Synthesis of 2,2-disubstituted 2,5-dihydro-4-methyloxazoles

Article abstract of DOI:10.1016/0040-4039(93)88036-I

2,2-Disubstituted 2,5-dihydro-4-methyloxazoles (1) were synthesized from 2-aminopropanol in three steps. 3p-Oxazolines 1 can be converted into various α-sulfinyl ketimines such as (SS)-{[(4-methylphenyl)sulfinyl]methyl}-2,2-diethyl-2,5-dihydrooxazo le (5)

Full text of DOI:10.1016/0040-4039(93)88036-I

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Vol. 33. No. 50.
7751-7754.1992
in
Synthesis of
Duy H.
Noureddine
Fengqi
and Laurent
of Chemistry, Kansas State University, Manhattan, Kansas 66506, U. S. A.
de Quimica
y Farmaceutica, Universidad de Sevilla, 41012
Spain
Abstract:
three steps.
(1) were synthesizedfrom
in
I
be converted into various a-sulfinyl ketimines such as
which was stereoselectively reduced with Dibal-H to
give
7.
In our studies of the asymmetric total synthesis nojirimycin’ via
we have investigated the preparation of the required precursor,
Several methods have been reported for the synthesis of
ketimines (such as
(1) (or
(1)
condensation of a-hydroxy ketones with ammonia and aromatic
or
(2) thermal
Scheme
1
1)
0
3
OH
2
la-e
4b: R = = (CH,),
R =
=
=
R =
HO
R
Raney Ni
7751

7752
decomposition of
of
chlorides,’ and (5) condensation of a-halo aldehydes with ammonia and ketones.*
in the presence of
(4) coupling of axomethine ylides with a-chloroacyl
However, the
group and a general method for the preparation of
(such as 1) was not available.
(3) photocyclixation
with carbonyl
produced from these methods contained
(or
Herein, we report a synthesis of from the condensation
with ketones follow
Table 1. Reaction Conditions for the Condensation of
Various Ketones, and Yields of
4 and
1.
Ketone 3
Solvent
(temp., time)
4
1
(yield)’
(yield)’
61%
none
3h)
98%
83%
93%
Cyclohexanone
(1.05)
93%
4h)
Acetylcyclohexane
Acetophenone
benzene
4h)
benzene
(80°C. 48h)
p-Nitroacetophenonc
79%
a. Isolated
b. Determined by NMR
c. Determined by
NMR, from column chromatography only 30% of pure compound was isolated
Condensation of
with ketones 3 in refluxing benzene (axeotropic removal of
water) (with
no solvent,
3 h) gave excellent yields of the
4. Yields and
hypochlorite (1.2 equiv)
reaction conditions are summarized in Table 1. N-Chlorination of 4 with
and sodium bicarbonate (1.2 equiv) in ether at 0°C for 3 h immediately followed by 2.2 equiv of potassium
superoxide
and a catalytic amount of
in ether at 25°C gave
1 (Table 1).
1 can be converted into various
ketimines (such as 5) which can lead to the
preparation of
treatment of
alcohols, a-amino acids, piperidines, and
For instance,
mp
la with 2.2 equiv of LDA in THF at
followed by
(c 2.5,
(6) provided a 76% yield of
ketimine 5;
(Scheme 2). Interestingly, ketimine 5 can be stereoselectively reduced with Dibal-H in THF to give 65%

7753
yield (based on recovered starting ketimine 5) of
of the sulfide derivative of 5. The absolute configuration at C-2 of 7 was determined by converting it into
by with Raney nickel in under
7 and in a ratio of
along with small amount
atm. of hydrogen.
The following experimental procedure for the preparation of
is representative. 14
from amino alcohol 2
and
A solution of 2.4 g (0.032
heated at 50°C under argon for 3 h. Most of the excess
mm Hg bath temperature) and the remaining trace of the material was removed under reduced
(30 mm Hg) at bath to leave 4.47 g (98% yield) of oxaxolidine as an oil. This was used in
the next step without further purification. An analytical sample can be obtained by distillation, bp
3.95 7.4, 1 H, CHO), 1 H, CHN), 3.1
7.4 2 H, 6.3 Me), 0.93
NMR (CDCl,) 8 99.7 (s, CNO), 72.6 (t,
mixture of 17.9 g (0.125 mol) of
of
I-propanol(2) and g (0.128 mol) of
was removed by distillation at
1 H, CHO), 1.65
3 H, Me), 0.88
3 H, CH,, NH), 1.55
7.4 Hz, 3 H, Me);
1.2
(t,
53.3
302.
30
17.5
8.9
8.12 (q). To a cold
oxaxolidine and 12.4 g (0.148 mol) of
solution of 5.97 g (0.147 mol) of
in
of ether under argon, was added slowly a cold
of ether via catmula. The mixture was stirred at
in
0°C for 3 h, filtered through Celite, and the filtrate concentrated on a rotary evaporator. The NMR
spectrum of the oily product obtained indicated it was the desired oxaxolidine. This oil was
dissolved in 500 of ether under argon, and 19.12 g (0.269 mol) of 0.4 g mmol) of
were added.
distillation under normal
g (65% yield) bp
7.4 Hz, 6 H, 2 Me);
the mixture was stirred at 25°C for 12 h, the solvent (ether) was removed by
the product obtained by distillation under reduced pressure to give 11.5
mm Hg; NMR (CDCl,) 4.5 2 H,
2.0 (s, 3 H, Me), 1.6 (m, 4
H, 2
7.4
0.8
NMR (CDCl,) 8 167.6 (s), 77.5 CO), 31.6 2 C), 15.5
2
Acknowledgement. We gratefully acknowledge financial support from the National Cancer Institute (CA
5
and American Heart Association, Kansas Affiliate.
References and Notes
Fellow of the Alfred Sloan Foundation,
to.
1993; author to whom correspondence should be directed
N.; Kumagai,
T.; Tsuruoka, T.; Yumoto, H.
Ser. A
2. Hua, D. H.; Miao, S. W.; Bravo, A. A.; Takemoto, D. J.
1991, II, 970 and references cited
therein.
3. Gaines, J. R.; Hansen, G. R.
4.
1963. 96.
Pfoertner, K.
Montavon, F.; Bemauer, K. Helv.
5. Prasad, G.;
6. Pfoertner, K.
7. Rao, M. N.;
M.; Jakob, J.; Martens, J.
9. A similar scheme for the preparation of
K. N. J. Org.
K.;
A. G.; Ayyangar, N. R. Tetrahedron
Ann. Chem.
F.;
E. He/v. Chim.
8.
1.
from norephedrine and
different: Padwa, A.;
aqueous formaldehyde has been reported. Although reaction conditions
J. R.;
M.;
N. J.; Cha, Y.; Gould, I. R. Am. Chem.
10.
F. E., Jr. Org. Chem.
15
11. This work will be published in due course.
When 5 was reduced with 2
of
a I:
(12 h), a
of 7 and
ratio of 7 and 8
NMR (CDCI,) 7.52 = 8 2 H,
yield) were
formed; in contrary, with
obtained. Pure 7:
in THF at -78°C (40 h) and
141.6” (c 0.75.

7754
7.33 (d,
(m, H,
8 Hz, 2 H, Ar),
2.95
(dd,
Hz, H, CHS), 2.88
(broad s, 2 H, OH, NH),
Me); NMR 141.6
Hz, H, CHO), 3.59
CHO), 3.26
(s, 3 H,
1 H,
Hz,
H, CHS), 2.42
2.37
Me), 0.85
(m, 4 H, 2 CH,), 6.88
Ar), 140.3 (s, 130.0 (d.
52.9 (d, CN). 26.28 (t), 26.2 (t), 21.3 (q,
7
3
7
3
63.39 CO), 61.22 CS), 57.29 (d,
p-Me), 9.87
Pure 8:
8
Hz, 2
3.25
7.33 (d,
8 Hz, 2 H), 3.71 (dd,
Hz,
CHO), 3.46 (dd,
2.42 (s, 3 H,p-Me). 1.8 (br. s, 2 H, OH,
7 Hz, 3 H, Me), 0.9 (t, 7 Hz, 3 H, Me); NMR
51.97 (d,
Hz, 1 H, CHO),
2 H, CS), 2.47
0.91. (t,
1 H,
1.5 1.3
4 H,
141.6
2
2
2 C). 63.47 CO), 61.74 (t, CS), 57.3 (d,
9.93 (q), 9.9 (q).
(t.
26.16
21.37
Antipode
and
was unequivocally synthesized from
with
mesylate
Oxazolidines 4b
indicated in Table 1 and
removed by distillation
e
were by refluxing 2 and ketones 3b e in benzene for the periods of time
removing
the reactions were completed, benzene was
reduced pressure. 4b: bp
mm Hg; NMR
3.95 (dd,
7.6 Hz, 6.4 Hz, H, CHO), 3.48
1.22 (d, 7.2 Hz, 3 H,
25.3 (t), 23.9
NMR 4.48 (s, 2 H,
110.5 (s), 75 (t, CO), 36.3 (t. 2 C), 24.95 (t), 23.2 2 C), 15.8 (q).
(2 stereoisomers in a ratio of 3.94 (dd,
3.12 (dd,
11 H), 1.23
5.4 Hz, 3 H, Me, isomer);
CHN).
1
CHN), 3.14 (dd,
8.4 Hz, 7.6 Hz,
CHO), 1.64-1.53
NMR
96.3 (s), 71.6 CO), 52.8
mm Hg; IR (neat) 1664
(t), 35.8
23.5 (t), 17.8 (q). lb: bp
2.02 (s, H, Me),
(m, H);
NMR
166.8
mm Hg; NMR
bp
Hz, 1 H,
=
CHO, 2 isomers), 3.5 3.2
H,
=
Hz, 1 H, CHO, isomer), 2.99 (dd,
5.3 Hz, 3 H, Me, 1 isomer), 1.18 (s, 3
Hz, 1 H, CHO, 1 isomer), 1.9 1.0
H, Me, 2 isomers), 1.17
72.2, 72.03
NMR
(2 isomers) 99.3 (s),
(d), 28.6, 28.35 (t), 28.06, 27.84 (t), 26.48,
IR (neat) v 1674 (C=N) cm”; NMR (CDCI,) 4.51
26.38 (t). 22.87.22.12 (q), 17.87, 17.08 (q).
14 Hz, H, CHO), 4.41
3 H, Me), 1.2 1.0 (m, 5 H);
27.16 (t), 26.92 (t), 26.29
Hz, H, CHO). 2.03 (s, 3 H, Me), 1.76 1.6 (m, 6
(s, 113.84 (s), 77.0
NMR (CDCI,) (2 stereoisomers in a
1.32 (s,
47.31
NMR
CH,), 23.47 (q, Me). 4d:
3 H, Ph), 4.14 (dd, 7.5, 6.5 Hz, H, CHO,
7.1 Hz, 1 H, CHO, major isomer), 3.6 (m, 1 H, CHN, minor isomer), 3.29
ratio of
7.6 7.56 (m, 2 H, Ph), 7.5 7.24
minor isomer), 3.83
7.1 Hz, 1 H, CHO, major isomer), 3.14
CHO, minor isomer), 1.99 (broad s, 1 NH), 1.65 (s, 3 H, Me, major isomer),
isomer), 1.24 6.2 Hz, 3 H, Me, minor isomer), 1.15 (d,
H, CHN, major isomer), 3.19 (dd,
Hz, 1 H,
3 H, Me, minor
6.2 Hz, 3 H, Me, major isomer);
NMR (CDCI,) 132.5
128.2, 128.0 (d, Ph), 127.13 (d, Ph),
124.9
Ph), 97.74 CNO),
(t.
(d, CHN), 29.41.29.01 (q. Me), 17.98, 17.63
NMR (CDCI,) 7.57 7.52 (m, 2 H), 7.39 7.27 (m, 3 H), 4.70
14 Hz, 1 H, CHO), 2.07 H, (s, 3 H. Me); NMR
Me). Id: IR (neat)
1661
14 Hz,
H, CHO), 4.53 (d,
167.6 (s,
144.23 (s, Ph), 128.3 (d, Ph), 127.4 (d, Ph), 125.0 (d, Ph), 112 (s, CNO), 76.37
CO),
29.17 (q. Me), 15.89 (q, Me).
mp 48 49%; NMR
9 Hz, 2 H, Ar), 7.75 (d. 9 Hz, 2 H, Ar), 4.13
stereoisomers in a ration of 2: 1
Hz, 1 H, CHO,
8.15
3.82
trans), 3.17
Me, cis);
7 Hz, H, CHO, trans), 3.6 3.5 (m, 1 H, CHN), 3.29 (dd,
1 H, CHO,
=
Hz, 1 H, CHO, cis), 3.1 (broad s, 1 H, NH),
6.3 Hz, 3 H, Me, trans), 1.03 (d,
(s, cis), 126.9, 126.43 (d, Ar), 123.4,
(q, Me), 18.7, 17.6 Me).
(s, 3 H, Me, trans), 1.58 (s, 3 H,
(d,
6.5 ‘Hz, 3 H, Me, cis); NMR
152.7 (s, Ar,
Ar), 96.9 (s, CNO), 72.3 (t,
53.5 (d,
IR (neat) v 1664
cm”;
4.53 (d,
128
14 Hz, H, CHO), 2.09 (s, 3 H, Me), 1.71 (s, 3 H, Me);
126.9 (s, Ar), 126.1 (d, Ar), 123.4 Ar), 110.8 (s. CNO), 76.7
Me), 17.63 (q. Me).
NMR (CDCI,) 168.7 (s,
29.2 (q,
(Received in USA 12 August 1992; accepted 22 September 1992)