only the phenyl- or alkyl-substituted oxzines at the 2-positions
but also the unsubstituted oxazine.
O(15)
Footnotes and References
C(14)
H(14a)
H(6b)
† E-mail: kanoh@kenroku.ipc.kanazawa-u.ac.jp
‡
H(14b)
C(6)
O(1)
C(7)
C(11)
C(5)
C(12)
C(9)
H(6a)
C(13)
H(4b)
C(2)
C(10)
Reagents and conditions: i, 3-methyl-3-(phthalimidomethyl)oxetane4 (1.0
equiv.), hydrazine hydrate (5 equiv.), in EtOH, 60 °C, 1.5 h, and then a
catalytic amount of Raney Ni (W-2), vigorous reflux, 81% (GLPC purity
96%), bp 90–95 °C/100 mmHg; ii, acylating reagents: (R1CO)2O,
HCO2COMe, or R1CO2H (DCC coupling), 76–92%; iii, 5 (1.0 equiv.),
R2Br (1.1 equiv.), K2CO3 (1.0 equiv.), NaOH (2.5 equiv.), Bun4NHSO4
(0.10 equiv.), in benzene, 40 °C to reflux, 3–15 h, 55–78%.
C(4)
C(8)
N(3)
H(4a)
Fig. 1 ORTEP view of 6a (30% probability thermal ellipsoids)
Although the secondary and tertiary amides of 5 are
isomerized giving structurally different products, these reac-
tions can be explained by the following mechanisms passing
through a common intermediate B (Scheme 2). Both isomeri-
zations begin with the coordination of Lewis acid E to oxetanyl
oxygen atom of 5, and then oxonium A undergoes intra-
molecular nucleophilic attack of the carbonyl oxygen atom by
neighboring group participation. The fate of the resulting B
determines the consequent chemoselection. For tertiary amides,
subsequent ring closure of B gives an equilibrium mixture of C
and CA. On the other hand, B is interconvertible to BA when R2
is a hydrogen atom. The iminium and ammonium salts, BA and
CA, are probably thermodynamically more stable than B and C,
and the catalytic turnover of Lewis acid would decrease as the
isomerization progresses. This was strongly supported by the
observation that the isomerization rates of 5 steeply slowed
down at increased yields of basic 6 and 7. In order to force these
reactions to completion, it was necessary to employ either high
temperature or a very large amount of Lewis acid, or both
(Table 1). Under such conditions, however, the yields of 7
began to decrease after reaching maxima at relatively early
stages, because of inevitable polymerization as a competing
reaction.
In the chemoselective isomerization of 5, moderate to fairly
good yields of 6 and 7 were obtained using simple operations.
Like other bicyclic amide acetals,6 compounds 7 are also
interesting in a variety of chemical transformations not only as
reactive amino ethers but also as ring-opening polymerizable
monomers.6,7 Numerous methods of preparing dihydro-1,3-ox-
azines appear in the literature.8 The advantages (as well as
differences) in the present reaction may be summarized as
follows: (a) the preparation of dihydro-1,3-oxazines having a
hydroxymethyl group, which is a useful functional group for
further modification. (b) A general method for obtaining not
§ Typical experimental procedure: To an anhydrous PhCl (1.0 ml) solution
of 5c (150 mg, 1.1 mmol) in a tube was added 1.0 mol l21 AlMe3 in hexane
(0.05 mmol) under nitrogen. The resulting solution was allowed to react at
120 °C for 24 h. After the reaction was quenched by addition of Et3N (0.1
ml) followed by MeOH (3.0 ml), the solvents were replaced by CH2Cl2 (10
ml). Distillation of the CH2Cl2-soluble part afforded 6c in 92% yield, bp
100–110 °C/0.1 mmHg. Similarly, the isomerization of 5f was carried out in
a small distillation flask at 120 °C for 1 h. After the addition of anhydrous
Et3N (0.1 ml) followed by CaH2 (ca. 50 mg), distillation of the resulting
mixture afforded 7f (0.12 g, 0.52 mmol) in 59% yield, bp 110–120 °C/0.1
mmHg. The product isolated was stable under nitrogen.
¶ All compounds were characterized by 1H NMR and IR spectroscopy,
although the IR spectra of 7 were always observed as a mixture of 7 and its
hydrolysis product. Selected data for 6a: mp 135–136 °C (CH2Cl2–hexane);
n
max(KBr)/cm21 3400 (OH), 1650 (CNN); the atomic numbering system
refers to that used in Fig. 1; dH(CDCl3, J/Hz) 7.89 (dd-like, J 6.9, 1.5, 2 H,
ArHo), 7.44–7.33 (m, 3 H, ArHm,p), 4.23 [dd, J 10.7, 2.4, 1 H, H(6b)], 3.92
[d-like, J 10.7, 1 H, H(6a)], 3.57, 3.47 [each d, J 10.7, 2 H, H (14a) and H
(14b), 3.48 [dd, J 16.9, 2.2, 1 H, H (4b)], 3.27 [d-like, J 16.6, 1 H, H(4a)],
2.02 (br s, 1 H, OH), 1.02 [s, 3 H, C(13) H3]; dC (100 MHz, CDCl3) 155.0
[C(2)], 133.3 [C(7)], 130.5 [C(10)], 128.0 [C(9), C(11)], 127.0 [C(8),
C(12)], 70.1 [C(6)], 65.8 [C(14)], 51.1 [C(4)], 32.7 [C(5)], 19.0 [C(13)].
HRMS: m/z 205.1115, calc. for C12H15NO2: 205.1104. Analysis for
C12H15NO2, found (calc.): C, 69.96 (70.22); H, 7.33 (7.37); N, 6.76
(6.82%). For 7f: dH(anhydrous CDCl3 under nitrogen, J/Hz) 7.60 (dd, J 6.8,
3.2, 2 H, ArHo), 7.38–7.29 (m, 3 H, ArHm,p), 3.98 (s, 4 H, OCH2), 2.99 (s,
2 H, NCH2), 2.36 (q, J 7.2, 2 H, CH2CH3), 0.94 (t, J 7.3, 3 H, CH2CH3), 0.88
(s, 3 H, CCH3). HRMS: m/z 233.1439, calc. for C14H19NO2: 233.1417.
∑ The hydrolysis product is 2-ethylaminomethyl-2-hydroxymethylpropyl
benzoate. The initially formed esters except for the benzoates and
isobutyrate were spontaneously converted to the corresponding amide-
substituted propanediols by acyl exchange.
** 6a: Mp 135–136 °C (CH2Cl2–hexane). Crystal data for 6a: space group
P21/c, Z
= 4, a = 11.044(1), b = 9.3865(8), c = 11.817(1) Å, b
= 116.336(8)°, Dc = 1.242 g cm23. 2816 measured, 2685 independent
reflections, of which 1813 were considered as observed [I > 3.00 s(I)].
R = 0.039, Rw = 0.035. CCDC 182/639.
1 M. P. Dreyfuss and P. Dreyfuss, in Encyclopedia of Polymer Science
and Engineering, Wiley, New York, 1987, vol. 10, pp. 653–670.
2 H. Ogawa, T. Hosomi, T. Kosaka, S. Kanoh, A. Ueyama and M. Motoi,
Bull. Chem. Soc. Jpn., 1997, 70, 175; M. Motoi, S. Sekizawa,
K. Asakura and S. Kanoh, Polym. J., 1993, 25, 1283 and references cited
therein.
3 E. J. Corey and N. Raju, Tetrahedron Lett., 1983, 24, 5571; P. Ducray,
H. Lamotte and B. Rousseau, Synthesis, 1997, 404.
4 S. Kanoh, T. Hashiba, K. Ando, H. Ogawa and M. Motoi, Synthesis,
1997, in the press.
5 T. Gajda and A. Zwierzak, Synthesis, 1981, 1005.
6 R. Feinauer, Synthesis, 1971, 16.
7 C. Lu and G. Odian, J. Polym. Sci., Part A: Polym. Chem., 1994, 32,
2283.
8 W. Seeliger, E. Aufderhaar, W. Diepers, R. Feinauer, R. Nehring,
W. Thier and H. Hellmann, Angew. Chem., Int. Ed. Engl., 1966, 5, 875
and references cited therein; Y. Ito, Y. Inubushi, M. Zenbayashi,
S. Tomita and T. Saegusa, J. Am. Chem. Soc., 1973, 95, 4447.
Scheme 2
Received in Cambridge, UK, 5th August 1997; 7/05679F
44
Chem. Commun., 1998