Tautomerism of α,β-Ethylenic Imines and Their Reactivity Toward Electrophilic Olefins

Article abstract of DOI:10.1021/ol991048o

(Matrix Presented) The equilibrium between α,β-ethylenic imines and their secondary enamine tautomer form has been demonstrated for the first time. These imines react with electrophilic olefins to give Michael adducts at either the α or the α′ position of the imine function.

Full text of DOI:10.1021/ol991048o

ORGANIC
LETTERS
1999
Vol. 1, No. 12
1901-1904
Tautomerism of r,â-Ethylenic Imines
and Their Reactivity toward Electrophilic
Olefins
,†
Ivan Jabin,* Gilbert Revial,‡ Michel Pfau,‡ Bernard Decroix,† and
Pierre Netchita1ılo†
URCOM, UniVersite´ du HaVre, Faculte´ des Sciences et Techniques,
25 rue Philippe Lebon, BP 540, 76058 Le HaVre Ce´dex, France, and ESPCI,
Laboratoire de Chimie Organique associe´ au CNRS (ESA 7084), 10 rue Vauquelin,
75231 Paris Ce´dex 05, France
Received September 15, 1999
ABSTRACT
The equilibrium between r,â-ethylenic imines and their secondary enamine tautomer form has been demonstrated for the first time. These
imines react with electrophilic olefins to give Michael adducts at either the r or the r′ position of the imine function.
It has been well known since the 1970s that the reaction of
imines with electrophilic olefins can lead to Michael adducts.1
However, the reactivity of their R,â-ethylenic counterparts
toward Michael acceptors has not yet been studied. Only
the Michael type reaction of imines conjugated with an
aromatic system (i.e., dihydroisoquinoline2 or substituted
acetophenone imines3) has been reported.
can possess two different enamine tautomeric forms and
therefore can give either Michael adducts at the R, R′, and
γ position or Diels-Alder adducts.
Imines are known to react through their secondary enamine
form (present in undetectable concentration at equilibrium)
with electrophilic olefins.4 In the interesting case of R,â-
ethylenic imines, one can anticipate that appropriate imines
† Universite´ du Havre.
‡ Laboratoire de Chimie Organique associe´ au CNRS (ESA 7084).
(1) Pfau, M.; Ribie`re, C. J. Chem. Soc., Chem. Commun. 1970, 66-67.
(2) Kametani, T.; Surgenor, S. A.; Fukumoto, K. Heterocycles 1980, 14,
303-310. Kametani, T.; Surgenor, S. A.; Fukumoto, K. J. Chem. Soc.,
Perkin Trans. 1 1981, 920-925. Kessar, S. V.; Singh, P.; Sharma, S. K.
Tetrahedron Lett. 1982, 23, 4179-4180. Bhattacharjya, A.; Bhattacharya,
P. K.; Pakrashi, S. C. Heterocycles 1983, 20, 2397-2400. Kobor, J.; Lazar,
J.; Fulop, F.; Bernath, G. J. Heterocycl. Chem. 1994, 31, 825-828. Kobor,
J.; Sohar, P.; Fulop, F. Tetrahedron 1994, 50, 4873-4886.
(3) Hoberg, H.; Kieffer, R. Justus Liebigs Ann. Chem. 1972, 760, 141-
150. Pfau, M.; Ughetto-Monfrin, J.; Joulain, D. Bull. Soc. Chim. Fr. 1979,
627-632. Tsuge, O.; Hatta, T.; Kuwata, M.; Yamashita, T.; Kakehi, A.
Heterocycles 1996, 43, 2083-2090.
Since our previous work dealt essentially with a general
method of “deracemizing alkylation” involving enantiose-
lective Michael addition of chiral cyclohexanone imines,5
the present study was undertaken to see if our method can
be extended to chiral cyclohexen-2-one imines. Consequently
it seemed necessary to us to show evidence of the tautom-
erism of R,â-ethylenic imines and to investigate their
reactivity toward electrophilic olefins.
(4) See ref 1. For a general reference on the chemistry of enamines, see:
Rappoport, Z. The Chemistry of Enamines (The Chemistry of Functional
Groups); John Wiley and son: New York, 1994.
(5) Pfau, M.; Revial, G.; Guingant, A.; d'Angelo, J. J. Am. Chem. Soc.
1985, 107, 273-274. Jabin, I.; Revial, G.; Melloul, K.; Pfau, M.
Tetrahedron: Asymmetry 1997, 8, 1101-1109 and references therein.
10.1021/ol991048o CCC: $18.00 © 1999 American Chemical Society
Published on Web 11/09/1999

1
Thus, we prepared the imines 2a-c and 4 from the
corresponding enones6 1a-c and 3 using the smooth TiCl4
activation method7 (Scheme 1).
An H NMR study in CD3OD of the imines 2a-c and 4
was then undertaken to confirm that an imine-enamine
tautomerism does occur and to see which enamine forms
are involved in this equilibrium. Scheme 2 shows the
Scheme 1
Scheme 2
deuterated compounds obtained after the times indicated to
reach a total exchange.
This NMR study has clearly confirmed for the first time
the tautomeric equilibrium between R,â-ethylenic imines and
their secondary enamine forms. In all cases the R′ position
relative to the imine group was deuterated in ca. 2 h.
Deuteration at other positions was observed only in the case
of imine 2b and in a much longer time (ca. 6 days).9 These
results strongly suggest that electrophilic olefins should be
reactive toward R,â-ethylenic imines. Moreover, in the case
of a Michael type reaction, it should occur preferably at the
R′ position.
In a first set of experiments, imines 2a-c and 4 were
reacted without solvent with phenyl acrylate10 (1.0-1.3
equiv) and the reaction products were analyzed by GC-MS.11
In all experiments, the structure of the major adducts (i.e.,
compounds 5-9 isolated by flash chromatography) results
from a Michael alkylation of the starting imines. Indeed,
under the reaction conditions, cyclization of the intermediate
Michael adducts occurred spontaneously leading to lactams
5-9.12 No adducts resulting from a Diels-Alder reaction
have been observed (Scheme 3).
The unsaturated imines 2a-c and 4 show a low reactivity
toward a very reactive Michael acceptor in comparison to
the simple imines.13 Indeed, we had to heat (55-70 °C) the
reaction mixture for 16-24 h in order to obtain a total
conversion of the imine. Even under these conditions (i.e.,
70 °C, 24 h, 1.3 equiv of phenyl acrylate, neat), imine 2b
which bears a bulky gem-dimethyl group was not reactive
enough toward phenyl acrylate, and isophorone 1b (resulting
from hydrolysis of imine 2b during workup) was the major
compound isolated after flash chromatography. Raising the
temperature of the reactions resulted in degradation of the
sensitive imines 2a-c and 4.
The imines 2a-c and 4 are temperature and light sensitive,
and consequently attempts to purify them by distillation
resulted in very low yields. However, 1H and 13C NMR and
GC-MS data for the crude imines 2a-c and 4 revealed in
all cases the presence of a single compound8 in accordance
with the structure displayed. Therefore, they were used
without further purification for the remaining part of this
work.
(6) Enones 1b,c and 3 are commercially available while enone 1a was
prepared according to the literature: Warnhoff, E. W.; Martin, D. G.;
Johnson, W. S. Org. Synth. Collect. Vol. IV 1967, 162-165.
(7) White, W. A.; Weingarten, H. J. Org. Chem. 1967, 32, 213-214.
(8) 1H and 13C NMR spectra of compounds 2a-c and 4 have shown
that imines 2b and 2c consist of a mixture of Z:E isomers and that imines
2a and 4 are single E isomers. The A1,3 strain in imine 2a prevents the
formation of the Z isomer. 2a: oil; EIMS m/z (rel int) 199 (M+, 28), 91
(base), 65 (19) 51 (18); IR (CHCl3) 1643, 1607, 1496, 1454 cm-1; 1H NMR
(200 MHz, CD3OD) δ 1.79 (tt, J1 ) 6.2 Hz, J2 ) 6.2 Hz, 2H), 1.87 (ddd,
J1 ≈ 1.5 Hz, J2 ≈ 1.5 Hz, J3 ≈ 1.5 Hz, 3H), 2.16 to 2.25 (m, 2H), 2.48 (t,
J ) 6.2 Hz, 2H), 4.65 (s, 2H), 6.33 to 6.36 (m, 1H), 7.15 to 7.33 (m, 5H);
13C NMR (50 MHz, CDCl3) δ 18.66, 22.61, 25.32, 27.07, 53.87, 126.3,
127.4 (2C), 128.2 (2C), 134.8, 135.9, 140.9, 167.5. 2b (mixture of Z:E
isomers): oil; EIMS m/z (rel int) 227 (M+, 17), 212 (45), 107 (10), 91
(base), 65 (15); IR (neat) 1636, 1607, 1495, 1453 cm-1 1H NMR (200
;
MHz, CD3OD) δ 0.99 (s, 6H), 1.87 and 1.91 (2s, 3H), 2.10 (d, J ) 11.1
Hz, 2H), 2.27 (d, J ) 10.3 Hz, 2H), 4.59 and 4.63 (2s, 2H), 6.02 and 6.44
(2q, J ) 1.5 Hz, 1H), 7.10-7.35 (m, 5H); 13C NMR (50 MHz, CDCl3) δ
24.04 and 24.61 (1C), 28.13, 28.62, 31.77, and 32.17 (1C), 39.54 and 44.73
(1C), 45.90 and 48.63 (1C), 53.81 and 54.56 (1C), 115.1, 126.4, 127.8 (2C),
128.3 (2C), 140.7 and 140.8 (1C), 146.3 and 150.3 (1C), 166.0 and 167.9
(1C). 2c (mixture of Z:E isomers): oil; EIMS m/z (rel int) 213 (M+, 19),
1
198 (11), 91 (base), 65 (17); IR (neat) 1632, 1607, 1495, 1454 cm-1; H
NMR (200 MHz, CD3OD) δ 1.10 and 1.12 (2s, 6H), 1.72 (t, J ) 6.7 Hz,
2H), 2.59 (t, J ) 6.7 Hz, 2H), 4.57 and 4.62 (2s, 2H), 6.03 and 6.31 (2d,
J ) 10.3 Hz, 1H), 6.24 and 6.47 (2d, J ) 10.3 Hz, 1H), 7.10-7.38 (m,
5H); 13C NMR (50 MHz, CDCl3) δ (major isomer) 23.51, 28.10 (2C), 32.11,
35.73, 54.70, 125.2, 126.9 (2C), 128.1 (2C), 128.8, 140.3, 148.4, 166.8. 4:
oil; EIMS m/z (rel int) 213 (M+, 43), 170 (38), 91 (base), 65 (19); IR
(9) In the case of imine 2c, only deuteration at the R′ position is possible.
(10) Reaction between methyl acrylate or methyl vinyl ketone and imines
2a-c and 4 were also attempted but resulted in the degradation of the
starting material. Consequently, much more reactive electrophilic olefins
(i.e., phenyl acrylate and maleic anhydride) were tested. Phenyl acrylate
was prepared according to the literature: Ahlbretch, A. H.; Codding, D.
W. J. Am. Chem. Soc. 1953, 75, 984.
(CHCl3) 1655, 1614, 1495, 1451 cm-1 1H NMR (200 MHz, CD3OD) δ
;
1.51-1.78 (m, 4H), 2.04 (s, 3H), 2.14-2.40 (m, 4H), 4.62 (s, 2H), 6.42
(tt, J1 ) 1.5 Hz, J2 ) 4.1 Hz, 1H), 7.05-7.30 (m, 5H); 13C NMR (50
MHz, CDCl3) δ 13.40, 21.93, 22.42, 24.66, 25.76, 54.67, 125.9, 127.1 (2C),
127.8 (2C), 130.2, 139.9, 140.8, 166.6.
(11) This technique permits the separation of the regioisomers and the
determination of their ratio. For further details, see the following refer-
ence: Jabin, I.; Revial, G.; Tomas, A.; Lemoine, P.; Pfau, M. Tetrahe-
dron: Asymmetry 1995, 6, 1795-1812.
1902
Org. Lett., Vol. 1, No. 12, 1999

was detected when the NMR study in CD3OD was done.14
This unexpected result indicates that tautomeric enamines
10 and 11 are present in the equilibrium even if deuteration
at the γ position is too slow to be observed.
Scheme 3
To confirm this result, another electrophilic olefin was
tested with imine 4. Thus, this latter was reacted with maleic
anhydride and the resulting crude carboxylic acid 12 was
directly esterified yielding after flash chromatography the
spirolactam 1315 in 32% overall yield from enone 3 (Scheme
4).
The Michael alkylation took place either at the R′ position
relative to the imine group (in the case of compounds 5, 7,
and 8) or at the R position (in the case of compounds 6 and
9), but no alkylation at the γ position was observed.
Formation of lactam 6 and spirolactam 9 is quite surprising
since no deuteration at the γ position of imines 2a and 4
Scheme 4
(12) For further details on the mechanism, see the following references:
Paulvannan, K.; Stille, J. R. J. Org. Chem. 1992, 57, 5319-5328. See also
ref 5 and Pfau, M.; Jabin, I.; Revial, G. J. Chem. Soc., Perkin Trans. 1
1993, 1935-1936. Jabin, I.; Revial, G.; Tomas, A.; Lemoine, P.; Pfau, M.
Tetrahedron: Asymmetry 1995, 6, 1795-1812. 5: oil; EIMS m/z (rel int)
253 (M+, 56), 162 (11), 91 (base), 65 (12); IR (neat) 1668, 1393 cm-1; 1H
NMR (200 MHz, CDCl3) δ 1.75-2.09 (m, 4H), 1.84 (s, 3H), 2.12-2.19
(m, 2H), 2.40-2.47 (m, 2H), 4.73 (s, 2H), 5.59-5.70 (m, 1H), 7.05-7.35
(m, 5H); 13C NMR (50 MHz, CDCl3) δ 18.98, 22.26, 24.71, 27.58, 32.61,
48.10, 123.2, 124.2, 126.8, 127.5 (2C), 128.0 (2C), 128.9, 136.0, 137.8,
172.5. 6: oil; EIMS m/z (rel int) 253 (M+, 24), 238 (21), 160 (11), 91
GC-MS analysis of the crude spirolactam 13 revealed that
it was the unique reaction product. In this case, Michael
alkylation took place regioselectively at the R position,
involving again addition of the secondary enamine 11 to the
electrophilic olefin. Moreover, the reaction proceeds dias-
tereoselectively since only one isomer was detected by GC-
MS and NMR analyses.
In conclusion, we have shown that R,â-ethylenic imines
are in equilibrium with their tautomeric secondary enamine
forms. Under our reaction conditions, they react with
electrophilic olefins, giving exclusively Michael adducts. The
Michael addition occurs either at the R or R′ position relative
to the imine group, and the regioselectivity at the R position
was predicted by tautomeric deuteration.
(base), 65 (12); IR (neat) 1652, 1455, 1386 cm-1 1H NMR (200 MHz,
;
CDCl3) δ 1.13 (s, 3H), 1.64 (ddd, J1 ) 3.2 Hz, J2 ) 5.9 Hz, J3 ) 13.4 Hz,
1H), 1.79-1.95 (m, 1H), 2.59-2.75 (m, 4H), 4.79 (d, J ) 16.0 Hz, 1H),
5.01-5.08 (m, 1H), 5.09 (d, J ) 16.0 Hz, 1H), 5.47 (ddd, J1 ≈ 2 Hz, J2 ≈
2 Hz, J3 ≈ 10 Hz, 1H), 5.54-5.70 (m, 1H), 7.08-7.37 (m, 5H); 13C NMR
(50 MHz, CDCl3) δ 24.27, 26.28, 29.07, 32.33, 33.46, 46.91, 103.3, 121.8,
126.4 (2C), 126.6, 128.3 (2C), 133.7, 137.4, 140.5, 168.6. 7: oil; EIMS
m/z (rel int) 267 (M+, 92), 252 (62), 224 (21), 91 (base); IR (neat) 1755,
1731, 1666, 1594 cm-1; 1H NMR (200 MHz, CDCl3) δ 0.97 (s, 6H), 2.16
(s, 2H), 2.32 (t, J ) 7.5 Hz, 2H), 2.66 (t, J ) 7.5 Hz, 2H), 4.94 (s, 2H),
5.50 (d, J ) 10.2 Hz, 1H), 5.82 (d, J ) 9.7 Hz, 1H), 7.13 to 7.44 (m, 5H);
13C NMR (50 MHz, CDCl3) δ 25.18, 27.32, 30.86, 31.54, 41.78, 45.02,
113.2, 117.6, 126.4 (2C), 126.7, 128.3 (2C), 130.3, 137.9, 138.2, 170.0. 8:
oil; EIMS m/z (rel int) 268 (22), 267 (M+, base), 266 (31), 224 (15), 189
(17), 91 (67); IR (neat) 1755, 1713, 1660 cm-1; 1H NMR (200 MHz, CDCl3)
δ 1.54-1.59 (m, 4H), 1.79-2.09 (m, 4H), 2.20 (ddd, J1 ≈ 6 Hz, J2 ≈ 6
Hz, J3 ≈ 9 Hz, 2H), 2.49 (dd, J1 ) 7.0 Hz, J2 ) 9.1 Hz, 2H), 4.77 (s, 2H),
5.16 (t, J ) 5.4 Hz, 1H), 5.58 (tt, J1 ≈ 2 Hz, J2 ≈ 2 Hz, 1H), 6.97-7.41
(m, 5H); 13C NMR (50 MHz, CDCl3) δ 19.21, 21.80, 22.34, 24.99, 28.20,
32.09, 45.93, 107.2, 126.7, 127.1 (2C), 128.1 (2C), 129.3, 133.5, 138.7,
144.9, 171.7. 9: oil; EIMS m/z (rel int) 268 (16), 267 (M+, 92), 252 (21),
239 (50), 238 (24), 91 (base); IR (neat) 1660, 1614, 1454 cm-1; 1H NMR
(200 MHz, CDCl3) δ 1.29 to 2.05 (m, 8H), 2.61 to 2.75 (m, 2H), 4.28 (d,
J ) 1.6 Hz, 1H), 4.43 (d, J ) 1.1 Hz, 1H), 4.95 (s, 1H), 4.97 (s, 1H),
5.30-5.40 (m, 1H), 5.80 (dt, J1 ) 3.8 Hz, J2 ) 10.2 Hz, 1H), 7.05-7.35
(m, 5H); 13C NMR (50 MHz, CDCl3) δ 17.88, 25.18, 28.49, 31.49, 32.46,
38.77, 47.08, 96.60, 126.5 (2C), 126.7, 128.3 (2C), 128.5, 132.5, 137.3,
149.2, 169.1.
(14) No clear deuteration at the γ position occurred even after 12 days
in CD3OD.
(15) 13: oil; EIMS m/z (rel int) 326 (22), 325 (M+, base), 265 (24), 252
1
(22), 91 (88); IR (neat) 1732, 1644 cm-1; H NMR (200 MHz, CDCl3) δ
1.10 to 2.10 (m, 6H), 2.41 (dd, J1 ) 7.5 Hz, J2 ) 15.6 Hz, 1H), 2.79 (dd,
J1 ) 7.5 Hz, J2 ) 16.1 Hz, 1H), 3.15 (t, J ) 7.5 Hz, 1H), 3.67 (s, 3H),
4.14 (d, J ) 1.6 Hz, 1H), 4.31 (d, J ) 2.1 Hz, 1H), 4.54 (d, J ) 15.6 Hz,
1H), 4.71 (d, J ) 15.6 Hz, 1H), 5.40 (dd, J1 ) 1.6 Hz, J2 ) 10.2 Hz, 1H),
5.92 (dt, J1 ) 3.8 Hz, J2 ) 9.7 Hz, 1H), 7.10 to 7.30 (m, 5H); 13C NMR
(50 MHz, CDCl3) δ 18.06, 24.30, 28.50, 29.82, 43.92, 45.93, 49.10, 51.73,
88.91, 127.2 (2C), 128.5 (2C), 129.4, 131.3, 136.0, 151.7, 172.3, 174.2.
(13) See ref 5.
Org. Lett., Vol. 1, No. 12, 1999
1903

Future efforts will be directed at the extension of this work
to chiral imines of cyclohexen-2-ones.
free of charge via the Internet at http://pubs.acs.org. This
material is also available from the author.
Supporting Information Available: Detailed descrip-
tions of experimental procedures. This material is available
OL991048O
1904
Org. Lett., Vol. 1, No. 12, 1999