Study on the isomerization of 1-acylazetidine. A comparative study with the case of 1-acylaziridine

Full text of DOI:10.1021/jo981901h

5686
J . Org. Chem. 1999, 64, 5686-5690
(1 mmol/1 mL), and the solution was heated at 70 °C.
Stu d y on th e Isom er iza tion of
After every 2 h (at 2, 4, and 6 h), a part of the reaction
mixture was removed and monitored. The 19F NMR
spectrum of each sample showed that it was a mixture
of residual 3, two diastereomeric oxazines, 2-[(R)-(R-
methoxy-R-trifluoromethyl)benzyl]-[(R) or (S)]-6-methyl-
5,6-dihydro-4H-1,3-oxazine [(R)(R)-4] and [(R)(S)-4], and
a substance 5a that would have formed from 4 by the
reaction with BF3‚OEt2. In every sample, the ratio of (R)-
(R)-4:(R)(S)-4 was found to be 80:20. Results are shown
in Table 1.
1-Acyla zetid in e. A Com p a r a tive Stu d y w ith
th e Ca se of 1-Acyla zir id in e
Aiko Nabeya* and Tadatoshi Endo
School of Dental Medicine, Tsurumi University,
Yokohama 230-8501, J apan
Takeshi Nishiguchi
Faculty of Agriculture, Yamaguchi University,
Yamaguchi 753-8515, J apan
Kenzi Hori
Faculty of Engineering, Yamaguchi University,
Yamaguchi 755-8611, J apan
Received September 18, 1998
Azetidine has often been compared with aziridine,
probably because it is also a small cyclic amine and the
molecule is also strained. A number of physical and
spectroscopic measurements have been done to inspect
if there is some resemblance between the two cyclic
amines. These results are collectively reviewed by Moore
and Ayers.1 In the review, it is mentioned as a general
remark that azetidine has certain behavioral similarities
to aziridine that stem from the small ring size and the
ring strain. However, the physical properties that reflect
the orbital hybridization closely resemble those of pyr-
rolidine, and thus, azetidine has few of the special
characteristics exhibited by aziridine.
Reaction of 3 with p-toluenesulfonic acid (TsOH) was
carried out in a similar way as above, and the reaction
mixture was inspected by 19F NMR spectroscopy. When
1.2 molar equiv of TsOH was used, the composition after
1 h of heating was found to be 7% 3, 39% ring-opened
addition product N-[(S)-3-tosyloxybutyl]-(R)-MTPA amide
(6), and 54% diastereomeric mixture of 4, of which 89%
was (R)(R) and 11% was (R)(S). Prolonged heating (4 h)
In a previous work,2 we have shown that 1-(R)-(R-
methoxy-R-trifluoromethylphenylacetyl)-(S)-2-methylazir-
idine (1) isomerizes to 2-(R)-(R-methoxy-R-trifluoromethyl)-
benzyl-(S)-5-methyl-1,3-oxazoline-2 (2) with complete
retention of the configuration at C-2 in the aziridine ring
when 1 is heated in benzene with BF3‚OEt2 for a short
period. Molecular orbital calculations using 1-formyl-
did not change the composition. On using 2.4 molar equiv
of TsOH, the reaction was practically complete in 1 h,
giving a mixture of 6% 6 and 94% 4 [90% (R)(R) and 10%
(R)(S)]. Results are summarized in Table 2. In a separate
experiment, 6 was heated in benzene in the presence of
TsOH at 70 °C. After 1 h, 87% of 6 was converted to 4,
and the ratio of (R)(R)- to (R)(S)-4 was found to be 93:7
(Table 3).
aziridine (1a ) as a model compound have shown that the
reaction is most likely to proceed by the SNi mechanism.
This result prompted us to investigate the isomerization
of an azetidine derivative to the corresponding oxazine
to see if an SNi-like process is also possible.
To obtain some clue as to the possible site of coordina-
tion of BF3 (ring nitrogen or carbonyl oxygen), 1-acetyl-
azetidine (7) was prepared, and the change in the 1H
NMR spectra was observed on addition of BF3‚OEt2. On
addition of 1.2 molar equiv of BF3‚OEt2, the triplets at
4.03 and 4.14 that were originally observed in the
spectrum of 7 disappeared, and two triplets at 4.33 and
4.43 appeared.
Resu lts a n d Discu ssion
Exp er im en ta l Resu lts. 1-(R)-[R-Methoxy-R-(trifluo-
romethyl)phenylacetyl]-(R)-2-methylazetidine (3) was pre-
pared from (S)-R-methoxy-R-(trifluoromethyl)phenylacetyl
chloride [(S)-MTPA chloride] and (R)-2-methylazetidine
and recrystallized from hexane to give an optically pure
sample (100% ee). To a solution of 58 mg (0.2 mmol) of 3
was added 0.24 mL of a solution of BF3‚OEt2 in benzene
Discu ssion
(1) Moore, J . A.; Ayers, R. S. In Heterocyclic Compounds, Small Ring
Heterocyles-Part-2; Hassner, A., Ed; Binghamton, New York, l983; p
4.
In the isomerization reaction of 3 with BF3‚OEt2, the
first step should be the coordination of BF3 to 3, because
the azetidine ring never opens without acids under the
(2) Hori, K.; Nishiguchi, T.; Nabeya, A. J . Org. Chem. 1998, 62, 3081.
10.1021/jo981901h CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/02/1999

Notes
J . Org. Chem., Vol. 64, No. 15, 1999 5687
Ta ble 1. Rea ction of (R)(R)-3 w ith BF 3‚OEt2
The next step will be the attack of the cabonyl oxygen
on the ring carbon adjacent to the nitrogen. The coordi-
nation of BF3 at the carbonyl oxygen should make the
nucleophilic attack easy. The coordination should induce
a positive charge on the nitrogen, and therefore, the
carbons adjacent to the nitrogen should also be positively
charged to some extent. The experimental results showed
that the ring opened exclusively at the N-CH(CH3) bond
and that the configuration at the carbon atom was
partially retained. If the isomerization took place by the
SNi mechanism as in 1, the configuration at the attacked
carbon should be completely retained. Therefore, the SNi
mechanism is ruled out. Because no nucleophiles that
might participate in the ring-opening reaction are present
in the reaction system, the SN1 mechanism is the only
possible one. It has been known that in many of the SN1
reactions starting from optically pure material the prod-
uct is a mixture of the inverted compound and the
racemic modification. The predominance of the inversion
over the retention in these cases has been attributed to
the shielding of the frontside of the carbonium ion by the
leaving group, which should lead to the preference of the
backside attack of the nucleophile to give the inverted
product.5 The reverse is the case with 3, where the
frontside attack should be more favored than the back-
side attack owing to the particular conformation, in which
the attacking carbonyl oxygen is favorably situated to
approach the carbonium ion from the same side as the
departing nitrogen. If the carbonyl oxygen attaches itself
to the carbonium ion before such a conformation col-
lapses, the retention of the configuration should result.
Thus far, it has been shown that, unlike the isomer-
ization of 1 to 2, the isomerization of 3 to 4 proceeds by
an SN1 mechanism. This difference seems to stem from
the difference of the substrate coordination site of BF3.
In 1-acetylazetidine, the coordination of BF3 at the
composition of reaction mixture (%)
reaction time (h) (R)(R)-3 4 [(R)(R)/(R)(S)] 5a [(R)(R)/(R)(S)]
2
4
6
46
22
1
49 [82/18]
70 [83/17]
91 [81/19]
5 [80/20]
8 [80/20]
8 [81/19]
Ta ble 2. Rea ction of (R)(R)-3 w ith TsOH
composition of reaction mixture (%)
mole ratio reaction
TsOH/3
time (h)
(R)(R)-3
6
4 [(R)(R)/(R)(S)]
1.2
1.2
1.2
2.4
2.4
1
2
4
1
2
7
6
3
0
0
39
34
30
6
54 [89/11]
60 [89/11]
67 [90/10]
94 [90/10]
97 [89/11]
3
Ta ble 3. Hea tin g of 6 in Ben zen e w ith TsOH
composition of reaction mixture (%)
reaction time (h)
6
4 [(R)(R)/(R)(S)]
1
2
13
8
87 [93/7]
92 [92/8]
reaction conditions mentioned above. There are two
possible sites for BF3 to coordinate: the ring nitrogen and
the carbonyl oxygen. Thus far, no report on the coordina-
tion site of BF3 to amides has been found. A number of
works have investigated the protonation site for amides
since the 1950s, and 1H NMR spectroscopic inspection
showed evidence for the O-protonation. As one of the most
prominent examples, Gillespie and Birchall3 showed the
1
signal of an O-H bond in the H NMR spectra of various
amides taken in FSO3H at low temperatures (-80 to -98
°C). Another example by Fraenkel and Niemann4 showed
that the unequivalency of the two methyl groups of DMF
1
(for example) in the H NMR spectrum was preserved in
strongly acidic media (such as H2SO4). In N,N-dimethyl-
amides (such as DMF or N,N-dimethylacetamide), the
1H NMR spectra in neutral media show two peaks for
the two N-methyl groups, demonstrating that the two
methyl groups are in different environments. This phe-
nomenon has been explained by the double bond char-
acter of the C-N bond of the amide. Thus, they concluded
that the preservation of the unequivalency in acidic
media should be strong evidence for the O-protonation,
because the N-protonation should lead to the free rotation
around the C-N bond and therefore should give a single
peak for the protons for the two methyl groups.
1
carbonyl oxygen was shown to be likely by the H NMR
analysis. In the case with 1-acylaziridines, however, MO
calculations have shown that the protonation at the ring
nitrogen is slightly more stable (1.8 kcal mol-1, calculated
using 1-formylaziridine as a model compound and proton)
1
than the protonation at the carbonyl oxygen.2 In the H
NMR spectra of 1-acylaziridines, the unequivalency has
never been observed between the protons or the substit-
uents on the 2- and 3-carbon atom. For example, 1-tolu-
oyl-cis-2,3-dimethylaziridine gave only one doublet (of
CHCH3, six protons) and one doublet-quartet (of CH-
1
1
In the H NMR spectra of all of the 1-acylazetidines
CH3, two protons) in the H NMR spectrum, indicating
tested (1-aroyl and 1-acetylazetidine, 7), there were
always two peaks (two protons each) observed assignable
to 2- and 4-CH2 of the azetidine ring, in contrast to the
case in 1-methyl and 1-tosylazetidine, in which only one
triplet (four protons) was found. This means that in
1-acylazetidines also, the C-N bond is restricted from
free rotation as a result of the double bond character of
the C-N bond as in typical amides. Amide 7 was chosen
that the rotation of the C-N bond is fairly fast. This
means that the double bond character of the C-N bond
is not so pronounced as in typical amides. It follows that
the ring nitrogen should be more basic than that in
ordinary amides, and therefore, the coordination of acids
at the nitrogen is likely. It was shown in our previous
paper2 that such an initial state of N-coordination is very
suitable for the reaction to go by the SNi mechanism. In
the case of 3, the lack of such anomaly will lead to the
coordination at the carbonyl oxygen and thus adversely
affect the SNi process because (1) the nucleophilic reactiv-
ity of the carbonyl oxygen is reduced by the coordination
and (2) the O-CH(CH3) distance is lengthened.
1
as a sample to see the change in the H NMR spectra on
addition of BF3‚OEt2. When 1.2 molar equiv of BF3‚OEt2
was added, the two triplets (of 2- and 4-CH2) appeared
at lower positions than before. The reappearance of the
two triplets for 2- and 4-CH2 is in good accord with the
coordination at the carbonyl oxygen.
In the reaction of (R)(R)-3 with TsOH, two routes are
possible that would give rise to 4: (1) via 6 by addition-
(3) Gillespie, R. J .; Birchall, T. Can. J . Chem. 1963, 41, 148.
(4) (a) Katritzky, A. R.; Phil, M. A. D.; J ones, R. A. Y. Chem. Ind.
1961, 722. (b) Fraenkel, G.; Niemann, C. Proc. Natl. Acad. Sci. U.S.A.
1958, 44, 688.
(5) Morrison, R. T.; Boyd, R. N. Organic Chemistry, 6th ed.; Prentice
Hall: New J ersey, 1992; p 194.

5688 J . Org. Chem., Vol. 64, No. 15, 1999
Notes
elimination mechanism and (2) proton-catalyzed direct
isomerization as in the case of BF3‚OEt2. If the reaction
goes exclusively by mechanism 2, the high ee value for 4
(80%) cannot be explained, becauase the ee value was
only 60% in BF3-catalyzed isomerization (Table 1). There-
fore, mechanism 2 does not seem to be important, though
it may not be excluded. If oxazine 4 is formed via 6
followed by ring closure (mechanism 1), the ring-closing
step should be accompanied by partial racemization,
because the ring-opening addition reaction of (R)(R)-3
and TsOH proceeded with complete inversion of the
configuration to give a single diastereomer, 6. Heating
of 6 with TsOH in benzene revealed that partial racem-
ization (∼15%) actually took place in the ring-closing
process (Table 3). The fact that the percentage of race-
mization at the ring-closing step is very close to that
observed in the reaction of (R)(R)-3 and TsOH (∼20%,
Table 2) suggests that mechanism 1 is very likely.
It is noted that the ring-closing step of 6 to 4 was
accompanied by partial racemization. This result makes
a marked contrast to the ring closure of the addition
1-Formyl-2-methylazetidine (3b) was used as a model
compound for 3 instead of 1-formylazetidine (3a ). In the
acid-catalyzed isomerization of 1-acyl-2-methylaziridines,
5-methyloxazolines resulting from the cleavage of the
N-CH(CH3) bond are the only2 or main (∼90%)8 product,
and we confirmed in the previous study2 that the
consideration of the substituent effect was essential in
the theoretical elucidation of the reaction mechanism.
Furthermore, it was found in the present study that
6-methyloxazine (from the N-CH(CH3) bond cleavage)
was the only product of isomerization, and no trace of
4-methyloxazine (from the N-CH2 bond cleavage) was
detected by 1H and 19F NMR spectroscopy. Therefore, 3b
should be more appropriate than 3a as the model of the
present study. As mentioned previously,2 calculations at
the MP2/6-31G**//RHF/6-31G* level of theory, using 1a
as a model compound, showed that the protonation at
the N-atom is 1.8 kcal mol-1 more favored than the
protonation at the carbonyl oxygen. In the case of
1-formyl-2-methylazetidine (3b), however, the O-proto-
nated form was found to be more stable than the
N-protonated one by 10.4 kcal mol-1 at the MP2 level.
This suggests that the predominance of 3(OH+) can be
expected in nonpolar solvents such as benzene.
Ab initio MO calculations9 optimized an open-chain
carbocationic intermediate, 3b(OH+,open). This makes a
marked contrast to the case in 1a , where no stable cation
was obtained. The energy level of the intermediate was
shown to be 42.0 kcal mol-1 above the level of 3b(OH+).10
Then, we found two TSs successively. One was the TS
for the ring-opening process of the four-membered ring,
product of 1 and TsOH, 8 to 2,2 where complete inversion
of the configuration took place to give 2 of 100% ee. (The
result was confirmed recently. See the Experimental
Section). This means that although the conversion of 8
to 2 proceeds completely by the SN2 mechanism, the
conversion of 6 to 4 does not go by the SN2 mechanism
exclusively under similar reaction conditions. The reason
for the difference has not been elucidated so far.
3b(OH+,3TS), with an imaginary frequency of 90.0 i cm-1
,
and the other was that for the ring-closing process to form
4b(OH+), 3b(OH+,4TS), with an imaginary frequency
158.9i cm-1. The TS structure11 of 3b(OH+,3TS) was
estimated to be 49.5 kcal mol-1 higher in energy than
3b(OH+), and that of 3b(OH+,4TS) was 43.3 kcal mol-1
higher than the same level, respectively. Results are
shown in Figure 2.
Molecu la r Or bita l Ca lcu la tion s
The ab initio MO calculations were performed by using
the GAUSSIAN94 program6 to obtain stable structures
of the bases and their protonated species and also the
structures of the transition states (TS) and the interme-
diates. The 6-31G* basis sets7 were used to optimize these
geometries. Vibrational frequency calculations were per-
formed for all of the geometries optimized in the present
study.
Con clu sion
The MO calculations using 3b as the model for 3 and
proton showed that O-protonation is much more favorable
than N-protonation. This might give support for the
O-coordination of BF3 from the energetic viewpoint. The
lengthening of the O-CH(CH3) distance on going from
the initial state to the transition state was shown to be
as follows: 2.902 Å for 3b(OH+) and 3.094 Å for 3b(OH+,
3TS), as shown in Figure 1. In contrast, the O-CH(CH3)
length was shown to be shortened in the case with 1a ,
from 2.876 Å in 1a (NH+) to 2.629 Å in 1a (NH+,TS).2
These results give support for the discussion on the
adverse effects of the O-coordination toward the SNi
process.
It was ascertained in a previous paper2 that 1-acyl-
aziridines isomerize to oxazolines by the SNi mechanism.
In contrast, the experimental results mentioned above
suggest that the isomerization of 1-acylazetidines to
oxazines does not proceed by the SNi mechanism but by
an SN1 mechanism under similar reaction conditions as
in 1. Here, mention is made of the elucidation of the
isomerization mechanism from the theoretical point of
view, forcusing our attention on the comparison of the
result with that obtained in 1-formylaziridine, 1a .
(8) Nishiguchi, T.; Tochio, H.; Nabeya, A.; Iwakura, Y. J . Am. Chem.
Soc. 1969, 91, 5841.
(9) Prior to ab initio MO calculations, we performed semiempirical
MO calculations (PM3, MOPAC Ver. 93; Stewart, J . J . P. Fujitsu
Ltd.: Tokyo, J apan, 1993) in search of the intermediate and the TSs
and used them as the initial geometries for the ab initio MO
calculations.
(10) For estimating free energy differences in the gas phase at 298
K, 1 atm, we used energies at the MP2/6-31G**//RHF/6-31G* level of
theory and those from the vibration frequency of the RHF/6-31G*
calculations without scale factor.
(11) Calculations using TSs obtained gave few geometries along the
IRC [(a) Fukui, K. Acc. Chem. Res. 1981, 14, 363. (b) Head-Gordon,
M.; Pople, J . A. J . Chem. Phys. 1988, 89, 5777.], probably because the
potential surfaces around these TSs are very flat.
(6) GAUSSIAN94; Frisch, M. J .; Trucks, G. W.; Schlegel, H. B.; Gill,
P. M. W.; J ohnson, B. G.; Robb, M. A.; Cheeseman, J . R.; Keith, T.;
Petersson, G. A.; Montgomery, J . A.; Raghavachari, K.; Al-Laham, M.
A.; Zakrzewski, V. G.; Ortiz, J . V.; Foresman, J . B.; Cioslowski, J .;
Stefanov, B. B.; Nanayakkara, A.; Challacombe, M.; Peng, C. Y.; Ayala,
P. Y.; Chen, W.; Wong, M. W.; Andres, J . L.; Replogle, E. S.; Gomperts,
R.; Martin, R. L.; Fox, D. J .; Binkley, J . S.; Defrees, D. J .; Baker, J .;
Stewart, J . P.; Head-Gordon, M.; Gonzalez, C.; Pople, J . A., Gaussian
Inc., Pittsburgh, PA, 1995.
(7) Hehre, W. J .; Ditchfield, R.; Pople, J . A. J . Chem. Phys. 1972,
56, 2257.

Notes
J . Org. Chem., Vol. 64, No. 15, 1999 5689
cal Co. (Milwaukee, WI). NMR spectra (1H, 19F, and 13C) were
recorded (270 MHz for 1H, 254 MHz for 19F, and 67.80 MHz for
13C) using TFA as a standard for 19F NMR.
P r ep a r a tion of (R)-2-Meth yla zetid in e. (S)-4-Amino-2-bu-
tanol was prepared from (S)-1,2-propanediol through four steps
in overall yield of 16%, bp 85-87 °C (19 mmHg). The optical
purity of the amino alcohol was found to be 100% ee from the
19F spectrum of its MTPA amide. From the amino alcohol, (R)-
2-methylazetidine was prepared according to the method re-
ported by Vaughan et al.12 in overall yield of 14%, bp 72-73 °C;
[R]20 -15.6 (c ) 4.90, hexane).13 The optical purity of the
D
azetidine was determined by the 19F NMR spectroscopy of 3
before recrystallization to be 90% ee.
1-[(R)-R-Meth oxy-r-(tr iflu or om eth yl)p h en yla cetyl]-(R)-
2-m eth yla zetid in e [(R)(R)-3]. Into an ice-cooled solution of 80
mg (1.1 mmol) of (R)-2-methylazetidine and 110 mg (1.1 mmol)
of Et3N in ether was added dropwise a solution of 253 mg (1.0
mmol) of (S)-MTPA chloride in ether. After 2 h of stirring, the
precipitated Et3NHCl was removed by filtration, and the filtrate
was washed with brine, dried (Na2SO4), and concentrated on a
rotary evaporator to give 3 (90% ee) in quantitative yield.
Recrystallization from hexane gave an optically pure sample of
(R)(R)-3: mp 103-105 °C; 1H NMR (C6D6) δ ∼0.94 (m, 1H), 1.29
(d, 3H, J ) 6.2 Hz), ∼1.6 (m, 1H), ∼2.95 (dt, 1H, J ) 6.6, 9.7
Hz), 3.38, 3.39 (s, 3H), ∼3.43 (dt, 1H, J ) 5.9, 9.7 Hz), ∼4.25
(m, 1H), ∼7.1 (m, 3H), 7.71 (d, 2H); 19F NMR (C6D6) δ 5.62 [(R)-
(S)-3 had a signal at 6.05]. Anal. Calcd for C14H16NO2F3: C,
58.33; H, 5.61; N, 4.88. Found: C, 58.34; H, 5.50; N, 4.90.
Rea ction of (R)(R)-3 w ith BF 3‚OEt2. Into a solution of 58
mg (0.2 mmol) of (R)(R)-3 in 1 mL of benzene (dried over CaH2)
was added 0.24 mL of a solution of BF3‚OEt2 in benzene (1
mmol/1 mL), and the reaction mixture was heated at 70 °C with
stirring. After 2 h of heating, 0.3 mL of the reaction mixture
was removed and taken up in benzene. The benzene solution
was washed with 1 N NaOH and brine, dried (Na2SO4), and
1
concentrated to give a sample for H and 19F NMR spectroscopy.
These spectra showed that the sample consisted of unreacted 3,
oxazines (R)(R)-4 and (R)(S)-4, and another substance 5a , 2-[(R)-
R-difluoroboryloxy-R-trifluoromethyl]-[(R) or (S)]-6-methyl-5,6-
dihydro-4H-1,3-oxazine. In a similar manner, a part of the
reaction mixture was removed and analyzed after 4 and 6 h.
Results are summarized in Table 1.
F igu r e 1.
Au t h en t ic Sa m p le of N-[(S)-3-Tosyloxyb u t yl]-(R)-r-
m eth oxy-r-(tr iflu or om eth yl)p h en yla ceta m id e (6). Starting
from 126 mg (0.5 mmol) of (S)-MTPA chloride and (S)-3-amino-
2-butanol, the crude amide was obtained. The crude amide was
dissolved in 1 mL of pyridine, and to this solution was added
200 mg (1.0 mmol) of TsCl and 24 mg (0.2 mmol) of DMAP. After
2 days of stirring at room temperature, water was added, and
the mixture was stirred for another 1 h. Then the mixture was
taken up in benzene, and the benzene solution was washed
successively with 1 N HCl, aqueous NaHCO3 and brine, and
dried (Na2SO4). Evaporation of the solvent (rotary) gave 110 mg
of crude 6. Column chromatography of the crude 6 (AcOEt/
hexane 25:75) gave 70 mg (30% based on MTPA chloride) of
1
analytical sample of 6: oil; H NMR (C6D6) δ 0.82 (d, 3H, J )
6.2 Hz), ∼1.34 (m, 1H), ∼1.6 (m, 1H), 1.84 (s, 3H), ∼3.0 (m, 1H),
3.21, 3.22 (s, 3H), ∼3.3 (m, 1H), ∼4.6 (m, 1H), 6.74 (d, 2H), ∼7.1
(m, 5H), 7.71 (d, 2H), 7.75 (d, 2H); 19F NMR (C6D6) δ 6.63. Anal.
Calcd for C21H24NO5F3S: C, 54.89; H, 5.26; N, 3.05. Found: C,
54.82, 55.08; H, 5.27, 5.37; N, 3.02, 2.93.
Au th en tic Sa m p le of 2-[(R)-r-Meth oxy-r-(tr iflu or om eth -
yl)b en zyl]-(R)-6-m et h yl-5,6-d ih yd r o-4H -1,3-oxa zin e [(R)-
(R)-4]. A solution of 50 mg (0.11 mmol) of 6 and 50 mg (0.9
mmol) of KOH in 1 mL of EtOH was stirred at room temperature
for 2 h. After concentration of the solution (rotary), the residue
was dissolved in benzene, and the benzene solution was washed
with water and dried (Na2SO4). After evaporation of the solvent,
the residue was recrystallized from hexane to give 25 mg (81%)
of (R)(R)-4: mp 110-111 °C; 1H NMR (C6D6) δ 0.75 (d, 3H, J )
6.2 Hz), ∼1.08 (m, 2H), ∼3.15 (ddd, 1H, J ) 16.9, 5.3, 9.7 Hz),
F igu r e 2. The energy relation diagram in kcal mol-1 units
among the reactant, the transition states, and the intermedi-
ate. Values in kcal mol-1 units are free energy differences at
298 K, 1 atm.
Finally, the presence of an open-chain carbocationic
intermediate, 3b(OH+,open) would explain the partial
racemization that took place during the isomerization,
and the small energy difference between the intermediate
and the second TS, 3b(OH+,4TS) might explain the
overwhelming predominance of the retention observed in
the experiment.
(12) Vaughan, W. R.; Klonowski, R. S.; McElhinney, R. S.; Millward,
B. B. J . Org. Chem. 1961, 26, 138.
Exp er im en ta l Section
Gen er a l In for m a tion . Elemental analyses were performed
by the Institute of Physical and Chemical Research, Wako,
Saitama. (S)-MTPA chloride was purchased from Aldrich Chemi-
(13) Reported value for (S)-2-methylazetidine: [R]20D +11.6 (c ) 1.0,
hexane). See Kostyanovsky, R. G.; Gella, I. M.; Markov, V. I.;
Samojlova, Z. E. Tetrahedron l974, 30, 39.

5690 J . Org. Chem., Vol. 64, No. 15, 1999
Notes
∼3.33 (ddd, 1H, J ) 3.5, 5.1 Hz), ∼3.54 (m, 1H), 3.540, 3.545 (s,
3H), ∼7.2 (m, 3H), 7.86 (d, 2H); 19F NMR (C6D6) δ 5.065; 13C
NMR (CDCl3) δ 20.99, 28.36, 42.18, 54.59, 54.62, 72.08, 83.80,
125.99, 127.32, 127.34, 127.99, 128.54, 128.88. Anal. Calcd for
C14H16NO2F3: C, 58.33; H, 5.61; N, 4.88. Found: C, 58.51; H,
5.55; N, 4.88.
vacuum at 110 °C for 1 h) in 0.5 mL of benzene was added a
solution of 58 mg (0.2 mmol) of (R)(R)-3 in 0.5 mL of benzene at
70 °C, and the solution was heated at the same temperature.
After 1, 2, and 4 h, 0.3 mL of the mixture was removed and
dissolved in benzene. The solution was washed with aqueous
NaHCO3 and brine, dried (Na2SO4), and concentrated to afford
a sample for 19F NMR analyses. In another run, 2.4 molar equiv
(vs 3) of TsOH was used. A solution of 58 mg (0.2 mmol) of (R)-
(R)-3 and 0.48 mmol of TsOH (92 mg of monohydrate was
dehydrated) in 2 mL of benzene was heated at 70 °C, and the
composition of the reaction mixture was analyzed as above
(Table 2).
Hea tin g of 6 in Ben zen e in th e P r esen ce of TsOH. A
solution of 46 mg (0.1 mmol) of 6 and 0.12 mmol of TsOH in 1
mL of benzene was heated at 70 °C, and the reaction mixture
was analyzed after 1 and 2 h as in the preceding experiment.
Results are summarized in Table 3.
Useful NMR data for (R)(S)-4: 1H NMR (C6D6) δ 0.70 (d, 3H,
J ) 6.2 Hz), 3.532, 3.537 (s, 3H); 19F NMR (C6D6) δ 4.936.
Au t h en t ic Sa m p le of 2-[(R)-r-d iflu or ob or yloxy-r-(t r i-
flu or om eth yl)ben zyl]-(R)-6-m eth yl-5,6-d ih yd r o-4H-1,3-oxa -
zin e [(R)(R)-5a ]. To a solution of 60 mg (0.21 mmol) of (R)-
(R)-4 in 0.5 mL of benzene, was added a solution of BF3‚OEt2 in
benzene (1 mmol/1 mL), and the mixture was heated at 70 °C
for 14 h. After addition of benzene to the reaction mixture, the
solution was washed with 2 N NaOH and brine, dried (Na2SO4),
and concentrated. Column chromatography of the residue using
ethyl acetate and hexane (AcOEt 30-50%) gave a solid material,
which was recrystallized from benzene and hexane to provide
Heating of 0.1 mmol of 8 and 0.12 mmol of TsOH in benzene
at 70 °C for 1 h resulted in the conversion of 22% of 8 to (R)-
(S)-2.
1
12 mg (19%) of (R)(R)-5a : mp 133-135 °C; H NMR (CDCl3) δ
1.59 (d, 3H, J ) 6.4 Hz), ∼1.8 (dddd, 1H, J ) 15.0, 7.7, 9.5 Hz),
∼2.25 (ddt, 1H, J ) 14.7 Hz), 3.60 (q, 2H, J ) 9.7 Hz), 4.84 (ddq,
1H, J ) 2.9, 6.4 Hz), 7.43 (m, 3H), 7.86 (t, 2H); 19F NMR (C6D6)
δ -1.18 (CF3); 13C NMR (CDCl3) δ 19.90 (C-CH3), 25.90 (CH2),
37.24 (CH2), 79.09 (CH), 126.60, 126.63, 128.53, 129.89. Anal.
Calcd for C13H13NO2BF5: C, 48.63; H, 4.08; N, 4.36. Found: C,
48.84, 48.89; H, 4.04, 4.09; N, 4.23, 4.24.
Ch a n ges in th e 1H NMR Sp ectr a of 1-Acetyla zetid in e
(7) on Ad d ition of BF 3‚OEt2. Amide 7 was prepared from
acetyl chloride, azetidine, and Et3N: 1H NMR (CDCl3) δ 1.84
(s, 3H), 2.26 (q, 2H), 4.03 (t, 2H), 4.14 (t, 2H). On addition of 1.2
molar equiv of BF3‚OEt2, the following peaks were observed: δ
2.23 (s, 3H), 2.49 (q, 2H), 4.32 (t, 2H), 4.42 (t, 2H).
Useful NMR data for (R)(S)-5a : 1H NMR (CDCl3) δ 1.64 (d,
3H, J ) 6.4 Hz); 19F NMR (C6D6) δ -1.27 (CF3).
Ack n ow led gm en t. The authors owe thanks to the
Computer Center, Institute for Molecular Science at the
Okazaki Research Institute for the use of the NEC HSP
computer and the library program GAUSSIAN94. This
work is supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education of J apan.
To obtain more information about 5, 2-[(R)-R-difluoroboryloxy-
R-(trifluoromethyl)benzyl]-5,6-dihydro-4H-1,3-oxazine (5b) was
prepared: mp 140-141 °C; IR (KBr) 1690 cm-1. Anal. Calcd for
C
12H11NO2BF5: C, 46.95; H, 3.61; N, 4.56, F (of CF3 only), 19.05.
Found: C, 46.99; H, 3.57; N, 4.53; F, 18.92, 19.17. The 19F NMR
spectroscopy (-200 to +150 ppm) was performed by Shonan
Analyses Center Inc., using TFA as external standard: 19F NMR
(470.40 MHz, CDCl3) δ -1.32 (s, 3F), -71.76 (dd, 1F, J ) 75.2,
28 Hz), -73.89 (dd, 1F, J ) 75.2, 15 Hz).
Su p p or tin g In for m a tion Ava ila ble: Energies of all
structures. This material is available free of charge via the
Internet at http://pubs.acs.org.
Rea ction of (R)(R)-3 w ith TsOH. Into a solution of 0.24
mmol of TsOH (46 mg of TsOH‚H2O was dehydrated under
J O981901H