazines 10a–d were formed as
single isomers. Attempts to determine the stereochemistry
by either coupling constant analysis or NOE experiments
were frustrated by line broadening in the 1H NMR spectra
for protons at the 3- and 6-positions.19 Corresponding
broadening was also observed in the 13C NMR spectra.
Removal of the Boc group from compound 10a, however,
gave compound 11 with a sharply defined 1H NMR spec-
trum. The proton at C6 showed coupling constants of 3.2
and 9.6 Hz, indicating an equatorial disposition of the
phenyl group. Through homonuclear decoupling experi-
ments, coupling constants between the proton at C3 and
the protons at C4 were revealed to be 3.3 and 2.2 Hz, in-
dicating an axial disposition of the allyl group and, there-
fore, cis stereochemistry for the heterocycle. Axial
allylation is consistent with the reaction being under ste-
reoelectronic control.20
H
O
N
2
1
a: PG = t-Boc
b: PG = Cbz
c: PG = CO2Me
Ph
6
3
11
Scheme 3 Allylation reactions
Table 1 N,O-Heterocycle Formation and Allylation
Entry
R
PG
n
Heterocycle, Allylation, Allylation
yield (%)
yield (%) dr
1
2
3
4
5
6
7
Ph
Ph
Ph
Ph
Ph
Ph
Me
t-Boc
Cbz
1
1
1
2
2
2
2
6a 54a
6b 41a
6c 56a
7a 57b
7b 85b
7c 73b
7d 63b
8a 44
8b 70
3.8:1
3.3:1
4.8:1
CO2Me
t-Boc
Cbz
8c 73
c
10a 55
10b 74
10c 68
10d 65
–
c
–
c
CO2Me
CO2Me
–
c
–
a Two-step procedure.
b One-pot procedure.
c Single isomer observed in the 1H NMR (300 MHz) spectrum of the
crude product.
control and excellent 1,4-stereocontrol which should
prove to be valuable in organic synthesis.
General Procedure for Allyation21
Boron trifluoride etherate (1.2 equiv) was added dropwise to a solu-
tion of the 3-methoxyheterocycle and allyltrimethylsilane (2 equiv)
in CH2Cl2 under nitrogen at –60 °C. The mixture was stirred over-
night at –60 °C, then quenched by addition of Et3N (0.5 equiv) at
that temperature. The mixture was allowed to warm to r.t., then di-
luted with H2O. The mixture was extracted with CH2Cl2 (3×). The
Figure 2 X-ray crystal structure of amino alcohol derivative 9
Allylation of these N,O-heterocycles provides a useful route
to derivatives of amino alcohols with useful 1,3-stereo- combined organic layers were dried (MgSO4) and concentrated un-
der reduced pressure. The product was purified by chromatography
on silica gel.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2266–2268

2268
R. W. Bates et al.
LETTER
(13) 5-Hydroxyisoxazolidines have also been prepared by the
Acknowledgment
reaction between hydroxylamines and α,β-unsaturated
aldehydes: Zelenin, K. N.; Motorina, I. A.; Sviridova, L. A.;
Bezhan, I. P.; Ershov, A. Y.; Golubeva, G. A.; Bundel, Y. G.
Chem. Heterocycl. Compd. 1988, 23, 1018.
We thank the Singapore Ministry of Education Academic Research
Fund Tier 2 (grant T206B1220RS) and Nanyang Technological
University for generous support of this work.
(14) Acid-catalysed exchange in 3-hydroxyisoxazolidines has
been reported: Motorina, I. A.; Sviridova, L. A.; Golubeva,
G. A.; Zelenin, K. N.; Bezhan, I. P.; Ershov, A. Y.; Bundel,
Y. G. Chem. Heterocycl. Compd. 1989, 24, 1373.
(15) Details have been deposited with the Cambridge
Crystallographic Data Centre and may be obtained at
http://www.ccdc.cam.ac.uk. CCDC deposition numbers: 7b:
878055 and 9: 877996.
(16) Characterisation Data for Compound 7b
Mp 69–71 °C. 1H NMR (400 MHz, CDCl3): δ = 7.25–7.50
(10 H, m), 5.35 (1 H, br), 5.33 (br d J = 12.0 Hz), 5.19 (d, J
= 12.0 Hz), 4.72 (br s, 1 H), 3.35 (3 H, br s), 2.35 (1 H, app
dq, J = 5.0, 12.0 Hz), 2.05–2.10 (1 H, m), 1.88–2.00 (1 H,
m), 1.79–1.84 (1 H, m), 1.80–2.40 (4 H, m).
(17) Spectroscopic Data for Compound trans-8a
1H NMR (400 MHz, CDCl3): δ = 7.37–7.28 (5 H, m), 5.85
(1 H, ddt, J = 17.3, 10.2, 7.1 Hz), 5.27 (1 H, t, J = 6.6 Hz),
5.21–5.14 (2 H, m), 4.39 (1 H, tt, J = 8.0, 5.0 Hz); 3.68 (3 H,
s), 2.65–2.38 (4 H, m). 13C NMR (100 MHz, CDCl3): δ =
157.5, 138.5, 134.0, 128.8, 118.4, 81.7, 59.0, 53.2, 40.0,
39.1.
(18) (a) Cicchi, S.; Goti, A.; Brandi, A.; Guarna, A.; Sarlos, F. D.
Tetrahedron Lett. 1990, 31, 3351. (b) Mulvihill, M. J.; Gage,
J. L.; Miller, M. J. J. Org. Chem. 1998, 63, 3357.
(19) Spectroscopic Data for Compound 10c
References and Notes
(1) Bates, R. W.; Boonsombat, J.; Lu, Y.; Nemeth, J. A.; Sa-Ei,
K.; Song, P.; Cai, M. P.; Cranwell, P. B.; Winbush, S. A.
Pure Appl. Chem. 2008, 80, 681.
(2) For the use of isoxazolidines for β-amino acid synthesis, see:
(a) Fuller, A. A.; Chen, B.; Minter, A. R.; Mapp, A. K.
Synlett 2004, 1409. (b) Examples in sedum alkaloid
synthesis may be found in: Bates, R. W.; Sa-Ei, K.
Tetrahedron 2002, 58, 5957.
(3) Bates, R. W.; Sa-Ei, K. Org. Lett. 2002, 4, 4225.
(4) (a) Bates, R. W.; Nemeth, J.; Snell, R. Synthesis 2008, 1033.
(b) Bates, R. W.; Lu, Y. J. Org. Chem. 2009, 74, 9460.
(c) Bates, R. W.; Lu, Y. Org. Lett. 2010, 12, 3938.
(5) For another noncycloaddition route to isoxazolidines, see:
Lemen, G. S.; Giampietro, N. C.; Hay, M. B.; Wolfe, J. P.
J. Org. Chem. 2009, 74, 2533.
(6) Also, 3,4-trans is favoured: Bates, R. W.; Lim, C. J. Synlett
2010, 866.
(7) Bates, R. W.; Snell, R. H.; Winbush, S. A. Synlett 2008,
1042.
(8) For recent reviews of N-acyliminium ion chemistry, see:
(a) Speckamp, N.; Moolenaar, M. J. Tetrahedron 2000, 56,
3817. (b) Yazici, A.; Pyne, S. G. Synthesis 2009, 339.
(c) Yazici, A.; Pyne, S. G. Synthesis 2009, 513.
(9) Niu, D.; Zhao, H.; Doshi, A.; Zhao, K. Synlett 1998, 979.
(10) Freire Castro, F. J.; Vila, M. M.; Jenkins, P. R.; Sharma, M.
L.; Tustin, G.; Fawcett, J.; Russell, D. R. Synlett 1999, 798.
(11) Certain 3-methoxyisoxazolidines and derivatives, prepared
by 1,3-dipolar cycloaddition, have been claimed as anti-acne
agents: (a) Castelhano, A. L.; DeYoung, L. M.; Krantz, A.;
Pliura, D. H.; Venuti, M. C. US 4912120 A1, 1990.
(b) Castelhano, A. L.; Krantz, A.; Pliura, D. H.; Venuti, M.
C.; DeYoung, L. M. EP 237082 B1, 1991.
1H NMR (400 MHz, CDCl3): δ = 5.67–5.78 (m, 1 H), 5.15
(1 H, ddd, J = 17.0, 3.0, 1.5 Hz), 5.08 (1 H, dt, J = 10.0,
1.0 Hz), 4.73 (1 H, br d), 4.35 (1 H, br), 3.78 (3 H, s), 2.70
(1 H, app quin, J = 7.0 Hz), 2.44 (1 H, app quin, J = 7.0 Hz),
2.10–2.20 (1 H, m), 1.9.0–2.05 (1 H, m), 1.8.0–1.90 (2 H,
m). 13C NMR (400 MHz, CDCl3): δ = 25.6, 26.6, 34.3, 53.2,
83.3 (br), 117.6, 126.6, 128.5, 128.6, 134.8, 139.4, 156.1.
(20) Stereoelectronic Effects in Organic Chemistry;
Deslongchamps, P., Ed.; Pergamon Press: Oxford, 1983,
211–221.
(21) All compounds used in this study were racemic.
(12) Grochowski, E.; Jurczak, J. Synthesis 1976, 682.
Synlett 2012, 23, 2266–2268
© Georg Thieme Verlag Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or
emailed to multiple sites or posted to a listserv without the copyright holder's express written permission.
However, users may print, download, or email articles for individual use.