Unexpected retro-Michael reaction of (-)-(1′S,4aS,8aR)- and (+)-(1′S,4aR,8aS)-4a-ethyl-1-(1-phenylethyl)octahydroquinolin-7-ones

Article abstract of DOI:10.1016/S0957-4166(02)00003-4

An unexpected retro-Michael reaction of (-)-(1′S,4aS,8aR)-and (+)-(1′S,4aR,8aS)-4a-ethyl-1-(1′-phenylethyl)octahydroquinolin- 7-ones 1 and 2 is described. In addition, a diastereospecific intramolecular Michael reaction of 3·HCl and 4·HCl is reported.

Full text of DOI:10.1016/S0957-4166(02)00003-4

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 3209–3211
Unexpected retro-Michael reaction of (−)-(1%S,4aS,8aR)- and
(+)-(1%S,4aR,8aS)-4a-ethyl-1-(1-phenylethyl)octahydroquinolin-
7-ones
E. Va´zquez,a A. Galindo,a,* D. Gnecco,a,* S. Berne`s,a J. L. Tera´na and R. G. Enr´ıquezb
aCentro de Qu´ımica del Instituto de Ciencias, BUAP, 14 Sur 6303, C.P. 72570, Ciudad Universitaria Puebla, Pue, Mexico
bInstituto de Qu´ımica, UNAM, Ciudad Universitaria Me´xico, D.F., Mexico
Received 9 November 2001; accepted 10 December 2001
Abstract—An unexpected retro-Michael reaction of (−)-(1%S,4aS,8aR)-and (+)-(1%S,4aR,8aS)-4a-ethyl-1-(1%-phenylethyl)octahydro-
quinolin-7-ones 1 and 2 is described. In addition, a diastereospecific intramolecular Michael reaction of 3·HCl and 4·HCl is
reported. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
Herein, we report an unexpected retro-Michael reaction
of 1 and 2 in diethyl ether/hydrochloric acid.3 Under
these conditions, the compounds were transformed into
(−)-(4S,1%%S)- and (+)-(4R,1%%S)-4-ethyl-4-[3%-(1%%-phenyl-
ethylamine)-propyl]-2-cyclohexen-1-one hydrochlorides
3·HCl and 4·HCl, respectively (Scheme 2).
Meyers et al.1 have reported that when (4R)-4-ethyl-4-
(2-carbamoylethyl)-2-cyclohexen-1-one I is heated in
benzene containing a catalytic amount of p-toluenesul-
fonic acid (TsOH) II was produced as a 3:1 mixture of
cis–trans isomers. They subsequently found that adding
ethylene glycol to II and heating at reflux with the acid
catalyst converted the 3:1 mixture to the single diox-
olane III and proposed that such a conversion was
undoubtedly the result of acid-catalyzed equilibration
via a retro-Michael reaction. They also reported that
heating I in benzene/p-toluenesulfonic acid and adding
ethylene glycol after several hours gave the ketal lactam
III as a single isomer in good yield (Scheme 1).
2. Results and discussion
Ethereal4 solutions of 1 or 2 were saturated with
gaseous hydrochloric acid and stirred for 15 min at
room temperature to give the retro-Michael products
3·HCl and 4·HCl, respectively, in quantitative yield.
Assignments of the 1H NMR of 3·HCl5 and 4·HCl6
were confirmed via 13C–1H NMR correlation
techniques.
In a previous publication2 we described the synthesis of
1 and 2 and additionally the preparation of (+)-
(4aS,8aR)-4a-ethyl-octahydroquinolin-7-one by cata-
lytic hydrogenation of 1 in MeOH, HCl, Pd/C at pH
ca. 5–6.
Thereafter, these compounds were crystallized and ana-
lyzed by X-ray diffraction. The absolute configuration
for C(4) of 3·HCl7 and 4·HCl8 was assigned as 4S and
Scheme 1.
* Corresponding authors. E-mail: gnecco@siu.cen.buap.mx
0957-4166/01/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00003-4

3210
E. Va´zquez et al. / Tetrahedron: Asymmetry 12 (2001) 3209–3211
Scheme 2.
4R, respectively, on the basis of the configuration at the
auxiliary center (1%%S) and was confirmed by the refine-
ment of a Flack parameter.7,8 Source of chirality: (−)-
(S)-1-phenylethylamine (Fig. 1).
ence of a rigid transition state, where the amino group
in each case is located exclusively over the favorable
diastereotopic face of the a,b-unsaturated cyclohexen-2-
one system with maximum orbital overlap to give the
enantiopure compounds 1 and 21,9 (Scheme 3).
In order to investigate the diastereoselectivity of the
intramolecular Michael reaction of 3·HCl and 4·HCl,
these compounds were treated with a sodium bicarbon-
ate aqueous solution (pH ca. 8) for 30 min at room
temperature and the reaction mixture extracted with
dichloromethane (4×20 mL) dried over Na2SO4 and the
solvent removed in vacuo to give 1 and 2 in quantita-
tive yield, respectively. All spectral properties of these
compounds were in complete agreement with those
reported in our previous paper.2
3. Conclusion
To our knowledge, this is the first report that describes
the conditions to transform 1 and 2 into 3·HCl and
4·HCl, respectively, via a retro-Michael reaction and a
diastereospecific intramolecular Michael-reaction of
3·HCl and 4·HCl, which led to the corresponding enan-
tiopure compounds 1 and 2, respectively, under mild
basic conditions, via a rigid transition state.
The diastereospecific intramolecular Michael reaction
observed in this process can be explained by the pres-
Figure 1. ORTEP view of the crystal structure of compounds 3·HCl and 4·HCl. For 3·HCl, disordered toluene molecule is omitted
for clarity and only one of the two molecules of the asymmetric unit is shown.

E. Va´zquez et al. / Tetrahedron: Asymmetry 12 (2001) 3209–3211
3211
Scheme 3.
Acknowledgements
2.30–2.45 (m, 2H-6); 2.60–2.80 (broad signal, 2H-3%);
4.10–4.30 (broad signal, 1H-1%%); 5.86 (d, H-2, 10.26); 6.64
(d, H-3, 10.26); 7.20–7.80 (m, 5H, f-H); 9.95–10.20 (two
broad signals, NH). 13C NMR: l (ppm, CDCl3): 8.47 (C-8);
20.75 (C-7); 20.83 (C-2%%); 30.20 (C-1%); 30.30 (C-5); 33.85
(C-6); 34.60 (C-2%); 38.16 (C-4); 46.24 (C-3%); 59.15 (C-1%%);
127.90 (2C-10); 128.60 (C-2); 129.45 (2C-11); 129.55 (C-
12); 135.92 (C-9); 157.68 (C-3); 199.35 (C-1).
D.G. and A.G. are grateful for financial support from
CONACyT-Me´xico (Project 28906N). E.V. thanks
CONACyT for a doctoral scholarship c121966. S.B
thanks CONACyT for financial support (retention
000027).
7. X-Ray analysis for 3·HCl10 (crystallized from toluene/ace-
tonitrile). Empirical formula: C19H28ClNO (C6H5CH3)0.5
pale yellow, irregular, crystal size: 0.28×0.18×0.06 mm3,
crystal system: triclinic, space group: P1, unit cell dimen-
References
1. Meyers, A. I.; Berney, D. J. Org. Chem. 1989, 54, 4673–
4676 and references cited therein.
2. Va´zquez, E.; Galindo, A.; Gnecco, D.; Berne`s, S. Tetra-
hedron: Asymmetry 2001, 12, 2099–2102 and references
cited therein.
3. Compounds 1 and 2 were converted to the corresponding
hydrochlorides at pH ca. 5–6.
4. The same behavior in methanolic and ethanolic solutions
of 1 or 2 saturated with gaseous hydrochloric acid was
observed.
,
sions: a=7.280(2), b=11.9321(14), c=13.2735(15) A, h=
77.780(6), i=88.113(15), k=88.525(12)°, volume 1126.1(4)
3
A , Z=2, density (calcd)=1.085 g cm−3, absorption coeffi-
,
cient=0.179 mm−1, F(000): 398; diffractometer used
,
Bruker P4, radiation: Mo-Ka (u=0.71073 A), 2q range:
3.14–50.00°, scan speed, 3.50–45° mn−1 in v, independent
reflections: 4491, R1 [2893 I>2|(I)]=6.82%, wR2=19.75%
for all data. Flack parameter=−0.03 (12). The crystallo-
graphic data have been deposited in CDCC, UK (No.
175496).
5. Compound 3·HCl. Rf=0.45 (SiO2/CH2Cl2:MeOH=
90:10); [h]D−50.5 (c 1.0, CH2Cl2). Mp 174–175°C; IR
8. X-Ray analysis for 4·HCl.10 (Crystallized from
dichloromethane/diethyl ether). Empirical formula:
C19H28ClNO, colorless needles, crystal size: 0.70×0.20×
0.14 mm3, crystal system: monoclinic, space group: P21,
(film): 3434, 2942, 2752, 1678, 1460, 703 cm−1. H NMR
1
(CDCl3, l ppm, J Hz): 0.84 (t, 3H-8, 7.33); 1.20–1.60 (m,
2H-1%, 2H-2%); 1.70–1.85 (m, 2H-5, 2H-7); 1.89 (d, 3H-2%%,
5.83); 2.25–2.50 (m, 2H-6); 2.55–2.75 (broad signal, 2H-3%);
4.10–4.30 (broad signal, 1H-1%%); 5.86 (d, 1H-2, 10.26); 6.63
(d, 1H-3, 10.26); 7.30–7.70 (m, 5H, f-H); 9.95–10.20 (two
broad signals, NH). 13C NMR: l (ppm, CDCl3): 8.47 (C-8);
20.73 (C-7); 20.80 (C-2%%); 30.22 (C-1%); 30.31 (C-5); 33.83
(C-6); 34.69 (C-2%); 38.20 (C-4); 46.10 (C-3%); 59.00 (C-1%%);
127.83 (2C-10); 128.70 (C-2); 129.52 (2C-11); 129.60 (C-
12); 135.85 (C-9); 157.50(C-3); 199.20 (C-1).
unit cell dimensions: a=11.3016(12), b=7.4150(8), c=
3
,
,
11.5933(11) A, i=99.948(4), volume 956.82(17) A , Z=2,
density (calcd)=1.117 g cm−3, absorption coefficient=
0.202 mm−1, F(000): 348; diffractometer used Bruker P4,
,
radiation: Mo-Ka (u=0.71073 A), 2q range: 3.66–54.98°,
scan speed, 2.50–25° mn−1 in v, independent reflections:
2703, R1 [1960 I>2|(I)]=4.52%, wR2=14.12% for all data.
Flack parameter=+0.02 (10). The crystallographic data
have been deposited in CDCC, UK (No. 175497).
9. Pearson, A. J.; Rees, D. C. J. Chem. Soc., Perkin Trans.
1 1982, 2467–2476 and references cited therein.
6. Compound 4·HCl. Rf=0.45 (SiO2/CH2Cl2:MeOH=
90:10); [h]D+16.0 (c 1.0, CH2Cl2). Mp 166–168°C. IR (film)
3427, 2965, 2753, 1681, 1460, 703 cm−1. 1H NMR (CDCl3,
l ppm, J Hz): 0.85 (t, 3H-8, 7.33); 1.20–1.60 (m, 2H-1%,
2H-2%); 1.70–1.80 (m, 2H-5, 2H-7); 1.88 (d, 3H-2%%, 6.23);
10. Sheldrick, G. M. SHELX-97 Users Manual; University of
Go¨ttingen: Germany, 1997.