Generation of quaternary stereocenters by asymmetric Michael reactions: Enamine regiochemistry as configuration switch

Article abstract of DOI:10.1002/chem.200401223

Regioselective enamine formation from cyclic β-diketones 1 is obtained by the appropriate choice of activating agent: Bronsted acid catalyzed condensation gives endocyclic enamines 3 as the thermodynamically favored products. Activation with Lewis acid BF

Full text of DOI:10.1002/chem.200401223

Generation of Quaternary Stereocenters by Asymmetric Michael Reactions:
Enamine Regiochemistry as Configuration Switch
Burkard Kreidler, Angelika Baro, Wolfgang Frey, and Jens Christoffers*[a]
Abstract: Regioselective enamine for-
mation from cyclic b-diketones 1 is ob-
tained by the appropriate choice of ac-
tivating agent: Brønsted acid catalyzed
condensation gives endocyclic enam-
ines 3 as the thermodynamically fa-
vored products. Activation with Lewis
acid BF3·OEt2 affords betaines 8 as in-
termediate products, which can be re-
acted with l-valine diethylamide (2) to
preferentially furnish exocyclic enam-
ines 4 as kinetic products. Derivatives
with quaternary stereocenters were ac-
cessible from both isomeric enamines
by using asymmetric, copper(ii)-cata-
lyzed Michael reactions at ambient
temperature. Both regioisomers afford
the triketones 7 with the same constitu-
tion but bearing the opposite absolute
configuration at the quaternary stereo-
center. Thus, both enantiomers of the
product are prepared by using the
same chiral auxiliary derived from l-
valine.
Keywords: boron · chiral auxilia-
ries · enamines · Michael addition ·
regioselectivity
Introduction
The stereoselective generation of quaternary stereocenters
is still one of the most challenging tasks in organic synthesis
ꢀ
and the definitive landmark for any asymmetric C C bond-
forming reaction.[1] Conjugate additions or 1,4-additions of
enolates or other carbon nucleophiles to acceptor-substitut-
ed olefins (Michael reaction) belong to the most important
and versatile group of reactions for the synthesis of quater-
nary as well as tertiary stereocenters.[2,3] Enantioselective
Michael reactions applying chiral Brønsted base catalysts[4]
or using metal catalysts together with chiral ligands[5] have
been established. In some cases, the application of chiral
auxiliaries, however, turned out to be more promising.[6]
Thus, the copper(ii)-catalyzed Michael reaction with l-valine
diethylamide as the chiral auxiliary is an established method
for the highly enantioselective construction of quaternary
stereocenters at ambient temperature.[7] The auxiliary initial-
ly reacts with the substrate, typically b-oxo esters and b-di-
ketones, to form chiral enamines. As shown in Scheme 1,
the reaction of b-diketones 1 might result in mixtures of iso-
meric enamines 3 and 4.[8] This fact may be used synthetical-
ly in the subsequent Michael reaction if both enamines 3
[a] B. Kreidler, A. Baro, W. Frey, Prof. J. Christoffers
Institut fꢀr Organische Chemie der Universitꢁt Stuttgart
Pfaffenwaldring 55, 70569 Stuttgart (Germany)
Fax : (+49)711-685-4269
Scheme 1. Regioisomeric enamines 3 and 4, derived from 1,3-diketones 1
and the chiral auxiliary l-valine diethylamide (2), gave Michael addition
products 7 with the opposite configuration.
E-mail: jchr@oc.uni-stuttgart.de
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ꢂ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/chem.200401223
Chem. Eur. J. 2005, 11, 2660 – 2667

FULL PAPER
and 4 are obtained regioselectively. According to the pro-
posed mechanism, the CuII-catalyzed addition reaction[9]
proceeds via a six-membered copper azadiketonato complex
6. Depending on the starting enamine, the acceptor methyl
vinyl ketone (5) either coordinates to the Cu center and at-
tacks from the back face (complex 6a) or through acceptor
coordination and attack occurs from the front face (complex
6b). Reaction intermediates 6a and b in the catalytic cycle
are constitutional isomers, yielding, after aqueous, acidic
workup, optically active triketones 7 and ent-7 with opposite
absolute configuration by use of the (S)-isomer of the valine
derivative (Scheme 1). However, in the case of cyclic 1,3-di-
ketone 1d (R, R’=-(CH2)4-) with an acetyl moiety (R’’=
Me), instead of an open-chain product, subsequent spirocyc-
lization of the exocyclic enamine (like 4) has been ob-
served.[10] The question arises as to whether the methyl
group (R’’=Me) is responsible for this spirocyclization and
it will be addressed in this work.
In the present paper we wish to report on the regioselec-
tive generation of enamines from cyclic b-diketones 1 and l-
valine diethylamide 2 by means of either Lewis or Brønsted
acid activation. The resulting regioisomers are then used in
asymmetric Michael reactions. Furthermore, we have pre-
pared homologous cyclic b-alkanoyl ketones in order to in-
vestigate whether the alkyl substituent influences the course
of the Michael reaction to give spirocyclic or open-chain ad-
dition products.
Scheme 2. Preparation of endo- and exocyclic enamines 3 and 4 and their
use as a configuration switch in asymmetric copper(ii)-catalyzed Michael
reactions.
Results and Discussion
Regioselective formation of endo- and exocyclic enamines
from b-diketones 1: Our synthetic strategy for selectively
preparing endo- and exocyclic enamines 3 and 4 is depicted
in Scheme 2.
In order to prepare exocyclic enamines 4a–f, which can
be considered as the kinetically favored regioisomers, b-di-
ketones 1a–f and the effective Lewis acid activating agent
[11]
BF3·OEt2 were first reacted in CH2Cl2 at ambient temper-
ature to give oxonia–boranuida betaines 8a–f in good yields
(Table 1). Betaines 8 are oils or crystalline solids stable to-
wards air and moisture.
Table 1. Prepared oxonia–boranuida compounds 8.
Betaine
n
R
Yield [%]
8a
8b
8c
8d
8e
8 f
0
0
0
1
1
1
Me
Et
nPr
Me
Et
81
62
91
85
90
84
Figure 1. a) Molecular structure of borate–betaine complex 8 f in the
solid state (ORTEP representation) and b) mesomeric structures. Select-
nPr
ꢀ
ꢀ
ꢀ
ed bond lengths (ꢃ): 1.31 (C1 O1), 1.37 (C1 C2), 1.38 (C2 C7), 1.30
ꢀ
(C7 O2).
From several betaines, single crystals suitable for X-ray
diffraction analysis were obtained by recrystallization from
diethyl ether. As exemplified for 8 f (Figure 1a),[12] all struc-
tures show planarity at the former b-diketone moiety and
ꢀ
have C C distances of 1.38 ꢃ representing a bond order of
about 1.5. Therefore, compound 8 f is best represented by
the two mesomeric structures depicted in Figure 1b.
Chem. Eur. J. 2005, 11, 2660 – 2667
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J. Christoffers et al.
The effect of ring size on the Brønsted acid catalyzed for-
mation of exo- or endocyclic enamines from a-acetylcyclo-
alkanones was investigated by Enriquez and Reynolds.[8] In
all cases, they observed mixtures of both isomers. In their
study, 2-acetylcyclohexanone (1d) showed a strong prefer-
ence for the endocyclic enamine, whereas its five-membered
homologue (1a) slightly preferred the exocyclic double
bond. These results are in accordance with the Dieckmann–
Kon rule[13] of the regioselective enolization of cyclic b-oxo
esters. In our studies we found that a-alkanoylcyclopenta-
nones 1a–c initially gave mixtures of both regioisomers in
the acid-catalyzed conversion with l-valine diethylamide,
with slight preference for the kinetically favored exocyclic
double bond (Table 2). However, prolonged heating of the
reaction mixture leads to isomerization of this double bond
to give the endocyclic enamines as thermodynamically fa-
vored products in good yields. For 1c, this isomerization
propionyl and butyryl derivatives 4e and 4 f (Table 2), how-
ever, the undesired endocyclic enamines 3e and 3 f could be
separated by column chromatography on alumina.
All kinetic enamines 4 were obtained as the (Z)-config-
ured isomers stabilized by hydrogen bonds between the ni-
1
trogen and oxygen atoms indicated by H chemical shifts of
around 12 ppm. These studies show that an appropriate
choice of activating agent (Brønsted vs Lewis acid) and tem-
perature allows the determination of the enamine-formation
position from b-diketones, in moderate to excellent selectivi-
ties.
Copper-catalyzed asymmetric Michael reactions: The behav-
ior of endocyclic enamines 3 and their exocyclic congeners 4
in asymmetric Michael reactions has been investigated.
They were stirred with a catalytic amount (5 mol%) of Cu-
(OAc)2·H2O in acetone to furnish a dark-green copper(ii)
azadionato complex. Methyl
vinyl ketone (5) was added, and
Table 2. Synthesis of endo- and exocyclic enamines 3 and 4 starting from b-diketones 1 and betaines 8, respec-
the reaction progress is visible
by the disappearance of the
green color. Whereas endocyclic
enamines 3 generally reacted
completely within 16 h, exocy-
clic enamines 4 required five
days until the reaction was fin-
ished. Hydrolysis with aqueous
hydrochloric acid finally afford-
ed the respective addition prod-
ucts (S)- and (R)-7 (Scheme 2,
Table 3).
tively.
SM[a]
n
R
Enamine
T [8C]
t
Yield [%]
exo:endo
1a
1b
1c
1d
1e
1 f
8a
8b
8c
8d
8e
8 f
0
0
0
1
1
1
0
0
0
1
1
1
Me
Et
nPr
Me
Et
nPr
Me
Et
nPr
Me
Et
3a
3b
3c
3d
3e
3 f
4a
4b
4c
4d
4e
4 f
100
65
100
50
23
5 d
14 d
48 h
18 h
72 h
16 h
16 h
16 h
16 h
16 h
16 h
16 h
65
62
77
63
87
88
93
91
13:87
3:97
0:100
0:100
0:100
0:100
100:0
100:0
100:0
97.5:2.5
63:37
68:32
55
0!23
0!23
0!23
0!23
0!23
0!23
82
87
52[b]
34[c]
nPr
As expected, in all cases the
opposite stereoisomer was ob-
[a] SM=Starting material. [b] 30% of isolated endocyclic enamine 3e. [c] 16% of isolated endocyclic enamine
3 f.
step proceeded quantitatively
(Table 2). No water-scavenging
agent was used in order not to
remove a needed equilibrium
component. In contrast to the
cyclopentanone series, the con-
version of all six-membered b-
diketones 1d–f gave the endo-
cyclic enamines 3d–f exclusively.
Betaines 8 were reacted with
Table 3. Formation of Michael addition products (S)-7 and (R)-7 from chiral endo- and exocyclic enamines,
respectively, and methyl vinyl ketone (5).
Starting with endocyclic enamines 3
Starting with exocyclic enamines 4
n
R
product
yield [%]
ee [%]
product
yield [%]
ee [%]
0
0
0
1
1
1
Me
Et
nPr
Me
Et
(S)-7a
(S)-7b
(S)-7c
(S)-7d
(S)-7e
(S)-7 f
46
85
69
67
76
73
87
88
82
96
97
98
(R)-7a
(R)-7b
(R)-7c
(R)-7d
(R)-7e
(R)-7 f
5[a]
30
73
–
72
23
61
13
39
–
67
83
[b]
[b]
nPr
[a] The respective spirocyclic imine 10a was obtained as the major product. [b] Exclusive formation of imine
l-valine diethylamide in MeCN 10d (see Scheme 3).
or CH2Cl2 to give the exocyclic
enamines 4 as major isomers in
all cases (Table 2). The five-membered betaines 8a–c
formed the exocyclic enamines 4a–c exclusively and in high
yields. However, the six-membered ring betaines 8d–f gave
mixtures of both regioisomers. Compound 4d was first ob-
tained as an exo:endo=80:20 mixture at ambient tempera-
ture. This selectivity could be enhanced to 97.5:2.5 in favor
of the exocyclic product 4d by lowering the temperature to
08C. Further temperature reduction did not affect the selec-
tivity any more. Lower selectivities were obtained for the
tained: endocyclic enamines afforded (S)-configured Mi-
chael products 7 showing positive optical rotation, whereas
all exocyclic enamines furnished the complementary (R)-
enantiomers 7 with negative optical-rotation values. All ee
values were determined by GLC on a chiral phase. Baseline
separation was optimized with racemic reference materials
prepared by conversion of b-diketones 1 with methyl vinyl
ketone (5) in the presence of catalytic quantities of
FeCl3·6H2O.[14]
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Chem. Eur. J. 2005, 11, 2660 – 2667

Enamine Regiochemistry
FULL PAPER
As can be seen from Table 3, for products (S)-7 derived
from endocyclic enamines 3, good yields of about 75% and
enantiomeric excesses from 82 to 98% were realized. In the
case of triketones (R)-7 from exocyclic enamines 4, yields
and selectivities were lower.
protonation, and thus, Robinson annulation to give an unde-
sired spirocyclic product from the exocyclic precursors is in-
hibited.
Table 3 reveals that acetylcyclopentanone (R)-7a was ob-
tained from the corresponding exocyclic enamine 4a in
trace amounts only. Instead, the spirocyclic imine 10a was
isolated as the major product (Scheme 3). In the case of the
Experimental Section
General: Melting points were measured on a Bꢀchi 510 apparatus and
are uncorrected. Starting materials 1a and d are commercially available.
BF3·OEt2 was purchased from Aldrich Chemical Co. The following com-
pounds were prepared according to literature procedures: 1b,c,e,f,[16]
3a,[17] d,[7b] 8a,[11] d,[17] 4a,e, and 10a,d.[17] Column chromatography was
carried out using Merck silica gel 60 or Merck basic alumina (act. I) with
petroleum ether (PE, b.p. 40–608C) and ethyl acetate (EA) as eluents.
1H NMR spectra were recorded on a Bruker ARX 500 (500 MHz) or a
Bruker ARX 300 (300 MHz) apparatus. 13C NMR spectra were recorded
on a Bruker ARX 500 (126 MHz), a Bruker ARX 300 (75 MHz), or a
Bruker AC 250 (63 MHz) apparatus. Multiplicities were determined with
distortionless enhancement by polarization transfer (DEPT) experiments.
19F NMR spectra were recorded on a Bruker AC 250 (250 MHz) appara-
tus with trifluoroacetic acid (d19F=ꢀ77.00 ppm) as internal standard. IR
sprectra were recorded on a Bruker Vector 22 (ATR=attenuated total
reflectance). GC analyses were performed with a HRGC 5300 (Carlo
Erba Strumentazione) with flame ionization detector (FID), and
a
Bondex una/b (20 mꢄ0.3 mm) or Lipodex E (25 mꢄ0.3 mm) column
with hydrogen carrier gas (0.4 bar).
General procedure for the preparation of endocyclic enamines 3: To a so-
lution of the respective b-diketone 1 and l-valine diethylamide (2) in tol-
uene (for 3b: CDCl3), a drop of concentrated hydrochloric acid was
added. The mixture was stirred at the respective temperature for the
time given in Table 2. After evaporation of all volatile materials, the resi-
due was purified by column chromatography (alumina, PE/EA).
Scheme 3. Formation of spirocyclic imines 10a,d from exocyclic enamines
4a,d.
N-(2-Propionyl-1-cyclopentenyl)-l-valine diethylamide (3b): According
to the general procedure, 2-propionylcyclopentanone (1b; 500 mg,
3.57 mmol), l-valine diethylamide (2; 500 mg, 2.90 mmol), and a drop of
concentrated hydrochloric acid were reacted in CDCl3 (3 mL). Chroma-
tography (alumina, PE/EA 1:2, Rf(silica gel)=0.28) yielded a mixture of
3b and 4b in a ratio of 93:7 (determined from integrals of the NH pro-
tons in the 1H NMR) as a pale-yellow solid (530 mg, 1.80 mmol, 62%).
M.p. 67–698C; [a]D20 = +150 (c=9.1 in CDCl3); 1H NMR (CDCl3,
six-membered exocyclic enamine 4d, the spirocyclic imine
10d was even formed exclusively. This result is in accor-
dance with a previous report.[10] Under the reaction condi-
tions used, the initial resultant imine intermediate 9 was evi-
dently deprotonated to give an aza enolate. The latter subse-
quently spirocyclizes in a Robinson-type annulation to yield
imines 10. A comparable spirocyclization was observed by
Pfau and co-workers when using phenethylamine as a chiral
auxiliary.[15]
The substitution of the methyl substituent by the longer
alkyl groups ethyl and propyl, indeed suppressed the spiro-
cyclization, and the respective exocyclic enamines 4b,c,e,f
furnished the desired open-chain Michael adducts 7b,c,e,f.
In these cases, the additional inductive effect of the substitu-
ent seems to destabilize a conceivable aza enolate, therefore
preventing it from deprotonation and annulation.
3
3
300 MHz): d=0.98 (d, J=6.6 Hz, 3H; CHCH3), 1.01 (d, J=6.6 Hz, 3H;
CHCH3), 1.10 (t, 3J=7.4 Hz, 3H; CH3), 1.12 (t, 3J=7.1 Hz, 3H;
NCH2CH3), 1.19 (t, 3J=7.1 Hz, 3H; NCH2CH3), 1.85 (quint, 3J=7.5 Hz,
2H; 4’-H), 2.08 (oct, 3J=6.7 Hz, 1H; CHCH3), 2.35 (q, 3J=7.4 Hz, 2H;
CH2Me), 2.56 (t, 3J=5.9 Hz, 2H), 2.59 (t, 3J=6.8 Hz, 2H), 3.17 (dt, 2J=
(ꢀ)13.7, 3J=6.9 Hz, 1H; NCH2), 3.30 (dt, 2J=(ꢀ)14.5, 3J=7.2 Hz, 1H;
NCH2), 3.38 (dt, 2J=(ꢀ)14.5, 3J=7.2 Hz, 1H; NCH2), 3.58 (dt, 2J=
(ꢀ)13.7, 3J=6.9 Hz, 1H; NCH2), 3.96 (dd, 3J=9.5, 3J=6.5 Hz, 1H;
CHNH), 9.75 ppm (brd, 3J=9.5 Hz, 1H; NH); 13C{1H} NMR (CDCl3,
126 MHz): d=8.14 (CH3), 12.72 (CH3; CH2CH3), 14.46 (CH3; CH2CH3),
17.72 (CH3; CHCH3), 19.68 (CH3; CHCH3), 21.25 (C-4’), 29.52 (CH2; C-
5’), 31.97 (CH2; CH2Me), 32.23 (CH; CHCH3), 33.22 (CH2; C-3’), 40.14
(CH2; NCH2), 41.44 (CH2; NCH2), 60.78 (CH; CHNH), 104.67 (C; C-2’),
168.86 (C; C-1’), 169.97 (C; CON), 196.65 ppm (C; COEt); IR (ATR):
n˜ =3248 (m), 2965 (m), 2934 (m), 1714 (m), 1622 (vs), 1553 (s), 1460 (m),
2357 (m), 1278 (w), 1244 (m), 1216 (m), 1184 (m), 1153 (m), 1097 (w),
1035 (m), 893 (m), 867 (w), 851 (w), 786 (m), 723 (w), 631 cmꢀ1 (vs); MS
(70 eV, EI): m/z (%): 294 (7) [M+], 251 (1), 228 (1), 194 (100) [M+
ꢀCONEt2], 150 (4), 128 (3), 100 (3) [CONEt2+], 72 (12) [NEt2+], 57 (4)
[C3H5O+]; elemental analysis calcd (%) for C17H30N2O2 (294.43): C
69.35, H 10.27, N 9.52; found: C 68.79, H 10.26, N 9.43; HRMS (70 eV,
EI): m/z calcd for C17H30N2O2: 294.2307; found: 294.2308.
Conclusion
We were able to point out that control of the regioselectivity
of endo- and exocyclic enamine formation allows the com-
plementary preparation of either stereoisomer of triketones
7 by using the same chiral auxiliary, that is, the (S)-enantio-
mer of valine diethylamide available from the natural
source. The regioselectively formed enamines thus act as a
configuration switch. Replacement of the acetyl moiety in
the cyclic b-diketones by propionyl or butyryl prevents de-
N-(2-Butyryl-1-cyclopentenyl)-l-valine diethylamide (3c): According to
the general procedure, 2-butyrylcyclopentanone (1c; 1.00 g, 6.48 mmol),
l-valine diethylamide (2; 1.11 g, 6.48 mmol), and four drops of concen-
trated hydrochloric acid were reacted in toluene (2 mL) for 2 d at 1008C.
Chromatography (alumina, PE/EA 1:1, Rf(silica gel)=0.24) yielded 3c as
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J. Christoffers et al.
a colorless solid (1.53 g, 4.96 mmol, 77%). M.p. 67–688C; [a]2D0 =+131
(c=25.0 in CDCl3); 1H NMR (CDCl3, 300 MHz): d=0.94 (t, 3J=7.4 Hz,
3H; CH3), 0.98 (d, 3J=6.8 Hz, 3H; CHCH3), 1.00 (d, 3J=6.9 Hz, 3H;
CHCH3), 1.11 (t, 3J=7.2 Hz, 3H; NCH2CH3), 1.19 (t, 3J=7.2 Hz, 3H;
NCH2CH3), 1.64 (sex, 3J=7.4 Hz, 2H; CH2Me), 1.84 (quint, 3J=7.6 Hz,
2H; 4’-H), 2.07 (oct, 3J=6.9 Hz, 1H; CHCH3), 2.28 (t, 3J=7.4 Hz, 2H),
2.44–2.54 (m, 2H), 2.59 (t, 3J=7.2 Hz, 2H; CH2Et), 3.18 (dq, 2J=
(ꢀ)13.7, J=6.9 Hz, 1H; NCH2), 3.25–3.47 (m, 2H; NCH2), 3.58 (dq, J=
(ꢀ)13.7, 3J=6.9 Hz, 1H; NCH2), 3.95 (dd, 3J=9.5, 3J=6.5 Hz, 1H;
CHNH), 9.79 ppm (brd, 3J=9.2 Hz, 1H; NH); 13C{1H} NMR (CDCl3,
126 MHz): d=12.90 (NCH2CH3), 14.24 (CH3), 14.64 (NCH2CH3), 17.81
(CHCH3), 17.91 (CH2), 19.85 (CHCH3), 21.41 (CH2), 29.78 (CH2), 32.15
(CH2), 32.37 (CH; CHCH3), 40.29 (CH2; NCH2), 41.59 (CH2; NCH2),
42.53 (CH2; CH2Et), 61.00 (CH; CHNH), 105.12 (C; C-2’), 164.22 (C; C-
1’), 170.09 (C; CON), 196.34 ppm (C; COPr); IR (ATR): n˜ =3262 (brw),
2959 (m), 2324 (w), 2872 (w), 2839 (w), 1714 (w), 1614 (vs), 1545 (s),
1449 (s), 1430 (s), 1360 (m), 1328 (m), 1314 (m), 1276 (s), 1237 (s), 1216
(s), 1176 (w), 1132 (m), 1119 (m), 1087 (m), 1034 (m), 949 (w), 824 (w),
702 cmꢀ1 (m); MS (70 eV, EI): m/z (%): 308 (3) [M+], 242 (4), 208 (39)
[M+ꢀCONEt2], 164 (2), 142 (20), 129 (4), 100 (17) [CONEt2+], 72 (100)
[NEt2+], 55 (5), 43 (11) [C3H7+]; HRMS (70 eV, EI): m/z calcd for
C18H32N2O2: 308.2464; found: 308.2464.
NCH2), 60.18 (CH; CHNH), 100.88 (C; C-2’), 159.60 (C; CON), 170.41
(C; C-1’), 198.93 ppm (C; COPr); IR (ATR): n˜ =2970 (w), 2926 (m),
2866 (w), 2834 (w), 1714 (w), 1630 (s), 1598 (s), 1558 (vs), 1486 (s), 1367
(m), 1338 (m), 1297 (m), 1276 (s), 1237 (m), 1207 (vs), 1168 (s), 1158 (s),
1134 (s), 1107 (m), 1096 (m), 1063 (s), 973 (w), 823 (m), 779 (m),
740 cmꢀ1 (w); MS (70 eV, EI): m/z (%): 322 (6) [M+], 279 (1) [M+
ꢀC3H7], 222 (100) [M+ꢀCONEt2], 178 (5), 152 (8), 100 (5) [CONEt2+],
82 (15), 72 (14) [NEt2+], 67 (7), 55 (6), 43 (8) [C3H7+]; HRMS (70 eV,
EI): m/z calcd for C19H34N2O2: 322.2620; found: 322.2619.
3
2
5-Ethyl-3,3-difluoro-4-oxa-2-oxonia-3-boratabicyclo[4.3.0]nona-1,5-diene
(8b): 2-Propionylcyclopentanone (1b; 6.00 g, 4.19 mmol) and BF3·OEt2
(7.10 g, 50.3 mmol) in CH2Cl2 (8 mL) were stirred for 90 h at 238C. The
mixture was poured into water (20 mL) and then extracted with CH2Cl2
(3ꢄ20 mL). After drying (MgSO4) and evaporation of all volatile materi-
als, the residue was purified by column chromatography (silica gel, PE/
EA 3:1 Rf =0.24) to yield 8b as a brown oil (4.68 g, 25.9 mmol, 62%).
1H NMR (CDCl3, 300 MHz): d=1.25 (t, 3J=7.5 Hz, 3H; CH3), 2.10 (tt,
3
3
3J=5.7, J=5.1 Hz, 2H; 8-H), 2.54 (q, J=7.2 Hz, 2H; CH2Me), 2.67 (dd,
3J=7.8, 3J=6.9 Hz, 2H), 2.75 ppm (t, 3J=7.8 Hz, 2H); 13C{1H} NMR
(CDCl3, 126 MHz): d=8.92 (CH3), 20.45 (CH2), 25.25 (CH2), 29.25
(CH2), 34.78 (CH2), 112.42 (C; C-6), 191.11 (C; CO), 199.29 ppm (C;
CO); 19F{1H} NMR (CDCl3, 235 MHz): d=ꢀ139.76 ppm (s); IR (ATR):
n˜ =2987 (w), 2946 (w), 1607 (s), 1538 (vs), 1462 (w), 1404 (w), 1383 (w),
1361 (w), 1311 (w), 1187 (m), 1088 (w), 1037 cmꢀ1 (m); MS (70 eV, EI):
m/z (%): 188 (18) [M+], 169 (4) [M+ꢀF], 159 (100) [M+ꢀC2H5], 131 (4),
103 (3), 79 (3), 65 (6) [BF2O+]; elemental analysis calcd (%) for
C8H11BF2O2 (187.98): C 51.11, H 5.90; found: C 51.21, H 5.95.
N-(2-Propionyl-1-cyclohexenyl)-l-valine diethylamide (3e): According to
the general procedure, 2-propionylcyclohexanone (1e; 800 mg,
5.19 mmol), l-valine diethyl amide (2; 1.00 g, 5.80 mmol), one drop of
concentrated hydrochloric acid, and molecular sieves (4 g, 4 ꢃ) were re-
acted in toluene (5 mL) for 3 d at 238C. Chromatography (alumina, PE/
EA 1:2, Rf(silica gel)=0.42) yielded 3e as a pale-yellow solid (1.40 g,
1.80 mmol, 87%). M.p. 538C; [a]2D0 =+255 (c=10.1 in CHCl3); 1H NMR
(CDCl3, 500 MHz): d=1.05 (d, 3J=6.8 Hz, 3H; CHCH3), 1.10 (d, 3J=
6.7 Hz, 3H; CHCH3), 1.12 (t, 3J=7.3 Hz, 3H; CH3), 1.14 (t, 3J=7.1 Hz,
3H; NCH2CH3), 1.19 (t, 3J=7.1 Hz, 3H; NCH2CH3), 1.59–1.69 (m, 4H;
3,3-Difluoro-5-propyl-4-oxa-2-oxonia-3-boratabicyclo[4.3.0]nona-1,5-
diene (8c): As reported above for 8b, 2-butyrylcyclopentanone (1c,
3.00 g, 19.5 mmol) and BF3·OEt2 (4.14 g, 29.2 mmol) were reacted for
16 h in CH2Cl2 (5 mL). Column chromatography (silica gel, PE/EA 3:1,
Rf =0.32) yielded 8c as a brown oil (3.57 g, 17.7 mmol, 91%). 1H NMR
(CDCl3, 300 MHz): d=1.00 (t, 3J=7.5 Hz, 3H; CH3), 1.76 (sex, 3J=
7.5 Hz, 2H; CH2Me), 2.09 (tt, 3J=7.8, 3J=6.6 Hz, 2H; 8-H), 2.48 (t, 3J=
7.2 Hz, 2H; CH2Et), 2.67 (dd, 3J=7.5, 3J=7.2 Hz, 2H), 2.75 ppm (t, 3J=
7.8 Hz, 2H); 13C{1H} NMR (CDCl3, 75 MHz): d=13.74 (CH3), 18.19
(CH2), 18.59 (CH2), 20.12 (CH2), 25.10 (CH2), 34.48 (CH2), 37.33 (CH2),
112.36 (C; C-6), 190.00 (C; CO), 199.00 ppm (C; CO); 19F{1H} NMR
(CDCl3, 235 MHz): d=ꢀ137.99 ppm (s); IR (ATR): n˜ =2966 (w), 2877
(w), 1970 (w), 1708 (m), 1601 (s), 1529 (vs), 1464 (w), 1405 (m), 1366
(m), 1311 (m), 1184 (s), 1100 (w), 1073 (m), 1033 cmꢀ1 (s); MS (70 eV,
EI): m/z (%): 202 (16) [M+], 183 (5) [M+ꢀF], 174 (9), 159 (100) [M+
ꢀC3H7], 131 (4), 121 (4), 103 (3), 91 (2) [HBF2O2+], 79 (4), 65 (9)
[BF2O+], 55 (3), 39 (5); HRMS (70 eV, EI): m/z calcd for C9H13BF2O2:
202.0977; found: 202.0977; elemental analysis calcd (%) for C9H13BF2O2
(202.01): C 53.51, H 6.49; found: C 53.97, H 6.60.
3
2
4’-H and 5’-H), 2.12 (oct, J=6.8 Hz, 1H; CHCH3), 2.20 (dt, J=(ꢀ)17.7,
3J=5.8 Hz, 1H; NCH2), 2.35–2.39 (m, 3H), 2.43 (q, 3J=7.3 Hz, 1H;
CH2Me), 2.44 (q, 3J=7.3 Hz, 1H; CH2Me), 3.27 (dq, 2J=(ꢀ)14.1, 3J=
7.0 Hz, 1H; NCH2), 3.41 (q, 3J=7.1 Hz, 1H; NCH2), 3.41 (q, 3J=7.2 Hz,
2
3
3
1H; NCH2), 3.53 (dq, J=(ꢀ)14.1, J=7.0 Hz, 1H; NCH2), 4.14 (dd, J=
8.4, 3J=6.8 Hz, 1H; CHNH), 11.80 ppm (d, 3J=8.2 Hz, 1H; NH);
13C{1H} NMR (CDCl3, 126 MHz): d=8.81 (CH3), 12.81 (CH3;
NCH2CH3), 14.43 (CH3; NCH2CH3), 18.60 (CH3; CHCH3), 19.99 (CH3;
CHCH3), 22.01 (CH2), 23.04 (CH2), 25.38 (CH2), 26.84 (CH2; C-6’), 32.06
(CH; CHCH3), 32.07 (CH2; CH2Me), 40.33 (CH2; NCH2), 41.56 (CH2;
NCH2), 60.01 (CH; CHNH), 100.76 (C; C-2’), 159.42 (C; C-1’), 170.48
(C; CON), 199.55 ppm (COEt); IR (ATR): n˜ =2967 (m), 2931 (m), 2871
(w), 2831 (m), 1714 (w), 1628 (s), 1595 (s), 1557 (s), 1455 (s), 1425 (s),
1367 (m), 1328 (m), 1276 (m), 1215 (vs), 1160 (m), 1138 (m), 1119 (s),
1097 (m), 1064 (m), 1040 (m), 1013 (w), 960 (m), 829 (m), 813 (m), 776
(w), 718 (w), 701 cmꢀ1 (w); MS (70 eV, EI): m/z (%): 308 (5) [M+], 208
(100) [M+ꢀCONEt2], 190 (4), 164 (4), 152 (11) [C9H14NO+], 125 (11),
110 (11), 82 (27), 72 (52) [NEt2+], 57 (15) [COEt+]; HRMS (70 eV, EI):
m/z calcd for C18H32N2O2: 308.2464; found: 308.2463.
5-Ethyl-3,3-difluoro-4-oxa-2-oxonia-3-boratabicyclo[4.4.0]deca-1,5-diene
(8e): 2-Propionylcyclohexanone (1e; 10.0 g, 64.8 mmol) and BF3·OEt2
(11.0 g, 77.8 mmol) were stirred in CH2Cl2 (10 mL) for 16 h. Evaporation
of all volatile materials and twofold recrystallization of the residue from
Et2O furnished 8e as colorless crystals (11.8 g, 58.40 mmol, 90%). M.p.
328C; 1H NMR (CDCl3, 500 MHz): d=1.24 (t, 3J=7.5 Hz, 3H; CH3),
1.74–1.81 (m, 4H; 8-H and 9-H), 2.39 (t, 3J=6.0 Hz, 2H; 7-H), 2.57 (t,
3J=6.2 Hz, 2H; 10-H), 2.60 ppm (q, 3J=7.4 Hz, 2H; CH2Me); 13C{1H}
NMR (CDCl3, 126 MHz): d=8.45 (CH3), 20.95 (CH2), 21.96 (CH2), 22.65
(CH2), 28.24 (CH2; COCH2), 32.45 (CH2; COCH2), 108.24 (C; C-6),
189.53 (C; CO), 195.21 ppm (C; CO); 19F{1H} NMR (CDCl3, 235 MHz):
d=ꢀ140.76 ppm (s); IR (ATR): n˜ =2945 (w), 1583 (s), 1516 (vs), 1385
(w), 1202 (m), 1050 cmꢀ1 (m); MS (70 eV, EI): m/z (%): 202 (21) [M+],
183 (5) [M+ꢀF], 173 (100) [M+ꢀC2H5], 125 (3), 79 (8), 57 (5) [C3H5O+];
HRMS (70 eV, EI): m/z calcd for C9H1310BF2O2: 201.1012; found:
201.1012; elemental analysis calcd (%) for C9H13BF2O2 (202.01): C 53.51,
H 6.49; found: C 53.97, H 6.65.
N-(2-Butyryl-1-cyclohexenyl)-l-valine diethylamide (3 f): According to
the general procedure, 2-butyrylcyclohexanone (1 f; 1.00 g, 6.16 mmol), l-
valine diethylamide (2; 1.27 g, 7.40 mmol), and one drop of concentrated
hydrochloric acid were reacted in toluene (5 mL) at 558C for 16 h. Chro-
matography (alumina, PE/EA 1:2, Rf(silica gel)=0.47) yielded 3 f as a
yellow oil (1.75 g, 5.43 mmol, 88%). [a]2D0 =+238 (c=19.2 in CDCl3);
1H NMR (CDCl3, 500 MHz): d=0.94 (t, 3J=7.5 Hz, 3H; CH3), 1.01 (d,
3J=6.8 Hz, 3H; CHCH3), 1.06 (d, 3J=6.6 Hz, 3H; CHCH3), 1.11 (t, 3J=
7.0 Hz, 3H; NCH2CH3), 1.16 (t, 3J=7.0 Hz, 3H; NCH2CH3), 1.61–1.67
(m, 6H; 4’-H, 5’-H, and CH2Me), 2.08 (oct, 3J=6.7 Hz, 1H; CHCH3),
2.17 (dt, 2J=(ꢀ)17.4, 3J=6.3 Hz, 1H), 2.32–2.38 (m, 5H), 3.24 (dq, 2J=
(ꢀ)13.6, 3J=6.7 Hz, 1H; NCH2), 3.38 (q, 3J=7.1 Hz, 2H; NCH2), 3.49
(dq, 2J=(ꢀ)13.9, 3J=6.7 Hz, 1H; NCH2), 4.10 (dd, 3J=7.9, 3J=7.1 Hz,
1H; CHNH), 11.84 ppm (brd, 3J=8.0 Hz, 1H; NH); 13C{1H} NMR
(CDCl3, 126 MHz): d=12.74 (CH3; NCH2CH3), 14.19 (CH3), 14.35 (CH3;
NCH2CH3), 18.16 (CH2; CH2Me), 18.58 (CH3; CHCH3), 19.92 (CH3;
CHCH3), 21.96 (CH2), 23.03 (CH2), 25.49 (CH2), 26.79 (CH2; C-6’), 31.97
(CH; CHCH3), 40.28 (CH2; NCH2), 41.09 (CH2; CH2Et), 41.40 (CH2;
3,3-Difluoro-5-propyl-4-oxa-2-oxonia-3-boratabicyclo[4.4.0]deca-1,5-
diene (8 f): As reported above for 8e, 2-butyrylcyclohexanone (1 f; 1.50 g,
8.92 mmol) and BF3·OEt2 (2.53 g, 17.8 mmol) were reacted in CH2Cl2
(2 mL). Chromatography (silica gel, PE/EA 3:1, Rf =0.32) and subse-
quent twofold recrystallization from Et2O yielded 8 f as a colorless oil
2664
ꢂ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2005, 11, 2660 – 2667

Enamine Regiochemistry
FULL PAPER
(1.62 g, 7.50 mmol, 84%). 1H NMR (CDCl3, 300 MHz): d=1.01 (t, 3J=
7.4 Hz, 3H; CH3), 1.71–1.81 (m, 6H; 8-H, 9-H, and CH2Me), 2.40 (brt,
3J=6.1 Hz, 2H; 7-H), 2.53 (t, 3J=7.6 Hz, 2H; CH2Et), 2.57 ppm (brt,
3J=5.7 Hz, 2H; 10-H); 13C{1H} NMR (CDCl3, 75 MHz): d=13.75 (CH3),
18.34 (CH2), 20.89 (CH2), 21.97 (CH2), 22.79 (CH2), 32.50 (CH2;
COCH2), 36.46 (CH2; COCH2), 108.65 (C; C-6), 189.83 (C; CO),
194.53 ppm (C; CO); 19F{1H} NMR (CDCl3, 235 MHz): d=ꢀ140.95 ppm
(s); IR (ATR): n˜ =2967 (m), 2938 (m), 2878 (w), 1739 (w), 1572 (s), 1511
(vs), 1457 (m), 1385 (s), 1368 (s), 1340 (s), 1306 (m), 1200 (s), 1181 (m),
1154 (s), 1141 (s), 1101 (w), 1076 (m), 1045 (vs), 1029 (vs), 1010 cmꢀ1 (s);
MS (70 eV, EI): m/z (%): 216 (16) [M+], 197 (5) [M+ꢀF], 173 (100) [M+
ꢀC3H7], 79 (8); elemental analysis calcd (%) for C10H15BF2O2 (216.03): C
55.60, H 7.00; found: C 55.47, H 6.89.
matography (alumina, PE/EA 1:1) furnished 3e (451 mg, 1.46 mmol,
30%, Rf(silica gel)=0.38). In a second fraction, 4e (Rf(silica gel)=0.14)
was isolated as a colorless solid (789 mg, 2.56 mmol, 52%). M.p. 958C;
[a]2D0 =+268 (c=12.2 in CHCl3); 1H NMR (CDCl3, 300 MHz): d=1.05
(d, 3J=6.8 Hz, 3H; CHCH3), 1.08 (d, 3J=6.8 Hz, 3H; CHCH3), 1.09 (t,
3J=7.7 Hz, 3H; CH3), 1.12 (t, 3J=7.1 Hz, 3H; NCH2CH3), 1.19 (t, 3J=
3
7.1 Hz, 3H; NCH2CH3), 1.63–1.73 (m, 4H; 4’-H and 5’-H), 2.11 (oct, J=
6.5 Hz, 1H; CHCH3), 2.33–2.49 (m, 6H; 3’-H, 6’-H, and CH2Me), 3.21–
3.54 (m, 4H; NCH2), 4.19 (dd, 3J=8.5, 3J=6.0 Hz, 1H; CHNH),
12.80 ppm (brs, 1H; NH); 13C{1H} NMR (CDCl3, 75 MHz): d=12.26
(CH3), 12.61 (CH3; NCH2CH3), 14.15 (CH3; NCH2CH3), 17.94 (CH3;
CHCH3), 19.87 (CH3; CHCH3), 20.94 (CH3), 22.71 (CH2), 24.02 (CH2),
25.42 (CH2), 31.63 (CH; CHCH3), 37.94 (CH2; C-3’), 40.14 (CH2; NCH2),
41.28 (CH2; NCH2), 60.53 (CH; CHNH), 99.95 (C; C-1’), 166.64 (C;
CNH), 170.03 (C; CON), 195.50 ppm (C-2’); IR (ATR): n˜ =2962 (m),
2930 (s), 2874 (m), 1633 (s), 1584 (vs), 1560 (vs), 1452 (s), 1377 (m), 1343
(m), 1320 (m), 1274 (s), 1237 (s), 1217 (m), 1158 (m), 1082 (m), 1053 (m),
971 (m), 825 cmꢀ1 (s); MS (70 eV, EI): m/z (%): 308 (8) [M+], 265 (1)
[M+ꢀC3H7], 208 (100) [M+ꢀCONEt2], 190 (2), 164 (4), 150 (4), 72 (4)
[NEt2+]; elemental analysis calcd (%) for C18H32N2O2 (308.47): C 70.09,
H 10.46, N 9.08; found: C 70.15, H 10.52, N 9.04.
General procedure for the preparation of exocyclic enamines 4: l-Valine
diethylamide (2) was added dropwise to a solution of the respective be-
taine 8 in MeCN or CH2Cl2 at 08C. The mixture was warmed up to 238C
and stirred for a further 16 h. All volatile materials were evaporated and
the residue purified by column chromatography (alumina, PE/EA).
N-[1-(2-Oxocyclopentylidene)propyl]-l-valine diethylamide (4b): Ac-
cording to the general procedure, betaine 8b (500 mg, 2.66 mmol) and l-
valine diethylamide (2; 600 mg, 3.48 mmol) were reacted in CH2Cl2
(2 mL). Chromatography (PE/EA 1:1, Rf(silica gel)=0.14) afforded 4b
as a pale-yellow oil (710 mg, 2.41 mmol, 91%). [a]2D0 =+230 (c=8.7 in
CDCl3); 1H NMR (CDCl3, 500 MHz): d=1.03 (d, 3J=6.8 Hz, 3H;
CHCH3), 1.06 (d, 3J=6.8 Hz, 3H; CHCH3), 1.09 (t, 3J=7.7 Hz, 3H;
CH3), 1.12 (t, 3J=7.1 Hz, 3H; NCH2CH3), 1.20 (t, 3J=7.1 Hz, 3H;
NCH2CH3), 1.84 (quint, 3J=7.8 Hz, 2H; 4’-H), 2.04–2.13 (m, 1H;
CHCH3), 2.16–2.23 (m, 2H; CH2CH3), 2.33 (t, 3J=7.9 Hz, 2H; 5’-H),
2.53 (t, 3J=7.1 Hz, 2H; 3’-H), 3.20–3.56 (m, 4H; NCH2), 4.14 (dd, 3J=
8.8, 3J=5.7 Hz, 1H; NHCH), 10.69 ppm (brd, 3J=9.2 Hz, 1H; NH);
13C{1H} NMR (CDCl3, 75 MHz): d=11.49 (CH3; CH2CH3), 12.78 (CH3;
NCH2CH3), 14.37 (CH3; NCH2CH3), 17.84 (CH3; CHCH3), 19.95 (CH2;
CHCH3), 20.47 (CH2; C-5’), 22.98 (CH2; CH2Me), 27.27 (CH2; C-4’),
31.96 (CH; CHCH3), 39.05 (CH2; C-3’), 40.19 (CH2; NCH2), 41.39 (CH2;
NCH2), 59.42 (CH; CHNH), 102.36 (C; C-1’), 161.59 (C; CNH), 170.19
(C; CON), 202.95 ppm (C; C-2’); IR (ATR): n˜ =2969 (s), 2936 (m), 2876
(m), 1713 (m), 1620 (vs), 1548 (m), 1464 (s), 1382 (m), 1250 (w),
1216 cmꢀ1 (w); HRMS (70 eV, EI): m/z calcd for C17H30N2O2: 294.2307;
found: 294.2306.
N-[1-(2-Oxocyclohexylidene)butyl]-l-valine diethylamide (4 f): Accord-
ing to the general procedure, betaine 8 f (500 mg, 2.31 mmol) and l-
valine diethylamide (2; 400 mg, 2.32 mmol) were reacted in CH2Cl2
(2 mL). Chromatography (alumina, PE/EA 1:2) afforded 3 f (117 mg,
0.36 mmol, 16%, Rf(PE/EA 1:1, silica gel)=0.29). In a second fraction,
4 f (Rf(PE/EA 1:2, silica gel)=0.11) was isolated as a colorless solid
(253 mg, 0.79 mmol, 34%). M.p. 698C; [a]2D0 =+25 (c=0.5 in CDCl3);
1H NMR (CDCl3, 500 MHz): d=0.99 (t, 3J=7.3 Hz, 3H; CH3), 1.04 (d,
3J=6.9 Hz, 3H; CHCH3), 1.08 (d, 3J=6.7 Hz, 3H; CHCH3), 1.11 (t, 3J=
7.0 Hz, 3H; NCH2CH3), 1.19 (t, 3J=7.1 Hz, 3H; NCH2CH3), 1.42–1.51
(m, 2H), 1.63–1.69 (m, 4H), 2.06–2.15 (m, 2H), 2.21–2.27 (m, 1H;
3
2
CHCH3), 2.35 (t, J=6.2 Hz, 4H; 3’-H and CH2Et), 3.27 (dt, J=(ꢀ)13.9,
3J=6.6 Hz, 1H; NCH2), 3.34–3.43 (m, 4H; NCH), 3.45 (dt, 2J=(ꢀ)13.6,
3J=7.0 Hz, 1H; NCH2), 4.16 (dd, 3J=8.4, 3J=6.0 Hz, 1H; CHNH),
12.89 ppm (brd, 3J=8.3 Hz, 1H; NH); 13C{1H} NMR (63 MHz, CDCl3):
d=12.73 (CH3; CHCH3), 14.31 (CH3; CHCH3), 14.52 (CH3), 18.05 (CH3;
NCH2CH3), 20.06 (CH3; NCH2CH3), 20.72 (CH2), 22.86 (CH2), 24.17
(CH2), 25.75 (CH2), 30.16 (CH2), 31.70 (CH; CHCH3), 38.07 (CH2;
CH2CO), 40.21 (CH2; NCH2), 41.34 (CH2; NCH2), 60.85 (CH; CHNH),
100.47 (C; C-1’), 165.71 (C; CNH), 170.15 (C; CON), 195.59 ppm (C; C-
2’); IR (ATR): n˜ =2964 (m), 2931 (s), 2870 (m), 2826 (w), 1737 (w), 1638
(s), 1588 (s), 1554 (vs), 1485 (m), 1451 (s), 1427 (m), 1376 (m), 1342 (m),
1319 (m), 1293 (s), 1270 (s), 1215 (m), 1157 (m), 1126 (s), 1104 (m), 1086
(s), 1066 (m), 1048 cmꢀ1 (w); MS (70 eV, EI): m/z (%): 322 (8) [M+], 279
(1) [M+ꢀC3H7], 222 (100) [M+ꢀCONEt2], 178 (3), 156 (2) [C10H16NO+],
124 (1), 72 (4) [NEt2+], 55 (3); HRMS (70 eV, EI): m/z calcd for
C19H34N2O2: 322.2620; found: 322.2620.
N-[1-(2-Oxocyclopentylidene)butyl]-l-valine diethylamide (4c): Accord-
ing to the general procedure, betaine 8c (210 mg, 1.03 mmol) and l-
valine diethylamide (2; 580 mg, 3.38 mmol) were reacted in CH2Cl2
(1 mL). Chromatography (alumina, PE/EA 1:1, Rf =0.41) yielded 4c as a
pale-yellow solid (263 mg, 0.85 mmol, 82%). [a]2D0 =+257 (c=10.0 in
CDCl3); 1H NMR (CDCl3, 300 MHz): d=0.99 (t, 3J=7.4 Hz, 3H; CH3),
3
3
1.03 (d, J=6.9 Hz, 3H; CHCH3), 1.05 (d, J=6.8 Hz, 3H; CHCH3), 1.12
3
3
(t, J=7.1 Hz, 3H; NCH2CH3), 1.21 (t, J=7.1 Hz, 3H; NCH2CH3), 1.42–
1.57 (m, 2H), 1.77–1.91 (m, 2H), 2.03–2.22 (m, 3H), 2.32 (t, 3J=7.8 Hz,
2H; 5’-H), 2.52 (dd, 3J=7.3, 3J=6.9 Hz, 2H; 3’-H), 3.18–3.58 (m, 4H;
NCH2), 4.12 (m, 1H; NHCH), 10.71 ppm (brd, 3J=9.2 Hz, 1H; NH);
13C{1H} NMR (CDCl3, 75 MHz): d=13.11 (CH3), 14.72 (CH3;
NCH2CH3), 14.73 (CH3; NCH2CH3), 18.14 (CH3; CHCH3), 20.32 (CH3;
CHCH3), 20.87 (CH2), 21.18 (CH2), 27.98 (CH2; C-4’), 32.25 (CH2;
CH2Et), 32.29 (CH; CHCH3), 39.45 (CH2; C-3’), 40.51 (CH2; NCH2),
41.71 (CH2; NCH2), 59.91 (CH; CHNH), 103.32 (C-1’), 160.74 (C; CNH),
170.56 (C; CON), 203.21 ppm (C; C-2’); IR (ATR): n˜ =2961 (m), 2935
(m), 2894 (m), 2838 (w), 2184 (brw), 1965 (brw), 1624 (vs), 1571 (vs),
1486 (m), 1453 (s), 1430 (s), 1379 (m), 1365 (m), 1341 (m), 1311 (m),
1289 (m), 1279 (m), 1250 (s), 1214 (s), 1179 (m), 1141 (m), 1123 (m),
1097 (s), 1067 (m), 1025 (m), 1007 (m), 947 (w), 877 (w), 835 (w), 778
(m), 756 (m), 726 (m), 683 cmꢀ1 (w); MS (70 eV, EI): m/z (%): 308 (5)
[M+], 265 (1) [M+ꢀC3H7], 208 (100) [M+ꢀCONEt2], 164 (3), 152 (1)
[C9H14NO+], 100 (3) [CONEt2+], 79 (1), 72 (5) [NEt2+], 55 (3); elemen-
tal analysis calcd (%) for C18H32N2O2 (308.46): C 70.09, H 10.46, N 9.08;
found: C 69.85, H 10.45, N 9.21.
General procedure for the preparation of racemic triketones 7: The re-
spective b-diketone 1, FeCl3·6H2O, and 5 were stirred in CH2Cl2 for 16 h
at 238C. After evaporation of all volatile materials, the residue was puri-
fied by column chromatography (silica gel, PE/EA).
General procedure for asymmetric Michael reactions: Cu(OAc)2·H2O
and the respective enamine 3 or 4 were stirred in acetone for 1 h at
238C. Then 5 was added and the mixture was stirred at 238C for the time
given. After evaporation of all volatile materials, hydrochloric acid (c=
1 moldmꢀ3) was added and the solution was stirred for 3 h at 08C. The
mixture was then extracted three times with CH2Cl2, the combined or-
ganic layers were washed with H2O, dried (MgSO4), and the solvent was
evaporated. The residue was purified by column chromatography (silica
gel, PE/EA).
rac-2-(3-Oxobutyl)-2-propionylcyclopentanone (rac-7b): According to
the general procedure, 2-propionylcyclopentanone (500 mg, 3.57 mmol),
FeCl3·6H2O (48 mg, 0.02 mmol), and 5 (500 mg, 7.13 mmol) were reacted
in CH2Cl2 (3 mL). Chromatography (silica gel, PE/EA 2:1, Rf =0.37)
N-[1-(2-Oxocyclohexylidene)propyl]-l-valine diethylamide (4e): Accord-
ing to the general procedure, betaine 8e (1.00 g, 4.95 mmol) and l-valine
diethylamide (2, 1.00 g, 5.90 mmol) were reacted in MeCN (3 mL). Chro-
yielded 7b as a
colorless oil (557 mg, 2.65 mmol, 74%). 1H NMR
(CDCl3, 300 MHz): d=1.01 (t, 3J=7.2 Hz, 3H; CH2CH3), 1.68 (dt, 2J=
(ꢀ)13.1, 3J=7.3 Hz, 1H; 4-H), 1.81–2.02 (m, 3H), 2.12 (s, 3H; COCH3),
Chem. Eur. J. 2005, 11, 2660 – 2667
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J. Christoffers et al.
2.13–2.23 (m, 1H), 2.28–2.40 (m, 4H), 2.52 (q, 3J=7.2 Hz, 2H; CH2Me),
2.51–2.60 ppm (m, 1H); 13C{1H} NMR (CDCl3, 75 MHz): d=7.87 (CH3;
CH2CH3), 19.44 (CH2), 27.63 (CH2), 29.99 (CH3), 31.75 (CH2), 32.08
(CH2), 38.49 (CH2), 38.74 (CH2), 66.99 (C; C-2), 207.30 (C), 207.43 (C),
216.45 ppm (C); IR (ATR): n˜ =2970 (m), 1732 (s), 1699 (vs), 1456 (m),
1406 (m), 1354 (m), 1317 (w), 1274 (w), 1143 (s), 1099 (m), 1073 (m),
930 cmꢀ1 (m); MS (70 eV, EI): m/z (%): 210 (5) [M+], 154 (79) [M+
ꢀCOꢀC2H4], 136 (47), 121 (12), 111 (17), 97 (100), 84 (31), 67 (5), 57
(92) [COEt+], 43 (62) [COMe+]; elemental analysis calcd (%) for
C12H18O3 (210.27): C 68.54, H 8.63; found: C 68.60, H 8.71.
150 (56), 135 (12), 125 (12), 121 (7), 111 (100), 98 (50), 81 (7), 67 (8), 57
(73) [COEt+], 43 (76) [COMe+]; HRMS (70 eV, EI): m/z calcd for
C13H20O3: 224.1412; found: 224.1413; elemental analysis calcd (%) for
C13H20O3 (224.30): C 69.61, H 8.99; found: C 69.18, H 9.04; GC: Bondex
unb; 3 min at 808C, then 2 Kminꢀ1 gradient; tR((S)-7e)=34.47 min; tR-
((R)-7e)=34.81 min.
(S)-2-(3-Oxobutyl)-2-propionylcyclohexanone ((S)-7e): According to the
general procedure, Cu(OAc)2·H2O (3.2 mg, 0.02 mmol), enamine 3e
(100 mg, 0.32 mmol), and 5 (45.0 mg, 0.65 mmol) were reacted in acetone
(0.5 mL) for 16 h. Chromatography (silica gel, PE/EA 3:1) yielded (S)-7e
(55 mg, 0.25 mmol, 76%). GC: Bondex unb; tR((S)-7e)=34.82 min; tR-
((R)-7e)=35.18 min; 97% ee; [a]2D0 =+150 (c=6.4 in CDCl3).
(S)-2-(3-Oxobutyl)-2-propionylcyclopentanone ((S)-7b): According to
the general procedure, Cu(OAc)2·H2O (3.4 mg, 0.02 mmol), enamine 3b
(100 mg, 0.34 mmol), and 5 (48 mg, 0.68 mmol) were reacted in acetone
(1 mL) for 16 h. Chromatography (silica gel, PE/EA 2:1) yielded (S)-7b
(61 mg, 0.28 mmol, 85%). GC: Bondex unb; temperature program: 3 min
at 808C, then 2.5 Kminꢀ1 gradient; tR((S)-7b)=26.60 min; 88% ee;
[a]2D0 =+95 (c=7.7 in CHCl3).
(R)-2-(3-Oxobutyl)-2-propionylcyclohexanone ((R)-7e): According to
the general procedure, Cu(OAc)2·H2O (3.2 mg, 0.02 mmol), enamine 4e
(100 mg, 0.32 mmol), and 5 (45.0 mg, 0.65 mmol) were reacted in acetone
(1 mL) for 5 d. Chromatography (silica gel, PE/EA 3:1) yielded (R)-7e
(52 mg, 0.23 mmol, 72%). GC: Bondex unb; tR((S)-7e)=34.81 min; tR-
((R)-7e)=35.14 min; 67% ee; [a]2D0 =ꢀ83 (c=6.5 in CDCl3).
(R)-2-(3-Oxobutyl)-2-propionylcyclopentanone ((R)-7b): According to
the general procedure, Cu(OAc)2·H2O (12 mg, 0.06 mmol), enamine 4b
(360 mg, 1.22 mmol), and 5 (171 mg, 2.45 mmol) were reacted in acetone
(2 mL) for 48 h. 5 (200 mg, 2.85 mmol) was added and the mixture was
stirred at 238C for a further 48 h. Chromatography (silica gel, PE/EA)
yielded (R)-7b (78 mg, 0.37 mmol, 30%). GC: Bondex unb; tR((R)-7b)=
26.90 min; 13% ee; [a]2D0 =ꢀ22 (c=12.5 in CDCl3).
rac-2-Butyryl-2-(3-oxobutyl)cyclohexanone (rac-7 f): According to the
general procedure, 2-butyrylcyclohexanone (168 mg, 1.00 mmol),
FeCl3·6H2O (13.5 mg, 0.05 mmol), and 5 (120 mg, 2.00 mmol) were react-
ed in CH2Cl2 (0.5 mL). Chromatography (silica gel, PE/EA 2:1, Rf =0.40)
1
yielded 7 f as a colorless oil (224 mg, 0.94 mmol, 94%). H NMR (CDCl3,
300 MHz): d=0.90 (t, 3J=7.4 Hz, 3H; CH3), 1.40–1.82 (m, 6H), 1.84–
1.97 (m, 2H), 2.03–2.09 (m, 1H), 2.11 (s, 3H; COCH3), 2.23–2.37 (m,
4H), 2.38–2.54 ppm (m, 3H); 13C{1H} NMR (CDCl3, 126 MHz): d=13.55
(CH3), 16.86 (CH2), 22.06 (CH2), 26.91 (CH2), 27.40 (CH2), 29.81 (CH3;
COCH3), 34.48 (CH2), 38.19 (CH2), 40.04 (CH2), 41.37 (CH2), 66.38 (C;
C-2), 207.46 (C), 209.15 (C), 210.00 ppm (C); IR (ATR): n˜ =2937 (m),
2872 (w), 1713 (s), 1692 (vs), 1452 (m), 1358 (s), 1310 (w), 1272 (w), 1237
(w), 1168 (m), 1129 (m), 1030 (w), 1011 (w), 954 cmꢀ1 (w); MS (70 eV,
EI): m/z (%): 238 (3) [M+], 168 (74) [M+ꢀCOꢀC3H6], 150 (75), 135
(10), 125 (7), 121 (5), 111 (100), 98 (53), 81 (5), 71 (56) [COPr+], 55 (8),
43 (38) [COMe+]; elemental analysis calcd (%) for C14H22O3 (238.32): C
70.56, H 9.30; found: C 70.56, H 9.29; GC: Bondex unb; 3 min at 808C,
then 2 Kminꢀ1 gradient; tR((S)-7 f)=38.18 min; tR((R)-7 f)=38.45 min.
rac-2-Butyryl-2-(3-oxobutyl)cyclopentanone (rac-7c): According to the
general procedure, 2-butyrylcyclopentanone (500 mg, 3.24 mmol),
FeCl3·6H2O (44 mg, 0.02 mmol), and 5 (454 mg, 6.48 mmol) were reacted
in CH2Cl2 (0.5 mL). Chromatography (silica gel, PE/EA 3:1, Rf =0.24)
1
yielded 7c as a colorless oil (668 mg, 2.98 mmol, 92%). H NMR (CDCl3,
300 MHz): d=0.88 (t, 3J=7.4 Hz, 3H; CH2CH3), 1.50 (sex, 3J=7.3 Hz,
2H; CH2Me), 1.67 (dt, 2J=(ꢀ)13.1, 3J=7.6 Hz, 1H; 4-H), 1.80–2.02 (m,
3H), 2.12 (s, 3H; COCH3), 2.14–2.22 (m, 1H), 2.27–2.40 (m, 4H), 2.43–
2.49 (m, 2H; CH2Et), 2.50–2.59 ppm (m, 1H); 13C{1H} NMR (CDCl3,
75 MHz): d=13.81 (CH3), 17.29 (CH2), 19.68 (CH2), 27.68 (CH2), 30.20
(CH3; COCH3), 32.06 (CH2), 38.70 (CH2), 38.88 (CH2), 40.39 (CH2),
67.36 (C; C-2), 206.86 (C), 207.43 (C), 216.54 ppm (C; C-1); IR (ATR):
n˜ =2965 (s), 1735 (s), 1704 (vs), 1407 (w), 1367 (m), 1277 (w), 1146 (m),
895 cmꢀ1 (m); MS (70 eV, EI): m/z (%): 224 (2) [M+], 154 (100) [M+
ꢀCOꢀC3H6], 136 (45), 121 (14), 111 (18), 108 (10), 97 (100), 84 (43), 71
(90) [COPr+], 55 (18), 43 (96) [COMe+]; elemental analysis calcd (%)
for C13H20O3 (224.30): C 69.61, H 8.99; found: C 69.42, H 9.12; GC:
Bondex unb; 5 min at 808C, then 1 Kminꢀ1 gradient; tR((S)-7c)=
52.98 min; tR((R)-7c)=53.49 min.
(S)-2-Butyryl-2-(3-oxobutyl)cyclohexanone ((S)-7 f): According to the
general procedure, Cu(OAc)2·H2O (15.4 mg, 0.08 mmol), enamine 3 f
(500 mg, 1.55 mmol), and 5 (217 mg, 3.10 mmol) were reacted in acetone
(3 mL) for 16 h. Chromatography (silica gel, PE/EA 2:1) yielded (S)-7 f
(268 mg, 1.12 mmol, 73%). GC: Bondex unb; tR((S)-7 f)=38.06 min; tR-
((R)-7 f)=38.31 min; 98% ee; [a]2D0 =+141 (c=16.2 in CDCl3).
(R)-2-Butyryl-2-(3-oxobutyl)cyclohexanone ((R)-7 f): According to the
general procedure, Cu(OAc)2·H2O (0.9 mg, 0.01 mmol), enamine 4 f
(30.0 mg, 0.09 mmol), and 5 (13.0 mg, 0.19 mmol) were reacted in acetone
(1 mL) for 5 d. Chromatography (silica gel, PE/EA 2:1) yielded (R)-7 f
(5 mg, 0.02 mmol, 23%). GC: Bondex unb; tR((S)-7 f)=38.07 min; tR-
((R)-7 f)=38.34 min; 83% ee.
(S)-2-Butyryl-2-(3-oxobutyl)cyclopentanone ((S)-7c): According to the
general procedure, Cu(OAc)2·H2O (6.5 mg, 0.03 mmol), enamine 3c
(200 mg, 0.65 mmol), and 5 (91.0 mg, 1.30 mmol) were reacted in acetone
(1 mL) for 16 h. Chromatography (silica gel, PE/EA 3:1) yielded (S)-7c
(100 mg, 0.45 mmol, 69%). GC: Bondex unb; tR((S)-7c)=53.15 min, tR-
((R)-7c)=53.69 min; 82% ee; [a]2D0 =+120 (c=22.9 in CDCl3).
(R)-2-Butyryl-2-(3-oxobutyl)cyclopentanone ((R)-7c): According to the
general procedure, Cu(OAc)2·H2O (12.9 mg, 0.07 mmol), enamine 4c
(100 mg, 0.32 mmol), and 5 (45.0 mg, 0.63 mmol) were reacted in acetone
(1 mL) for 5 d. Chromatography (silica gel, PE/EA 3:1) yielded (R)-7c
(53 mg, 0.24 mmol, 73%). GC: Bondex unb; tR((S)-7c)=53.12 min, tR-
((R)-7c)=53.61 min; 39% ee; [a]2D0 =ꢀ64 (c=7.3 in CDCl3).
rac-2-(3-Oxobutyl)-2-propionylcyclohexanone (rac-7e): According to the
general procedure, 2-propionylcyclohexanone (2.99 g, 13.0 mmol),
FeCl3·6H2O (129 mg, 0.65 mmol), and 5 (1.80 g, 25.7 mmol) were reacted
in CH2Cl2 (2 mL). Chromatography (silica gel, PE/EA 2:1, Rf =0.33)
yielded 7e as a colorless oil (2.60 g, 11.6 mmol, 89%). 1H NMR (CDCl3,
300 MHz): d=1.04 (t, 3J=7.2 Hz, 3H; CH3), 1.42–1.57 (m, 2H), 1.58–
1.83 (m, 3H), 1.86–2.01 (m, 2H), 2.11 (s, 3H; COCH3), 2.23–2.55 ppm
(m, 7H); 13C{1H} NMR (CDCl3, 75 MHz): d=8.22 (CH3; CH2CH3), 22.57
(CH2), 27.44 (CH2), 27.94 (CH2), 30.35 (CH3), 31.87 (CH2), 35.19 (CH2),
38.72 (CH2), 41.77 (CH2), 66.78 (C; C-2), 208.08 (C; COMe), 210.50 (C;
CO), 210.61 ppm (C; CO); IR (ATR): n˜ =2941 (s), 2870 (m), 1716 (vs),
1696 (s), 1453 (w), 1356 (w), 1169 (w), 1131 (w), 902 cmꢀ1 (w); MS
(70 eV, EI): m/z (%): 224 (5) [M+], 206 (2), 168 (42) [M+ꢀCOꢀC2H4],
Acknowledgements
This work was generously supported by the Fonds der Chemischen Indus-
trie. B.K. thanks the Landesgraduiertenfçrderung Baden-Wꢀrttemberg
for a fellowship.
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Enamine Regiochemistry
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Received: November 30, 2004
Published online: February 24, 2005
Chem. Eur. J. 2005, 11, 2660 – 2667
www.chemeurj.org
ꢂ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2667