Double Isomerization of Oxetane Amides to Azetidine Esters with Ring Expansion and Contraction

Full text of DOI:10.1021/jo991888g

J . Org. Chem. 2000, 65, 2253-2256
2253
Sch em e 1. Ch em oselective Isom er iza tion of
Oxeta n es Ha vin g a Ca r bon yl F u n ction a l Gr ou p
Dou ble Isom er iza tion of Oxeta n e Am id es to
Azetid in e Ester s w ith Rin g Exp a n sion a n d
Con tr a ction
Shigeyoshi Kanoh,* Tomonari Nishimura, and
Yukiko Kita
Department of Industrial Chemistry, Faculty of
Engineering, Kanazawa University, Kodatsuno,
Kanazawa 920-8667, J apan
Hiroshi Ogawa and Masatoshi Motoi*
Graduate School of Natural Science and Technology,
Kanazawa University, Kodatsuno,
Kanazawa 920-8667, J apan
Masako Takani
Faculty of Pharmaceutical Sciences, Kanazawa University,
Takara-machi, Kanazawa 920-0934, J apan
Toshiyuki Tanaka
Department of Pharmacognosy, Gifu Pharmaceutical
University, Mitahora-higashi, Gifu 502-8585, J apan
react intermolecularly even in the presence of Lewis acid.
The intramolecular nucleophilic reaction is probably
facilitated by the accessibility of the carbonyl oxygen to
the R-carbon (relatively 1,6-positioned) in the oxonium
species generated by the Lewis acid.
Received December 7, 1999
In tr od u ction
Oxetane has been long known as a cyclic ether pos-
sessing ring-opening polymerizability,1 and the cationic
polymerization has been developed as a broadly ap-
plicable method for synthesizing functionalized poly-
ethers.2,3 An interesting exception to this generally
accepted concept was found by Corey et al. in ortho ester
(5) synthesis by the Lewis acid catalyzed isomerization
of oxetane esters (4) (eq 3 in Scheme 1).4 Thereafter, we
have reported a series of similar acid-catalyzed isomer-
izations of oxetanes having a carbonyl functional group
at the 3-position.5,6 These reactions can be viewed as
chemoselective transformation of the oxetane series into
other heterocyclic compounds, as shown in Scheme 1:
oxetane tert-amides (1) and oxetane imides (6) to bicyclic
acetals (2 and 7, respectively) (eqs 1 and 4)5,6 and oxetane
sec-amides (8) to substituted 5,6-dihydro-4H-1,3-oxazines
(9) (eq 5).5 It is notable that the oxetanyl group does not
This paper reports a novel mode of the Lewis acid
catalyzed isomerization of oxetane tert-amides (1: N-alkyl-
N-(3-methyl-3-oxetanyl)methylacylamides, acyl ) R1CO,
alkyl ) R2). The isomerization of 1 gives two heterocyclic
compounds quite different from each other. One is a
bicyclic acetal (2) produced by the single isomerization
as previously reported,5 and the other is an azetidine
derivative (3) having an ester group at the 3-position (eq
2). The latter reaction is an unusual, counterintuitive
transformation consisting of two key steps: a four-
membered oxetane ring in 1 enlarges first to a [2.2.2]-
dioxazabicycle, which is in turn rearranged to a different
four-membered azetidine ring. Hereafter, the overall
reaction sequence is expressed by the term of “double
isomerization” to distinguish it from the known single
isomerizations of carbonyl-functionalized oxetanes, as in
eqs 1 and 3-5.
(1) Rose, J . B. J . Chem. Soc. 1956, 542-546.
(2) Reviews on the cationic ring-opening polymerization of oxe-
tane: (a) Dreyfuss, M. P.; Dreyfuss, P. In Encyclopedia of Polymer
Science and Engineering, 2nd ed.; Mark, H. F., Bikales, N. M.,
Overberger, C. G., Menges, G., Eds.; J ohn Wiley and Sons: New York,
1987; Vol. 10, pp 653-670. (b) Penczek, S.; Kubisa, P. In Comprehensive
Polymer Science; Allen, G., Ed.; Pergamon Press: Oxford, 1989; Vol.
3, pp 751-786. (c) Desai, H. In Polymeric Materials Encyclopedia;
Salamone, J . C., Ed.; CRC Press: New York, 1996; Vol. 11, pp 8268-
8279.
(3) Our previous works on the cationic ring-opening polymerization
of substituted oxetanes: (a) Ogawa, H.; Kodera, Y.; Kanoh, S.; Ueyama,
A.; Motoi, M. Bull. Chem. Soc. J pn. 1998, 71, 433-442. (b) Hiruma,
T.; Kanoh, K.; Yamamoto, T.; Kanoh, S.; Motoi, M. Polym. J . 1995,
27, 78-89. (c) Motoi, M.; Saito, E.; Kyoda, S.; Takahata, N.; Nagai, S.;
Arano, A. Polym. J . 1991, 23, 1225-1241. (d) Motoi, M.; Nagahara,
S.; Akiyama, H.; Horiuchi, M.; Kanoh, S. Polym. J . 1989, 21, 987-
1001.
Resu lts a n d Discu ssion
Preliminary results were gathered from the reaction
of 1j7 (R1 ) Ph, R2 ) Et) under different reaction
conditions such as catalyst, solvent, and temperature
(Table 1). When the reaction of 1j in the presence of a
catalytic amount of boron trifluoride etherate (BF3‚OEt2)
was carried out in chlorobenzene at 130 °C, the single
isomerization of the type in eq 1 took place. As a result,
(7) N-Ethyl-N-(3-methyl-3-oxetanyl)methyl benzamide (1j): colorless
liquid; bp 140 °C (1 mmHg); 1H NMR (CDCl3, 70 °C) δ 7.35-7.38 (m,
HPh), 4.61 (d, trans-OCH2 to 3-CH3), 4.30 (d, cis-OCH2 to 3-CH3), 3.66
(s, 3-CH2N), 3.29 (q, NCH2CH3), 1.39 (s, 3-CH3), 1.10 ppm (t, NCH2CH3);
13C NMR (CDCl3, 25 °C) δ 172.5 (CdO), 136.6 (ipso-CPh), 129.2, 128.4,
126.2 (other-CPh), 81.7 (C2 and C4), 50.3 (3-CH2N), 44.8 (NCH2CH3),
40.5 (C3), 21.8 (3-CH3), 13.6 ppm (NCH2CH3); IR (neat) 1630 (νCdO),
(4) (a) Corey, E. J .; Raju, N. Tetrahedron Lett. 1983, 24, 5571-5574.
(b) Ducray, P.; Lamotte, H.; Rousseau, B. Synthesis 1997, 404-406.
(5) Nishimura, T.; Kanoh, S.; Senda, H.; Tanaka, T.; Ando, K.;
Ogawa, H.; Motoi, M. J . Chem. Soc., Chem. Commun. 1998, 43-44.
(6) Kanoh, S.; Hashiba, T.; Ando, K.; Ogawa, H.; Motoi, M. Synthesis
1997, 1077-1080.
975, 820 cm-1 (νcyclic ether); HRMS found, m/e 233.1427 (calcd for C14H19
NO2, m/e 233.1417).
-
10.1021/jo991888g CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/16/2000

2254 J . Org. Chem., Vol. 65, No. 7, 2000
Notes
Ta ble 1. Dou ble Isom er iza tion of 1ja
Ta ble 2. Yield s (%, 1H NMR) of 3 Obta in ed in th e Dou ble
Isom er iza tion of 1a -ta
yield (%) b
R1
entry catalyst (mol %) solvent temp (°C) time (h) 2j
3j
-C6H4-p-X
1
2
3
4
BF3‚OEt2 (5)
BF3‚OEt2 (5)
PhCl
PhCl
130
130
130
150
150
150
150
1.5
24
56c
0
14
0
0
0
0
0
R2 Me
Me
Et e, 0 f, 2
Pr m , 0 n , 6 o, 12
Bn q, 0 r , 47 s, 62
Et
Pr
Bn NO2
Cl
H
OMe t-Bu
d , 54
CF3SO3CH3 (5) PhCl
CF3SO3CH3 (2) PhNO2
72
96
68
96
96
53
73
48
20
34
a , 0
b, 0
c, 6
g, 10
h , 58 i, 56 j, 73 k , 64 l, 42
5
CF3SO3H (2)
BnTAd (5)
BnTAd (5)
PhNO2
PhNO2
PhNO2
p , 70
t, 75
6
7e
0
a
The reaction of 1 (0.9 mmol) in anhydrous nitrobenzene (1.0
mL) was carried out using MeOTf (2 mol %) at 150 °C for 48-96
a
Reaction conditions: 1j (224 mg, 0.92 mmol), anhydrous
solvent (1.0 mL). Determined by 1H NMR. The remainder was a
b
h.
polymeric product. c Isolated yield. Benzylthiolanium hexafluo-
d
roantimonate. e The reaction was started from 2j.
at 1720 cm-1, indicating an ester but not an amide. The
C-H connectivity based on the COLOC correlation
lr
(correlation spectroscopy via long-range coupling,
J
CH
) 8 Hz) revealed clear evidence that 3j is (1-ethyl-3-
methyl-3-azetidinyl)methyl benzoate (Figure 1). Each of
the isomerization products, 2j and 3j, was produced with
complete selection by controlling reaction conditions,
especially catalyst and temperature. When the reaction
of 1j with MeOTf was run at 150 °C using anhydrous
nitrobenzene as a solvent, 3j was obtained as the major
isomerization product (entry 4). Under these reaction
conditions, TfOH and benzylthiolanium hexafluoroani-
timonate (BnTA)11 also acted as catalysts for yielding 3j
(entries 5 and 6). However, the isomerization by any
catalyst was more or less accompanied by polymerization,
and hence the yield of 3j began to decrease after reaching
maximum. On the other hand, a control reaction starting
from 2j also gave 3j (entry 7). This evidently reveals that
the reaction process from 1j to 3j is a double isomeriza-
tion via 2j.
lr
The double isomerization of 1a -t with various com-
binations of R1 and R2 groups was carried out using
MeOTf in nitrobenzene at 150 °C. The yields of 3 are
summarized in Table 2, where the R1 and R2 groups are
arranged in the order of increasing bulkiness. From the
variation in the yield of 3, an apparent tendency can be
seen that the smaller the R1 and/or R2 groups are, the
more the yield of 3 decreases. Less bulky acetamides (R1
) Me) brought about no double isomerization regardless
of the R2 groups. These acetamides, of course, brought
about the single isomerization, though the resulting
intermediates 2 were consumed by cationic polymeriza-
tion. Similarly, N-methyl-substituted amides (R2 ) Me),
except for the exceedingly bulky pivalamide (1d ), hardly
yielded 3. The combination of the R1 and R2 groups
leading to more than moderate yields of 3 strongly
suggests that the steric repulsion between both groups
plays an important role in the ring contraction process
of the intermediate 2.
A plausible mechanism for the double isomerization
of 1 can be explained as shown in Scheme 2. The reaction
begins with the coordination of an acid catalyst E to the
oxetanyl oxygen of 1,6 and the resulting oxonium A
undergoes the intramolecular nucleophilic attack of the
amide carbonyl oxygen. As has been recognized by NMR
analysis,12 most 1 also exist as mixtures of two conform-
ers as a result of the restricted rotation around the amide
F igu r e 1. COLOC spectrum of 3j in CDCl3 (400 MHz,
J
CH
) 8 Hz). Selected C-H long-range correlations: A ) Cd-He,
B and C ) Cd-Hc, D ) Cd-Hf, E ) Cb-trans-Hc to 3-CH3, F
1
) Cg-Hf. Asterisks refer to residual J CH correlations.
bicyclic acetal 2j8 was produced in the early stage of the
reaction (entry 1). After 24 h, however, it was completely
converted into a polyether having benzamide pendants
(entry 2), probably owing to the cationic double ring-
opening polymerization.9 The use of aluminum Lewis acid
catalysts such as trimethylaluminum, aluminum triphen-
oxide, and methylaluminum bis(2,6-di-tert-butyl-4-me-
thylphenoxide)10 led to fundamentally similar results.
In sharp contrast, the reaction using MeOTf as a
catalyst gave together with 2j another product (3j) having
the same molecular weight as those of 1j and 2j (entry
3). The 1H NMR spectrum of 3j showed two sets of
doublets at δ 3.03 and 3.21 ppm (Figure 1), suggesting
isolated methylene protons characteristic of a four-
membered ring. However, a similar type of double
doublets due to the oxetanyl O-methylene protons of 1j
appeared much more downfield at δ 4.30 and 4.61 ppm.7
The IR spectrum of 3j showed a strong stretching band
(8) 7-Ethyl-4-methyl-1-phenyl-2,6,7-dioxazabicyclo[2.2.2]octane (2j):
isolated yield, 54%; colorless liquid; bp 100-120 °C (1 mmHg); 1H NMR
(anhydrous CDCl3) δ 7.60 (dd, o-HPh), 7.29-7.38 (m, m- and p-HPh),
3.98 (s, endo-OCH2), 2.99 (s, endo-NCH2), 2.36 (q, NCH2CH3), 0.94 (t,
NCH2CH3), 0.88 ppm (s, Cq-CH3); HRMS found, m/e 233.1439 (calcd
for C14H19NO2, m/e 233.1417).
(9) Kanoh, S.; Nishimura, T.; Senda, H.; Ogawa, H.; Motoi, M.;
Tanaka, T.; Kano, K. Macromolecules 1999, 32, 2438-2448.
(10) MAD was prepared according to Aida’s method and recrystal-
lized from toluene-hexane under nitrogen: Takeuchi, D.; Aida, T.
Macromolecules 1996, 29, 8096-8100.
(11) BnTA was prepared by Endo’s method and recrystallized from
2-propanol: 60% yield, mp 112-113 °C (lit. mp 121.5-122 °C): Endo,
T.; Uno, H. J . Polym. Sci., Polym. Lett. Ed. 1985, 23, 359-363.
(12) Challis, B. C.; Challis, J . A. In Comprehensive Organic Chem-
istry; Barton, D., Ollis, D., Sutherland, I. O., Eds.; Pergamon Press:
Oxford, 1979; Vol. 2, pp 957-1065.

Notes
J . Org. Chem., Vol. 65, No. 7, 2000 2255
Sch em e 2. P la u sible Mech a n ism for th e Dou ble
Isom er iza tion of 1 to 3
be limited by the vigorous reaction conditions and
requirement of bulkiness of at least either R1 or R2 group
in the starting 1. The double isomerization should be
rather deemed to be of primary interest on the basis of
the curious mechanistic aspect.
Con clu sion
In summary, the reaction of tert-amide-substituted
oxetanes (1), preferably benzamide and pivalamide de-
rivatives, with MeOTf in anhydrous nitrobenzene at 150
°C has been found to give ester-substituted azetidines
(3) via bicyclic acetals (2). This transformation seems
unusual and counterintuitive, in that the overall reaction
sequence is a double isomerization involving both ring
expansion and contraction. Under acid catalysis, 1 un-
dergoes ring expansion by the neighboring group par-
ticipation of the amide carbonyl group, and then steric
repulsion between the adjacent R1 and R2 groups in the
intermediate 2 likely prompts C-N bond scission fol-
lowed by ring contraction.
C-N bonds. The s-cis conformation with respect to the
R1 and R2 groups should be required for the neighboring
group participation. The ratios of s-cis and -trans isomers
were estimated at nearly 8:2 in CDCl3 at 25 °C, while
NMR temperature-dependent line shape analysis showed
that the isomer-separated signals of 1 began to broaden
or coalesced up to 70 °C. The C-N bonds might become
considerably free at the reaction temperature as high as
150 °C. On the other hand, the pivalamides, such as 1d
and 1l, stay in the favorable s-cis conformation indepen-
dent of temperature. The resulting 1,3-oxazin-2-ylium
cation B brings about subsequent ring closure to give the
oxonium species C of 2. Since 2 is not only a cyclic ether
but also a cyclic amine, C would change into the more
stable ammonium cation D, which suffers steric repulsion
between the adjacent R1 and R2 groups. This makes the
C-N+ bond scission feasible, and the resulting 1,3-
dioxan-2-ylium cation E closes in another way to form
an azetidine ring. The stabilization of the cation E might
be a less crucial factor, because the double isomerization
of N-ethylbenzamides (1h -k ) resulted in the roughly
comparable yields of 3 regardless of the great difference
in the electronic effect of the p-X-substituent.
Exp er im en ta l Section
1
Gen er a l Meth od s. H, 13C, and COLOC NMR spectra were
measured in commercial or anhydrous CDCl3 at 400 MHz for
1H nuclei. IR spectra were recorded in the FT mode. Trimethyl-
aluminum in hexane and TfOH were used as received. Boron
trifluoride etherate and MeOTf were purified by fractional
distillation under reduced pressure in a nitrogen atmosphere.
Anhydrous reagents, such as triethylamine, chlorobenzene, and
nitrobenzene, were purified by the conventional methods and
distilled under dry nitrogen before use.
The oxetane amides 1 were synthesized from the known
oxetane phthalimide (Scheme 3), which was prepared from
Sch em e 3a
In our examination, MeOTf is the preferred catalyst.
The very reactive methylating reagent is likely to be
extremely short-lived and simply to be serving to gener-
ate in situ the true catalytic species, presumably TfOH,
following methylation or by hydrolysis with water im-
purity. The higher yield of 3 for entry 4 over entry 5, in
other words, the higher polymer yield for entry 5, may
be a specious consequence resulting from the polymeri-
zation of 3. The intermediates A-F are regarded as
potential initiating species for cationic ring-opening
polymerization, and protonated species and methylated
species (E ) H, Me) could possess different polymeriza-
bility. Catalysis of thermal latent Lewis acid BnTA,
which generates benzyl cation above its decomposition
temperature of 80 °C,11 would be analogously interpreted,
though the inevitable polymerization of 3 was accelerated
to a greater extent by this catalyst.
a
(a) (EtO)2CO, KOH. (b) TsCl, aq. NaOH, (c) Potassium
phthalimide (d) i. N2H4‚H2O; ii. Raney Ni (W-2). (e) (R1CO) 2O, or
R1COCl, TEA, or R1COOH, DCC, DMAP. (f) R2Br, K2CO3, NaOH,
Bu4NHSO4.
trimethylolethane according to the procedure described in our
previous paper.6 The phthalimide was converted into oxetanyl-
methylamine,5 which was acylated and then N-alkylated14 to
give 1 as a mixture of two rotational isomers, except for 1d and
1l with the s-cis conformer predominating.
Gen er a l P r oced u r e for th e Dou ble Isom er iza tion of 1.
A representative procedure of the double isomerization of 1 is
described as follows. To a tube containing 1j (224 mg, 0.92 mmol)
and anhydrous nitrobenzene (1.0 mL) was charged MeOTf in
anhydrous nitrobenzene (0.43 mol L-1, 0.05 mL, 0.02 mmol)
under a nitrogen atmosphere. The resulting solution was allowed
to stand at 150 °C for 96 h. The reaction was quenched with
anhydrous triethylamine (0.1 mL), and then the mixture was
evaporated. The residue was purified by column chromatography
on alumina (EM Aluminumoxid 90; 70-230 mesh ASTM) with
ethyl acetate-hexane (2/3 v/v) followed by distillation in vacuo
to give 3j in 63% isolated yield (141 mg). If the boiling point of
3 was assumed lower than or close to that of nitrobenzene, the
product was gained by chromatographic workup without evapo-
ration of the solvent. The isolation of 3c and 3f failed because
The double isomerization of oxetane tert-amides 1
serves as a quite different entry into azetidines than the
general synthetic methods,13 which concern the cycliza-
tion of R,γ-difunctionalized alkanes or the reduction of
â-lactams and malonimides. However, the scope of the
reaction for 1,3-substituted azetidine ring formation may
(13) (a) Cromwell, N. H.; Philips, B. Chem. Rev. 1979, 79, 331-358.
(b) Moore, J . A.; Ayers, R. S. In Chemistry of Heterocyclic Compounds;
Hassner, A., Ed.; Wiley: New York, 1983; Part 2, pp 1-217. (c) Davies,
D. E.; Starr, R. C. In Comprehensive Heterocyclic Chemistry; Lwowski,
W., Ed.; Pergamon Press: Oxford, 1984; Vol. 7, pp 237-284.
(14) Gajda, T.; Zwierzak, A. Synthesis 1981, 1005-1008.

2256 J . Org. Chem., Vol. 65, No. 7, 2000
Notes
of poor yields. As example, (1-ethyl-3-methyl-3-azetidinyl)methyl
benzoate (3j): pale yellow liquid; bp 130-140 °C (1 mmHg); 1H
NMR (CDCl3) δ 8.05 (d, J ) 7.81 Hz, 2H, o-HPhCO), 7.57 (t, J )
7.32 Hz, 1H, p-HPhCO), 7.45 (t, J ) 7.57 Hz, 2H, m-HPhCO), 4.33
(s, 2H, 3-CH2O), 3.21 (d, J ) 7.32 Hz, 2H, trans-NCH2 to 3-CH3),
3.03 (d, J ) 7.33 Hz, 2H, cis-NCH2 to 3-CH3), 2.51 (q, J ) 7.16
Hz, 2H, NCH2CH3), 1.38 (s, 3H, 3-CH3), 0.97 ppm (t, J ) 7.33
Hz, 3H, NCH2CH3); 13C NMR (CDCl3) δ 166.5 (CdO), 132.9 (p-
Sch em e 4
atmosphere because of high sensitivity to moisture; yield was
43-73%. In air, compounds 2 were readily hydrolyzed to amino
esters (10). In the cases of 2a -c, e, f, m , and q having relatively
less bulky R1 and/or R2 groups, acyl transfer following hydrolysis
eventually gave amide alcohols (11) as final products (Scheme
4).
C
PhCO), 130.2 (ipso-CPhCO), 129.5 (o-CPhCO), 128.3 (m-CPhCO), 70.4
(3-CH2O), 62.0 (C2 and C4), 53.4 (NCH2CH3), 34.5 (C3), 22.7
(3-CH3), 12.2 ppm (NCH2CH3); IR (neat) 1720, 1270, 1110 cm-1
HRMS found, m/e 233.1427 (calcd for C14H19NO2, m/e 233.1417).
Isola tion of In ter m ed ia te 2. Similarly, the single isomer-
ization of 1 using BF3‚OEt2 as a catalyst was carried out in
anhydrous chlorobenzene at 130 °C for 1-1.5 h. The reaction
was quenched first with anhydrous triethylamine, and then a
small amount of calcium hydride was added. Distillation in vacuo
directly from the mixture gave 2, which was stored in a nitrogen
;
Su p p or tin g In for m a tion Ava ila ble: Characterization
data and copies of 1H NMR spectra for compounds 1-3 (33
pages). This material is available free of charge via the
Internet at http://pubs.acs.org.
J O991888G