Regioselective enamine formation from oxonia-boranuida-betaines and their application in asymmetric Michael reactions

Article abstract of DOI:10.1002/ejoc.200300191

β-Diketonato borate betaines 2 are readily accessible by the reaction of β-dicarbonyl compounds 1 with BF₃·OEt₂. Reaction of borates 2 with L-valine diethylamide (3a) gives almost exclusively the exocyclic enamines 4 as the kinetic p

Full text of DOI:10.1002/ejoc.200300191

FULL PAPER
Regioselective Enamine Formation from Oxonia-Boranuida-Betaines and Their
Application in Asymmetric Michael Reactions
Jens Christoffers,*[a] Burkard Kreidler,[a] Sven Unger,[a] and Wolfgang Frey[a]
Keywords: β-Dicarbonyl compounds / Enamines / Michael addition / Regioselectivity / Boron
β-Diketonato borate betaines 2 are readily accessible by the
ity in copper-catalyzed asymmetric Michael reactions with
reaction of β-dicarbonyl compounds 1 with BF3·OEt2. Reac- methyl vinyl ketone (8). But interestingly, exo- and endo-
tion of borates 2 with
L
-valine diethylamide (3a) gives almost
cyclic enamines are complementary with respect to stereo-
chemistry of the subsequent Michael reactions since they
give stereocenters with opposite configurations.
exclusively the exocyclic enamines 4 as the kinetic products.
In contrast, direct, acid catalyzed conversion of β-diketones
1 with the chiral auxiliary 3a yield the endocyclic enamines
5 as the thermodynamic products. Both enamines 4 and 5
give products with quaternary stereocenters in high selectiv-
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2003)
Introduction
2. Results and Discussion
2.1 Formation of Borate Betaines
The stereoselective formation of quaternary stereocenters
is still a challenging task and the definitive touchstone for
every asymmetric CϪC bond forming reaction.[1] The
Michael reaction, the conjugate or 1,4-addition of enolates
to acceptor-substituted olefins, is a fundamental CϪC
coupling reaction, being catalyzed not only by Brönstedt
bases,[2] but also by a number of metal compounds.[3] Estab-
lished methods for catalytic enantioselective Michael reac-
tions often cannot prove their efficiency if quaternary stere-
ocenters are the synthetic target.[4] In some cases, the use
of chiral auxiliaries turns out to give superior results.[5] Re-
cently, we have introduced a new procedure for the con-
struction of quaternary stereocenters at ambient tempera-
ture applying -valine diethylamide as the chiral auxiliary
and copper() as the catalyst.[6] β-Oxo esters and β-dike-
tones are typical substrates, which are initially converted
with the auxiliary to form enamines. However, a consider-
able regioselectivity problem in the enamine forming step is
observed when β-diketones are utilized as donors. Herein
we report the preparation of β-diketonatoboron difluorides
and their application as starting materials in the enamine
formation, resulting in considerable regioselectivity in this
step, at least in certain cases.
The boranuida cycles 2aϪ2g were prepared by simply
treating dicarbonyl compounds 1aϪ1g with a small excess
of BF3·OEt2 at ambient temperature in an inert solvent
(CH2Cl2) (Scheme 1).[7] The solid compounds (apart from
2e) can be recrystallized from Et2O to yield analytically
pure, air-stable materials. The optically active derivative 2e
1
was obtained as an oil, which was pure by H NMR spec-
troscopy. All products 2aϪ2g have been fully characterized
spectroscopically.[8] 19F NMR resonances appear in the
range of δ ϭ Ϫ149 to Ϫ140 ppm. The quaternary 13C res-
onances in the sp2-region have been assigned by 2D-1H,13C
[a]
Institut für Organische Chemie der Universität Stuttgart,
Pfaffenwaldring 55, 70569 Stuttgart, Germany,
Fax: (internat.) ϩ49-(0)711-6854269
E-mail: jchr@po.uni-stuttgart.de
Scheme 1. Formation of oxonia-boranuida-betaines 2 from β-dicar-
bonyl compounds 1; reagents and conditions: (a) 1. CH2Cl2, 23 °C,
16 h, 2. crystallization; for 2e: yield without crystallization
Eur. J. Org. Chem. 2003, 2845Ϫ2853
DOI: 10.1002/ejoc.200300191
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2845

J. Christoffers, B. Kreidler, S. Unger, W. Frey
FULL PAPER
correlation for all products 2 (COLOC experiments). In the
In all solved structures the boranuida cycle is planar. In
cases of 2b, 2c, 2d, and 2f single crystals were obtained be- diketone-derived cycles 2b, c both the CϪO and the CϪC
ing suitable for X-ray structure analysis. While the structure bond length of the π-system are identical within the exper-
of 2b has already been published,[9] ORTEP representations imental error. The CϪC bond lengths represent a bonding
of betaines 2c, 2d and 2f[10] are given in Figure 1.
order of about 1.5, which can be rationalized by an average
of both mesomeric structures 2 and 2Ј shown in Figure 2.
In contrast, the lactam and ester derived betaines 2d and 2f
exhibit significantly different CϪO and CϪC bond lengths,
thus, their bonding situation is represented only by one of
the two structures 2 and 2Ј (2 for 2d, 2Ј for 2f). Obviously, a
ketene semi aminal/acetal structure is avoided in these cases.
Figure 2. Mesomeric structures of betaines 2
2.2 Reaction with Amines
The regioselectivity of enamine formation from α-acetyl
cycloalkanones was reported to be dependent on the ring
size.[11] From our work, however, an endocyclic enamine 5
is known to be the thermodynamically favoured product in
the cases of the α-acetylcyclopentanone (1a) and -hexanone
(1b) (vide infra). Therefore we were pleased to find that
boranuida cycles 2a and 2b smoothly reacted with the
auxiliary 3a to form almost exclusively the exocyclic enam-
ines 4a and 4b as products. For the seven-membered ring
2c, however, a mixture of exo- and endocyclic enamine (4c/
5c, 70:30) was obtained (Scheme 2).
Figure 1. Molecular structures of 2c (a), 2d (b), 2f (c) in the solid
˚
state (ORTEP-representations); selected bond lengths (A): 2c:
1.2964(16) (C1ϪO1), 1.3927(18) (C1ϪC2), 1.386(2) (C2ϪC3),
1.2999(18) (C3ϪO3); 2d: 1.305(3) (C1ϪO1), 1.423(4) (C1ϪC2), Scheme 2. Regioselective formation of exocyclic enamines 4 with
1.351(4) (C2ϪC3), 1.323(3) (C3ϪO3); 2f: 1.333(4) (C1ϪO1), the chiral auxiliary -valine diethylamide (3a); starting material 2c
1.357(4) (C1ϪC2), 1.407(4) (C2ϪC3), 1.293(3) (C3ϪO3)
(5%) was recovered in case of 4c/5c
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Eur. J. Org. Chem. 2003, 2845Ϫ2853

Regioselective Enamine Formation from Oxonia-Boranuida-Betaines
FULL PAPER
Compounds 2f and 2g, derived from β-oxo esters 1f and
1g, also react with primary amines such as benzylamine
(3b). In contrast to the β-diketonato cogeners enamines are
not formed as the products. The boronato difluoride moiety
activates the ester carbonyl function towards an attack of
the nucleophilic amine and the substitution products 6a and
6b are obtained. This reactivity can be explained by the fact
that only the enol-borate resonance structure is found in
the solid state as depicted in Scheme 3. Interestingly, the
boronato moiety is retained during this conversion. Com-
pounds 6a and 6b are found to be stable towards air and
moisture and can even be chromatographed on SiO2 with-
out significant decomposition. In order to cleave the bo-
ronato chelate prolonged conversion with half concd. hy-
drochloric acid is required as shown for the formation of
amide 7 from 6b (Scheme 3). Lactam-derived 2d also reacts
with -valine amide 3a, however, the yield of enamine 4d
(Scheme 4) is not superior to the one achieved by direct,
acid-catalyzed conversion of lactam 1d with 3a (48%). In
Scheme 4. Reaction of exocyclic enamines 4 with methyl vinyl ke-
tone (8); reagents and conditions: (a) Cu(OAc)2·H2O (10 mol%), 8
(2Ϫ3 equiv.), acetone, 23 °C, 16 h; (b) HClϪH2O, 23 °C, 5 h; spiro-
cycles 10b and 10d were isolated only on an analytical scale
the formation of the heterocyclic enamine 4d a regioselectiv- spirocenter, imine 9b was hydrolytically cleaved and the spi-
ity problem is of course not observed. Very recently, in situ rocycle 10b analyzed by GLC on a chiral phase. Indeed,
formed β-diketonatoboron difluorides have been utilized this material 10b had an optical purity of 87% ee, which
for allylations.[12]
clearly relates to the 86% de of the parent imine 9b. Anal-
ogously, 9d was converted to 10d with Ͼ95% ee determined
by GLC on a chiral phase. Both spirocycles 10b and 10d
were prepared only on an analytical scale, but their identity
was without doubt proved by comparison with the racemic
materials rac-10b and rac-10d, which were synthesized on
larger scale to elucidate their constitutions and to develop
GLC conditions for baseline resolution of the enantiomers
(vide infra). Actually the 1,3-diketo constitution of 10b[13]
was confirmed by X-ray single crystal analysis,[9] whereas
the β-oxolactam structure of 10d was established by 2D-1H,
13C spectroscopy and by comparison with the regioisomeric
δ-oxolactam 12.
For comparison with these results we focused our atten-
tion in further studies on stereoselectivities and configura-
tions of the products obtained from the regioisomeric endo-
cyclic enamines 5a and 5b,[6b] which are accessible as the
thermodynamic products in acid-catalyzed conversions of
β-diketones 1a and 1b with -valine amide 3a (Scheme 5).
The Michael reaction with methyl vinyl ketone (8) gave the
open-chain 1,5-diketones 11a and 11b in good to excellent
Scheme 3. Reaction of oxonia-boranuida-betaines 2f, g with ben-
zylamine (3b); reagents and conditions: (a) 3b (1.2Ϫ20 equiv.),
CH2Cl2, 23 °C, 16 h; (b) HClϪH2O (6 mol/L), 23 °C, 16 h
2.3 Michael Reactions
The exocyclic enamines 4a, 4b and 4d were treated with selectivity (87% ee for 11a and 96% ee for 11b). In contrast
methyl vinyl ketone (8) in the presence of a catalytic amount to conversions of the exocyclic compounds 4a, b, d no spiro-
of Cu(OAc)2·H2O to give the spirocyclic imines 9a, 9b, and cyclic products were detected. The five-membered ring
9d as the only isolable, unique products. Interestingly, the product 11a could be analyzed directly by GLC on a chiral
Michael reaction did not stop at the stage of the open-chain phase, the homologue 11b, however, gave no sufficient base-
1,5-dicarbonyl products, but subsequent Robinson annu- line resolution. We therefore performed spirocyclization to
lation occurred. The auxiliary is retained in the product ent-10b,[6b] which turned out to be, as expected, the enanti-
since an imine moiety in a neopentyl environment exhibits omer of 10b obtained from exocyclic enamine 4b.
reasonable hydrolytic stability and therefore survives the
In summary, we conclude that control of endo- and exo-
workup procedure and purification by chromatography. cyclic enamine formations enables the complementary
Whereas only one diastereomer of lactam 9d is obtained preparation of either enantiomer of spirocycle 10a with
1
with a single signal set in the H NMR spectrum (Ͼ95% high selectivity applying the chiral auxiliary with the same
de), compounds 9a (57% de) and 9b (86% de) additionally absolute configuration.
1
show a minor diastereomer in H NMR spectra. To deter-
Finally, we mention our efforts to prepare racemic spiro-
mine whether this diastereomer is the epimer regarding the lactam rac-10d, since we had to tackle again an interesting
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J. Christoffers, B. Kreidler, S. Unger, W. Frey
FULL PAPER
available. BF3·OEt2 was purchased from Aldrich Chemical Co.
Spectroscopic data of 1c were identical with the literature.[15] The
following compounds were prepared according to literature pro-
cedures: 1c,[16] 1d,[17] 1e,[17] 3a,[6b] 5b,[6b] rac-11a,[18] and rac-11b.[19]
Column chromatography was carried out by using Merck SiO2 60
or Merck basic Alumina (act. I) with petroleum ether (PE, b.p.
40Ϫ60 °C) and ethyl acetate (EA) as eluents. 19F NMR spectra
were recorded on a Bruker ARX 300 (282 MHz) with TFA (δ19F ϭ
Ϫ77 ppm) as internal standard. 13C NMR multiplicities were deter-
mined with DEPT experiments or proton-coupled measurements,
carbonyl carbon resonances were assigned with COLOC experi-
ments. GC analysis was performed with
a HRGC 5300
(CarloϪErba Strumentazione) with FID, and a column Bondex
unα/β (20 m ϫ 0.3 mm) or Lipodex E (25 m ϫ 0.3 mm) with hydro-
gen carrier gas (0.4 bar).
General Procedure for the Preparation of Boranuida Compounds 2:
BF3·OEt2 (1.2 equiv.) was added to a solution of the respective β-
dicarbonyl compound 1aϪg (1 equiv.) in CH2Cl2 (3Ϫ7 mol/L) at
23 °C, and the mixture was then stirred for 16 h or 21 h (for 2d).
After removal of all volatile materials under high vacuum, the resi-
due was recrystallized twice from Et2O.
Scheme 5. Formation of endocyclic enamines 5 and subsequent
Michael reactions with methyl vinyl ketone (8); reagents and con-
ditions: (a) for 5a: toluene, 100 °C, 5 d, cat. HCl; for 5b: see ref.[6b]
;
(b) 1. Cu(OAc)2·H2O (5Ϫ10 mol%), 8 (3 equiv.), acetone, 23 °C,
16 h, 2. HClϪH2O (2 mol/L), 3 h, 23 °C; (c) concd. H2SO4 (10
equiv.), 0 °C, 4 h, 2. H2O (ice). Enamine 5a was isolated as a mix-
ture of 5a:4a, 87:13, while 5b was formed exclusively
3,3-Difluoro-5-methyl-4-oxa-2-oxonia-3-boranuidabicyclo[4.3.0]-
nona-1,5-diene (2a): According to the General Procedure, 1a
(2.00 g, 15.8 mmol) and BF3·OEt2 (2.70 g, 19.0 mmol) in CH2Cl2
(5 mL) were converted to yield 2a as a colorless solid (2.22 g,
regioselectivity problem. The open-chain precursor rac-11d
was available by copper-catalyzed conversion of donor 1d
with methyl vinyl ketone (8). Cyclization under standard
Robinson conditions (pyrrolidine, glacial acetic acid)[14] af-
forded the δ-oxolactam 12, being the ‘‘wrong’’ regioisomer
(Scheme 6). The constitution of 12 was established by the
3J(1H,13C) correlation of the methyl protons to the spiro
carbon atom in a 2D-1H,13C NMR experiment. The β-oxo-
1
12.7 mmol, 81%). M.p. 64 °C (58Ϫ60 °C[8c]). H NMR (300 MHz,
CDCl3): δ ϭ 2.04Ϫ2.16 (m, 2 H), 2.27 (s, 3 H), 2.68 (dd, J ϭ 7.6,
J ϭ 7.1 Hz, 2 H), 2.76 (t, J ϭ 8.0 Hz, 2 H) ppm. 13C{1H} NMR
(125 MHz, CDCl3): δ ϭ 20.44 (CH2), 22.72 (CH3), 25.58 (CH2),
34.90 (CH2), 113.09 (C), 187.36 (CϭO, endo), 199.55 (CϭO, exo)
ppm. 19F{1H} NMR (282 MHz, CDCl3): δ ϭ Ϫ141.32 (s) ppm. IR
(ATR): ν˜ ϭ 2920 (m), 2880 (m), 1706 (m), 1600 (s), 1526 (vs), 1380
(s), 1345 (s), 1310 (s), 1191 (s), 1150 (s) cmϪ1. MS (70 eV, EI):
lactam rac-10d was obtained under acidic conditions, and m/z (%) ϭ 174 (36) [Mϩ], 159 (100) [Mϩ Ϫ CH3], 131 (13) 118
its signal sets in 1H and 13C NMR spectra are isomorphous
(11). C7H9BF2O2 (173.96): calcd. C 48.33, H 5.22; found C 48.31,
3
to those of regioisomer 12, however, J(1H,13C) coupling
H 5.15.
constants are different and specifically fit to the consti-
tution of 10d shown in the Schemes.
3,3-Difluoro-5-methyl-4-oxa-2-oxonia-3-boranuidabicyclo[4.4.0]-
deca-1,5-diene (2b): According to the General Procedure, 1b (10.0 g,
71.3 mmol) and BF3·OEt2 (12.2 g, 85.6 mmol) in CH2Cl2 (10 mL)
were converted to yield 2b as colorless crystals (11.4 g, 61.0 mmol,
1
85%). M.p. 79 °C (79Ϫ79.6 °C[8a]). H NMR (300 MHz, CDCl3):
δ ϭ 1.75Ϫ1.85 (m, 4 H), 2.30 (s, 3 H), 2.38Ϫ2.41 (m, 2 H),
2.55Ϫ2.59 (m, 2 H) ppm. 13C{1H} NMR (125 MHz, CDCl3): δ ϭ
20.88 (CH2), 21.90 (CH2), 22.24 (CH3), 23.12 (CH2), 32.42 (CH2),
108.92 (C), 190.01 (CϭO, endo), 191.86 (CϭO, exo) ppm. 19F{1H}
NMR (282 MHz, CDCl3): δ ϭ Ϫ140.03 (s) ppm. IR (ATR): ν˜ ϭ
1583 (s), 1507 (vs), 1462 (m), 1405 (m), 1364 (s), 1350 (s), 1331 (s),
1304 (m), 1201 (m), 1138 (s), 1089 (m), 1041 (vs) cmϪ1. HRMS for
C8H11BF2O2 (70 eV, EI): calcd. 188.0820, found 188.0820.
C8H11BF2O2 (187.98): calcd. C 51.11, H 5.90; found C 51.08, H
5.84.
Scheme 6. Preparation of racemic spirolactam derivatives rac-10d
9,9-Difluoro-11-methyl-10-oxa-8-oxonia-9-boranuidabicyclo-
[5.4.0]undeca-7,11-diene (2c): According to the General Procedure,
and 12; reagents and conditions: (a) Cu(OAc)2·H2O (5 mol%), 8
(1.5 equiv.), acetone, 23 °C, 16 h; (b) 1. concd. H2SO4, 23 °C, 16 h,
1c (5.00 g, 32.4 mmol) and BF3·OEt2 (5.00 g, 35.6 mmol) in
CH2Cl2 (5 mL) were converted to yield 2c as colorless crystals
(6.09 g, 30.0 mmol, 93%). M.p. 86 °C. 1H NMR (300 MHz,
CDCl3): δ ϭ 1.62 (quint., J ϭ 5.5 Hz, 2 H), 1.71Ϫ1.87 (m, 4 H),
2.33 (s, 3 H), 2.45Ϫ2.49 (m, 2 H), 2.70Ϫ2.74 (m, 2 H) ppm.
13C{1H} NMR (75 MHz, CDCl3): δ ϭ 22.51 (CH3), 24.30 (CH2),
26.05 (CH2), 27.90 (CH2), 31.24 (CH2), 38.53 (CH2), 113.73 (C),
2. H2O (ice); (c) pyrrolidine (0.5 equiv.), glacial acetic acid (0.5
equiv.), 23 °C, 16 h
Experimental Section
General: Melting points were measured on a Büchi 510 and are
uncorrected. Starting materials 1a, 1b and 1f are commercially 188.71 (CϭO, exo), 196.71 (CϭO, endo) ppm. 19F{1H} NMR
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Regioselective Enamine Formation from Oxonia-Boranuida-Betaines
FULL PAPER
(282 MHz, CDCl3): δ ϭ Ϫ141.45 (s) ppm. IR (ATR): ν˜ ϭ 2939 CDCl3): δ ϭ 1.53 (quint., J ϭ 5.6 Hz, 2 H), 1.67Ϫ1.72 (m, 2 H),
(m), 1574 (s), 1510 (vs), 1440 (s), 1370 (s), 1349 (s), 1308 (m), 1216 1.75Ϫ1.79 (m, 2 H), 2.39Ϫ2.43 (m, 2 H), 2.61Ϫ2.65 (m, 2 H), 4.07
(m), 1179 (s), 1149 (vs), 1055 (s), 1028 (vs) cmϪ1. MS (70 eV, EI):
(s, 3 H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ ϭ 22.69 (CH2),
24.20 (CH2), 27.15 (CH2), 31.53 (CH2), 37.80 (CH2), 55.96 (CH3),
m/z (%) ϭ 202 (100) [Mϩ], 187 (80) [Mϩ Ϫ CH3], 183 (47), 174
(30), 159 (71), 132 (28), 118 (11), 93 (29). C9H13BF2O2 (202.01): 99.15 (C), 173.75 (C), 190.60 (C) ppm. 19F{1H} NMR (282 MHz,
calcd. C 53.51, H 6.49; found C 53.28, H 6.45.
CDCl3): δ ϭ Ϫ142.98 (s) ppm. IR (ATR): ν˜ ϭ 2929 (m), 2859 (m),
1597 (s), 1498 (vs), 1388 (m), 1368 (s), 1042 (vs) cmϪ1. MS (70 eV,
EI): m/z (%) ϭ 218 (62) [Mϩ], 199 (20) [Mϩ Ϫ F], 176 (10), 138
(100), 110 (75), 82 (36), 67 (21), 55 (48). C9H13BF2O3 (218.01):
calcd. C 49.58, H 6.01; found C 49.39, H 6.01.
10-Benzyl-3,3-difluoro-5-methyl-10-aza-3-boranuida-4-oxa-2-oxo-
niabicyclo[4.4.0]deca-1,5-diene (2d): According to the General Pro-
cedure, 1d (231 mg, 1.00 mmol) and BF3·OEt2 (156 mg, 1.10 mmol)
in CH2Cl2 (1 mL) were converted. After all volatile materials were
removed at 50 °C under high vacuum, crystallization from CH2Cl2
General Procedure for the Preparation of Exocyclic Enamines 4: To
gave 2d (245 mg, 0.878 mmol, 88%) as a colorless solid. M.p. 119 a stirred solution of the respective diketonatoboron difluoride 2 in
1
°C. H NMR (500 MHz, CDCl3): δ ϭ 1.89 (quint., J ϭ 6.4 Hz, 2
H), 2.12 (s, 3 H), 2.47 (t, J ϭ 6.4 Hz, 2 H), 3.36 (t, J ϭ 6.4 Hz, 2 H), After being warmed up to 23 °C, the solution was stirred for a
4.74 (s, 2 H), 7.30Ϫ7.41 (m, 5 H) ppm. 13C{1H} NMR (125 MHz,
further 16 h. The solvent was evaporated and the residue purified
MeCN was added dropwise -valine diethylamide (3a) at 0 °C.
CDCl3): δ ϭ 20.19 (CH3), 21.15 (CH2), 21.93 (CH2), 47.26 (CH2), by column chromatography (Al2O3, PE/EA).
51.66 (CH2), 92.84 (C), 128.31 (CH), 128.33 (CH), 128.97 (CH),
N-[1-(2-Oxocyclopentylidene)ethyl]-L-valine Diethylamide (4a): Ac-
134.27 (C), 164.99 (C), 173.73 (C) ppm. 19F{1H} NMR (282 MHz,
CDCl3): δ ϭ Ϫ146.79 (s) ppm. IR (ATR): ν˜ ϭ 1598 (s), 1577 (s),
1493 (s), 1453 (m), 1437 (m), 1310 (s), 1219 (m), 1134 (s), 1072 (s),
1051 (vs), 1004 (vs), 975 (m), 924 (m), 896 (m), 870 (s), 751 (m),
728 (m), 702 (m) cmϪ1. C14H16BF2NO2 (279.09): calcd. C 60.19,
H 5.78, N 5.02; found C 60.23, H 5.75, N 4.94.
cording to the General Procedure, from 2a (100 mg, 0.57 mmol)
and 3a (295 mg, 1.71 mmol) in MeCN (2 mL) and chromatography
[PE/EA, 1:1, Rf(SiO2) ϭ 0.11] was obtained 4a as colorless crystals
(149 mg, 0.53 mmol, 93%), [α]2D0 ϭ ϩ220 (c ϭ 7.7, CDCl3). M.p.
72 °C. 1H NMR (500 MHz, CDCl3): δ ϭ 1.02 (d, J ϭ 7.0 Hz, 3
H), 1.04 (d, J ϭ 7.0 Hz, 3 H), 1.12 (t, J ϭ 7.0 Hz, 3 H), 1.22 (t,
(1ЈR,2ЈS,5ЈR)-3,3-Difluoro-5-menthyloxy-4-oxa-2-oxonia-3-bor- J ϭ 7.0 Hz, 3 H), 1.83 (quint., J ϭ 7.0 Hz, 2 H), 1.88 (s, 3 H), 2.10
anuidabicyclo[4.3.0]nona-1,5-diene (2e): According to the General
Procedure, 1e (500 mg, 1.88 mmol) and BF3·OEt2 (266 mg,
(oct., J ϭ 6.4 Hz, 1 H), 2.33 (t, J ϭ 7.9 Hz, 2 H), 2.52 (t, J ϭ
7.1 Hz, 2 H), 3.17Ϫ3.24 (m, 1 H), 3.28Ϫ3.35 (m, 1 H), 3.39Ϫ3.47
(m, 1 H), 3.53Ϫ3.60 (m, 1 H), 4.16 (dd, J ϭ 8.9, J ϭ 6.4 Hz, 1 H),
1.88 mmol) in CH2Cl2 (0.5 mL) were converted to yield 2e as a
1
brown oil (575 mg, 1.83 mmol, 97%, without recrystallization). H 10.67 (d, br., J ϭ 8.4 Hz, 1 H) ppm. 13C{1H} NMR (75 MHz,
NMR (300 MHz, CDCl3): δ ϭ 0.80 (d, J ϭ 6.9 Hz, 3 H), 0.91 (d, CDCl3): δ ϭ 12.88 (CH3), 14.62 (CH3), 16.39 (CH3), 17.81 (CH3),
J ϭ 7.0 Hz, 3 H), 0.94 (d, J ϭ 6.6 Hz, 3 H), 1.34 (t, J ϭ 7.1 Hz, 1
H), 1.49Ϫ1.59 (m, 2 H), 1.70Ϫ1.84 (m, 4 H), 1.97Ϫ2.13 (m, 4 H), 40.35 (CH2), 41.61 (CH2), 59.15 (CH), 103.25 (C), 156.38 (C),
2.55 (t, J ϭ 7.7 Hz, 2 H), 2.66 (t, J ϭ 8.0 Hz, 2 H), 5.04 (td, J ϭ 170.06 (C), 202.14 (C) ppm. IR (ATR): ν˜ ϭ 2961 (s), 2874 (m),
19.87 (CH3), 20.36 (CH2), 28.00 (CH2), 32.20 (CH), 39.15 (CH2),
10.8, J ϭ 4.5 Hz, 1 H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ ϭ 1628 (vs), 1572 (vs), 1432 (s), 1379 (m), 1339 (m), 1247 (vs), 1216
16.45 (CH3), 19.76 (CH2), 20.54 (CH3), 21.83 (CH3), 23.51 (CH2), (m), 1181 (m), 1125 (m), 1097 (m), 1070 (m) cmϪ1. HRMS for
24.13 (CH2), 26.59 (CH), 31.39 (CH), 33.82 (CH2), 33.86 (CH2), C16H28N2O2 (70 eV, EI): calcd. 280.2151, found 280.2153.
40.59 (CH2), 46.98 (CH), 81.37 (CH), 97.48 (C), 171.25 (C), 191.87 C16H28N2O2 (280.41): calcd. C 68.53, H 10.06, N 9.99; found C
(C) ppm. 19F{1H} NMR (282 MHz, CDCl3): δ ϭ Ϫ141.97 (s), 68.53, H 10.00, N 9.87.
Ϫ142.03 (s) ppm. IR (ATR): ν˜ ϭ 2955 (m), 2928 (m), 1613 (s),
N-[1-(2-Oxocyclohexylidene)ethyl]-L-valine Diethylamide (4b): Ac-
1529 (vs), 1478 (s), 1374 (m), 1216 (m), 1118 (s), 1043 (vs) cmϪ1
.
cording to the General Procedure, from 2b (150 mg, 0.79 mmol)
and 3a (408 mg, 2.38 mmol) in MeCN (1 mL) and chromatography
[PE/EA, 1:3, Rf(SiO2) ϭ 0.14] was obtained 4b as a pale yellow oil
(202 mg, 0.69 mmol, 87%), [α]2D0 ϭ ϩ180 (c ϭ 4.1, CHCl3). 1H
NMR (300 MHz, CDCl3): δ ϭ 1.04 (d, J ϭ 6.7 Hz, 3 H), 1.06 (d,
HRMS for C16H25BF2O2 (70 eV, EI): calcd. 314.1865, found
314.1862.
3,3-Difluoro-5-ethoxy-4-oxa-2-oxonia-3-boranuidabicyclo[4.4.0]-
deca-1,5-diene (2f): According to the General Procedure, 1f (3.00 g,
17.6 mmol) and BF3·OEt2 (2.50 g, 17.6 mmol) in CH2Cl2 (3 mL) J ϭ 6.7 Hz, 3 H), 1.12 (t, J ϭ 7.1 Hz, 3 H), 1.20 (t, J ϭ 7.1 Hz, 3
were converted to yield 2f as pale yellow crystals (2.43 g, H), 1.65Ϫ1.69 (m, 4 H), 1.89 (s, 3 H), 2.13 (q, J ϭ 7.3 Hz, 1 H),
1
11.1 mmol, 63%). M.p. 64 °C. H NMR (300 MHz, CDCl3): δ ϭ 2.31Ϫ2.33 (m, 4 H), 3.17Ϫ3.60 (m, 4 H), 4.16 (t, J ϭ 6.5 Hz, 1 H),
1.44 (t, J ϭ 7.2 Hz, 3 H), 1.66Ϫ1.80 (m, 4 H), 2.26 (t, J ϭ 6.2 Hz, 12.90 (d, br., J ϭ 7.7 Hz, 1 H) ppm. 13C{1H} NMR (75 MHz,
2 H), 2.44 (t, J ϭ 6.0 Hz, 2 H), 4.53 (q, J ϭ 7.1 Hz, 2 H) ppm. CDCl3): δ ϭ 12.85 (CH3), 14.50 (CH3), 14.94 (CH3), 18.02 (CH3),
13C{1H} NMR (125 MHz, CDCl3): δ ϭ 14.08 (CH3), 20.40 (CH2), 19.98 (CH3), 22.77 (CH2), 24.09 (CH2), 26.57 (CH2), 31.93 (CH),
21.34 (CH2), 21.57 (CH2), 31.16 (CH2), 66.17 (CH2), 95.49 (C),
38.01 (CH2), 40.40 (CH2), 41.59 (CH2), 60.45 (CH), 100.97 (C),
173.76 (C), 183.35 (C) ppm. 19F{1H} NMR (282 MHz, CDCl3): 162.51 (C), 169.94 (C), 194.76 (C) ppm. IR (ATR): ν˜ ϭ 2966 (m),
δ ϭ Ϫ142.76 (s) ppm. IR (ATR): ν˜ ϭ 2939 (m), 1604 (s), 1520 (vs),
1492 (vs), 1449 (s), 1374 (s), 1339 (vs), 1170 (s), 1041 (vs) cmϪ1
HRMS for C9H13BF2O3 (70 eV, EI): calcd. 218.0926, found
218.0926. C9H13BF2O3 (218.01): calcd. C 49.58, H 6.01; found C
49.17, H 5.96.
2931 (s), 2873 (m), 1642 (vs), 1590 (vs), 1557 (s), 1461 (m), 1272
(m) cmϪ1. HRMS for C17H30N2O2 (70 eV, EI): calcd. 294.2307,
found 294.2307.
.
N-[1-(2-Oxocycloheptylidene)ethyl]-L-valine Diethylamide (4c) and
N-(2-Acetyl-1-cycloheptenyl)- -valine Diethylamide (5c): According
L
9,9-Difluoro-11-methoxy-10-oxa-8-oxonia-9-boranuidabicyclo-
[5.4.0]undeca-7,11-diene (2g): According to the General Procedure,
1g (10.0 g, 58.4 mmol) and BF3·OEt2 (12.4 g, 87.6 mmol) in
CH2Cl2 (10 mL) were converted to yield 2g as colorless crystals
to the General Procedure, from 2c (1.00 g, 4.95 mmol) and 3a
(850 mg, 4.95 mmol) in MeCN (4 mL) and chromatography [PE/
EA, 2:1, Rf (SiO2) ϭ 0.11] was obtained a mixture 4c/5c as a yellow
oil (1.01 g, 3.29 mmol, 66%) in a ratio of 7:3 (determined from
1
(8.86 g, 40.6 mmol, 70%). M.p. 79 °C. 1H NMR (300 MHz, integrals of the NH protons in the H NMR).
Eur. J. Org. Chem. 2003, 2845Ϫ2853
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2849

J. Christoffers, B. Kreidler, S. Unger, W. Frey
FULL PAPER
4c: H NMR (300 MHz, CDCl3): δ ϭ 1.01 (d, J ϭ 6.7 Hz, 3 H), 1 H), 9.78 (d, br., J ϭ 9.5 Hz, 1 H) ppm. 13C{1H} NMR (75 MHz,
1
1.03 (d, J ϭ 7.8 Hz, 3 H), 1.11 (t, J ϭ 7.1 Hz, 3 H), 1.20 (t, J ϭ CDCl3): δ ϭ 12.90 (CH3), 14.70 (CH3), 17.64 (CH3), 19.80 (CH3),
7.1 Hz, 3 H), 1.58Ϫ1.85 (m, 6 H), 2.05Ϫ2.12 (m, 1 H), 2.35 (s, 3
21.38 (CH2), 28.09 (CH3), 30.15 (CH2), 32.19 (CH2), 32.47 (CH),
H), 2.46Ϫ2.52 (m, 2 H), 2.70Ϫ2.74 (m, 2 H), 3.13Ϫ3.58 (m, 4 H), 40.33 (CH2), 41.68 (CH2), 60.56 (CH), 105.35 (C), 164.48 (C),
4.11 (t, J ϭ 8.0 Hz, 1 H), 12.42 (d, br., J ϭ 8.0 Hz, 1 H) ppm. 170.01 (C), 193.67 (C) ppm. IR (ATR): ν˜ ϭ 2966 (s), 2936 (m),
13C{1H} NMR (75 MHz, CDCl3): δ ϭ 12.86 (CH3), 14.49 (CH3), 1624 (vs), 1555 (s), 1465 (m), 1282 (m) cmϪ1. HRMS for
15.85 (CH3), 18.00 (CH3), 19.84 (CH3), 22.53 (CH2), 25.10 (CH2), C16H28N2O2 (70 eV, EI): calcd. 280.2151, found 280.2154.
28.27 (CH2), 28.31 (CH2), 31.33 (CH2), 31.67 (CH), 40.43 (CH2),
5-(N-Benzylamino)-3,3-difluoro-4-oxa-2-oxonia-3-boranuidabi-
44.08 (CH2), 60.12 (CH), 105.88 (C), 159.61 (C), 170.23 (C), 200.81
cyclo[4.4.0]deca-1,5-diene (6a): 3b (295 mg, 2.75 mmol) was added
(C) ppm. 5c: 1H NMR (500 MHz, CDCl3): δ ϭ 0.92 (d, J ϭ 6.7 Hz,
dropwise to a solution of 2f (500 mg, 2.29 mmol) in CH2Cl2
3 H), 0.95 (d, J ϭ 6.8 Hz, 3 H), 1.13 (t, J ϭ 7.0 Hz, 3 H), 1.22 (t,
(1 mL), and the reaction mixture was stirred at 23 °C for 24 h.
J ϭ 7.1 Hz, 3 H), 1.49Ϫ1.55 (m, 2 H), 1.60Ϫ1.75 (m, 4 H), 1.97
Evaporation of all volatile materials under high vacuum and chro-
(q, J ϭ 6.9 Hz, 1 H), 2.02 (s, 3 H), 2.09Ϫ2.14 (m, 2 H), 2.48Ϫ2.52
matography (SiO2, PE/EA, 3:1, Rf ϭ 0.54) yielded 6a (481 mg,
(m, 2 H), 3.37 (q, J ϭ 7.2 Hz, 1 H), 3.38 (q, J ϭ 7.0 Hz, 1 H),
1.72 mmol, 75%) as a colorless solid. M.p. 141 °C. 1H NMR
3.45Ϫ3.52 (m, 2 H), 4.76 (dd, J ϭ 9.2, J ϭ 6.9 Hz, 1 H), 12.14 (d,
(300 MHz, CDCl3): δ ϭ 1.71Ϫ1.76 (m, 4 H), 2.08Ϫ2.12 (m, 2 H),
br., J ϭ 7.7 Hz, 1 H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ ϭ
2.37Ϫ2.41 (m, 2 H), 4.65 (d, J ϭ 5.7 Hz, 2 H), 5.87 (s, br., 1 H),
12.86 (CH3), 14.49 (CH3), 18.01 (CH3), 19.79 (CH3), 19.80 (CH3),
7.30Ϫ7.43 (m, 5 H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ ϭ
24.35 (CH2), 25.95 (CH2), 27.30 (CH2), 28.27 (CH2), 31.17 (CH2),
21.00 (CH2), 21.76 (CH2), 22.08 (CH2), 30.94 (CH2), 45.05 (CH2),
32.08 (CH), 38.48 (CH2), 41.65 (CH2), 59.68 (CH), 106.47 (C),
95.03 (C), 126.28 (CH), 128.57 (CH), 129.25 (CH), 136.25 (C),
167.93 (C), 170.18 (C), 193.86 (C) ppm. Isomeric mixture 4c/5c: IR
168.16 (C), 175.35 (C) ppm. 19F{1H} NMR (282 MHz, CDCl3):
(ATR): ν˜ ϭ 3310 (m, br.), 2969 (s), 2930 (vs), 2856 (m), 1643 (s),
δ ϭ Ϫ145.44 (s) ppm. IR (ATR): ν˜ ϭ 3395 (s), 1600 (vs), 1525
1584 (vs), 1512 (vs), 1438 (m), 1372 (m) cmϪ1. HRMS for
(vs), 1336 (m), 1195 (m), 1114 (s), 1027 (s) cmϪ1. C14H16BF2NO2
C18H32N2O2 (70 eV, EI): calcd. 308.2464, found 308.2461.
(279.09): calcd. C 60.25, H 5.78, N 5.02; found C 60.27, H 5.81,
N 4.93.
N-[1-(3-Benzyl-2-oxo-3-azacyclohexylidene)ethyl]-L-valine Diethyl-
amide (4d): Under exclusion of moisture and air, 1d (1.40 g, 11-(N-Benzylamino)-9,9-difluoro-10-oxa-8-oxonia-9-boranuidabi-
6.05 mmol) and 3a (1.04 g, 6.03 mmol) were added to molecular
sieves (5 g, 4 A) in dry toluene (3.6 mL). After addition of 2 drops
cyclo[5.4.0]undeca-7,11-diene (6b): 3b (4.9 g, 46 mmol) was added
dropwise to 2g (0.50 g, 2.3 mmol), and the reaction mixture was
stirred at 23 °C for 24 h. Evaporation of all volatile materials under
high vacuum and chromatography (SiO2, CH2Cl2, Rf ϭ 0.27)
yielded 6b (506 mg, 1.73 mmol, 75%) as a colorless solid. M.p. 107
°C. 1H NMR (500 MHz, CDCl3): δ ϭ 1.53Ϫ1.59 (m, 2 H),
1.64Ϫ1.69 (m, 2 H), 1.73Ϫ1.78 (m, 2 H), 2.19Ϫ2.21 (m, 2 H),
˚
of concd. H2SO4, the reaction mixture was stirred at 60 °C for 16 h,
then decanted, and the molecular sieves washed with toluene. The
combined organic layers were evaporated and the residue chroma-
tographed on Al2O3 (PE/EA, 2:1, Rf ϭ 0.38) to yield 4d (1.12 g,
2.89 mmol, 48%) as a colorless oil, [α]2D0 ϭ ϩ130 (c ϭ 4.05, CHCl3).
1H NMR (500 MHz, CDCl3): δ ϭ 1.02 (d, J ϭ 7.0 Hz, 3 H), 1.08 2.53Ϫ2.55 (m, 2 H), 4.60 (d, J ϭ 5.7 Hz, 2 H), 6.30 (s, br., 1 H),
(d, J ϭ 7.0 Hz, 3 H), 1.12 (t, J ϭ 7.0 Hz, 3 H), 1.18 (t, J ϭ 7.0 Hz,
3 H), 1.73Ϫ1.79 (m, 2 H), 1.86 (s, 3 H), 2.04Ϫ2.13 (m, 1 H), 2.40
7.30Ϫ7.39 (m, 5 H) ppm. 13C{1H} NMR (125 MHz, CDCl3): δ ϭ
23.99 (CH2), 24.38 (CH2), 26.62 (CH2), 30.99 (CH2), 36.81 (CH2),
(t, J ϭ 7.0 Hz, 2 H), 3.14 (t, J ϭ 5.7 Hz, 2 H), 3.23Ϫ3.31 (m, 1 45.21 (CH2), 98.11 (C), 128.27 (CH), 128.43 (CH), 129.08 (CH),
H), 3.40 (q, J ϭ 7.0 Hz, 2 H), 3.46Ϫ3.54 (m, 1 H), 4.03 (t, J ϭ 135.57 (C), 167.54 (C), 182.51 (C) ppm. 19F{1H} NMR (282 MHz,
7.6 Hz, 1 H), 4.59 (d, J ϭ 15.3 Hz, 1 H), 4.68 (d, J ϭ 15.3 Hz, 1
H), 7.19Ϫ7.30 (m, 5 H), 10.63 (d, J ϭ 8.3 Hz, 1 H) ppm. 13C{1H} 1592 (vs), 1520 (s), 1331 (m), 1222 (s), 1189 (m), 1027 (s) cmϪ1
NMR (125 MHz, CDCl3): δ ϭ 12.73 (CH3), 14.33 (CH3), 15.08 HRMS for C15H18BF2NO2 (70 eV, EI): calcd. 293.1399, found
(CH3), 18.95 (CH3), 19.93 (CH3), 23.33 (CH2), 26.20 (CH2), 31.99 293.1399. C15H18BF2NO2 (293.12): calcd. C 61.46, H 6.19, N 4.78;
CDCl3): δ ϭ Ϫ149.74 (s) ppm. IR (ATR): ν˜ ϭ 3371 (m), 2927 (m),
.
(CH), 40.19 (CH2), 41.27 (CH2), 46.89 (CH2), 49.63 (CH2), 61.65
(CH), 90.50 (C), 126.63 (CH), 127.73 (CH), 128.20 (CH), 138.68
(C), 154.56 (C), 169.03 (C), 171.27 (C) ppm. IR (ATR): ν˜ ϭ 2980
(vs), 2965 (vs), 2835 (m), 1650 (vs), 1610 (vs), 1600 (vs), 1485 (vs),
1460 (vs), 1450 (vs), 1430 (vs), 1412 (vs), 1380 (s), 1350 (vs), 1340
(vs), 1300 (vs), 1280 (vs), 1260 (vs), 1210 (s), 1195 (vs), 1170 (m),
found C 61.06, H 6.19, N 4.71.
N-Benzyl-2-oxocycloheptanecarboxamide (7): A solution of 6b
(40 mg, 0.14 mmol) in 1,4-dioxane (1 mL) and hydrochloric acid
(1 mL, 1 mol/L) was stirred at 23 °C for 16 h. The mixture was
extracted with CH2Cl2 (2 ϫ 5 mL), and the combined organic lay-
ers were dried (MgSO4). Evaporation of all volatile materials under
high vacuum and chromatography (SiO2, PE/EA, 1:1, Rf ϭ 0.29)
yielded 7 (29 mg, 0.11 mmol, 81%) as a colorless solid. M.p. 83Ϫ84
°C. 1H NMR (300 MHz, CDCl3): δ ϭ 1.39Ϫ1.45 (m, 1 H),
1.49Ϫ1.68 (m, 2 H), 1.85Ϫ1.96 (m, 4 H), 2.17Ϫ2.22 (m, 1 H),
2.55Ϫ2.61 (m, 2 H), 3.41 (dd, J ϭ 11.0, J ϭ 4.0 Hz, 1 H), 4.41 and
1125 (m), 1090 (m), 1070 (m), 1020 (m), 720 (s), 680 (s) cmϪ1
.
HRMS for C23H35N3O2 (70 eV, EI): calcd. 385.2729, found
385.2729.
N-(2-Acetyl-1-cyclopentenyl)-L-valine Diethylamide (5a): To a mix-
ture of β-diketone 1a (1.00 g, 7.90 mmol) and 3a (1.40 g,
8.20 mmol) in toluene (3 mL) were added 2 drops of concd. HCl.
After stirring for 5 d at 100 °C, no further conversion was detected
by GC. The mixture was evaporated and the residue chromato-
graphed (Al2O3, PE/EA, 3:1, Rf ϭ 0.18) to yield 1.45 g (5.14 mmol,
4.48 (AB part of an ABX system, JAB ϭ 14.9, JAX ϭ 5.5, JBX
ϭ
5.6 Hz, 2 H), 7.06 (s, br., 1 H), 7.24Ϫ7.38 (m, 5 H) ppm. 13C{1H}
NMR (75 MHz, CDCl3): δ ϭ 23.36 (CH2), 27.26 (CH2), 28.14
(CH2), 28.15 (CH2), 42.51 (CH2), 42.57 (CH), 58.21 (CH2), 126.39
(CH), 126.56 (CH), 127.65 (CH), 137.06 (C), 167.93 (C), 211.76
(C) ppm. IR (ATR): ν˜ ϭ 3362 (m, br.), 2923 (m), 2854 (m), 1702
(s), 1640 (vs), 1559 (m), 1452 (m), 1317 (m), 1028 (s) cmϪ1. HRMS
for C15H19NO2 (70 eV, EI): calcd. 245.1416, found 245.1416.
65%) of an isomeric mixture 5a/4a, (87:13) as a yellow oil. [α]2D0
ϭ
ϩ110 (c ϭ 3.1, CDCl3). 1H NMR (300 MHz, CDCl3): δ ϭ 0.98 (d,
J ϭ 6.8 Hz, 3 H), 1.00 (d, J ϭ 6.9 Hz, 3 H), 1.12 (t, J ϭ 7.1 Hz, 3
H), 1.19 (t, J ϭ 7.2 Hz, 3 H), 1.85 (dd, J ϭ 7.4, J ϭ 7.1 Hz, 2 H),
2.04 (s, 3 H), 2.06Ϫ2.13 (m, 1 H), 2.42Ϫ2.54 (m, 2 H), 2.59 (dd,
(R)-N-(9-Methyl-1-oxospiro[4.5]dec-8-en-7-ylidene)-
L-valine
Di-
J ϭ 7.3, J ϭ 5.9 Hz, 2 H), 3.11Ϫ3.62 (m, 4 H), 3.95 (t, J ϭ 9.6 Hz, ethylamide (9a):
A
mixture of 2a (200 mg, 0.71 mmol) and
2850  2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org
Eur. J. Org. Chem. 2003, 2845Ϫ2853

Regioselective Enamine Formation from Oxonia-Boranuida-Betaines
Cu(OAc)2·H2O (14 mg, 0.070 mmol) in acetone (1 mL) was stirred (CH3), 27.36 (CH2), 30.06 (CH2), 31.52 (CH), 32.39 (CH2), 39.44
FULL PAPER
at 23 °C for 1 h. After addition of 8 (100 mg, 1.43 mmol), the mix-
ture was stirred for a further 16 h. Evaporation of all volatile mate-
(CH2), 40.84 (CH2), 46.91 (C), 49.47 (C), 49.91 (CH2), 73.60 (CH),
115.19 (CH), 126.55 (CH), 127.25 (CH), 127.95 (CH), 137.41 (C),
rials and chromatography (Al2O3, EA, Rf ϭ 0.50) gave 9a (91 mg, 150.07 (C), 168.05 (C), 171.35 (C) 171.42 (C) ppm. IR (neat): ν˜ ϭ
0.27 mmol, 37%) as a pale yellow oil, 57% de (calcd. from integrals
of olefinic protons in the 1H NMR spectrum). Major diastereomer:
1H NMR (300 MHz, CDCl3): δ ϭ 0.84 (d, J ϭ 6.5 Hz, 3 H), 0.96
(d, J ϭ 6.8 Hz, 3 H), 1.03 (t, J ϭ 7.1 Hz, 3 H), 1.05 (t, J ϭ 7.1 Hz,
3 H), 1.18Ϫ1.23 (m, 4 H), 1.48Ϫ1.61 (m, 2 H), 1.67Ϫ1.81 (m, 1 H)
1.87 (s, 3 H), 2.10Ϫ2.23 (m, 4 H), 3.06Ϫ3.55 (m, 4 H), 3.88 (d, J ϭ
9.9 Hz, 1 H), 6.21 (sext., J ϭ 1.6 Hz, 1 H) ppm; minor dia-
2970 (m), 1640 (vs), 1635 (vs), 1450 (m), 1440 (m) cmϪ1. HRMS
for C27H39N3O2 (70 eV, EI): calcd. 437.3042, found 437.3042.
rac-3-Methylspiro[5.5]undec-2-ene-1,7-dione (rac-10b): To rac-11b
(997 mg, 4.74 mmol) was added dropwise concd. H2SO4 (2 mL),
and the reaction mixture was stirred at 0 °C for 4 h. After dilution
with ice (10 g), the mixture was extracted with CH2Cl2 (3 ϫ 5 mL).
The combined organic layers were washed with H2O (5 mL) and
dried (MgSO4). Evaporation of all volatile materials and chroma-
tography (SiO2, PE/EA, 5:1, Rf ϭ 0.24) yielded 10 (420 mg,
2.18 mmol, 46%) as colorless crystals. Spectroscopic data were in
accordance with the literature.[19] GC: Bondex unα/β, temperature
program: 3 min at 100 °C, then 1 K minϪ1 gradient to 130 °C, tR(S-
10b) ϭ 28.36 min, tR(R-10b) ϭ 29.11 min.
1
stereomer: H NMR (500 MHz, CDCl3): δ ϭ 0.78 (d, J ϭ 6.3 Hz,
3 H), 4.04 (d, J ϭ 8.9 Hz, 1 H), 6.15 (sext., J ϭ 1.3 Hz, 1 H) ppm.
All other signals overlap with resonances of the major dia-
stereomer. Major diastereomer: 13C{1H} NMR (75 MHz, CDCl3):
δ ϭ 12.50 (CH3), 14.10 (CH3), 18.62 (CH2), 19.53 (CH3), 20.57
(CH3), 24.24 (CH3), 28.26 (CH2), 29.93 (CH2), 31.83 (CH), 34.88
(CH2), 38.79 (CH2), 39.55 (CH2), 40.61 (CH2), 55.71 (C), 73.37
(CH), 115.32 (CH), 151.66 (C), 168.84 (C), 171.43 (C), 220.59 (C)
ppm. IR (ATR): ν˜ ϭ 2962 (s), 2933 (s), 2870 (m), 1702 (m), 1626
(vs), 1455 (s), 1379 (s), 1215 (s) cmϪ1. HRMS for C20H32N2O2
(70 eV, EI): calcd. 332.2464, found 332.2454.
(S)-3-Methylspiro[5.5]undec-2-ene-1,7-dione (10b): Cu(OAc)2·H2O
(68.0 mg, 0.34 mmol) and 8 (810 mg, 10.19 mmol) were added to a
solution of 4b (1.00 g, 3.40 mmol) in acetone (10 mL), and the reac-
tion mixture was stirred at 23 °C for 16 h. After evaporation of all
volatile materials, hydrochloric acid (5 mL, 2 mol/L) was added,
and the reaction mixture was stirred at 23 °C for 3 h. After extrac-
tion with CH2Cl2 (3 ϫ 5 mL), the combined organic layers were
dried (MgSO4) and the solvents evaporated. The residue was chro-
matographed (SiO2, PE/EA, 5:1) to give 10b in analytical amounts.
GC: Bondex unα/β, tR(S-10b) ϭ 28.24 min, 87% ee.
(R)-N-(3-Methyl-7-oxospiro[5.5]dec-2-en-1-ylidene)-
L-valine
Di-
ethylamide (9b): As described for 9a, enamine 4b (711 mg,
2.41 mmol), Cu(OAc)2·H2O (24 mg, 0.12 mmol) and 8 (508 mg,
7.24 mmol) were reacted in acetone (10 mL). Evaporation of all
volatile materials and chromatography (Al2O3, EA, Rf ϭ 0.78)
yielded 9b (380 mg, 1.09 mmol, 46%) as a yellow oil, 86% de (calcd.
from integrals of olefinic protons in the 1H NMR spectrum). Major
diastereomer: 1H NMR (300 MHz, CDCl3): δ ϭ 0.93Ϫ1.03 (m, 12
H), 1.58Ϫ1.72 (m, 4 H), 1.83 (s, 3 H), 1.93Ϫ2.04 (m, 1 H),
2.11Ϫ2.23 (m, 4 H), 2.30Ϫ2.49 (m, 4 H), 3.16Ϫ3.46 (m, 4 H), 3.96
(d, J ϭ 9.6 Hz, 1 H), 6.15 (sext., J ϭ 1.5 Hz, 1 H) ppm; minor
diastereomer: 1H NMR (300 MHz, CDCl3): δ ϭ 0.81 (d, J ϭ
6.4 Hz, 3 H), 4.07 (d, J ϭ 8.4 Hz, 1 H), 6.08 (sext., J ϭ 1.4 Hz, 1
H) ppm. All other signals overlap with resonances of the major
diastereomer. Major diastereomer: 13C{1H} NMR (75 MHz,
CDCl3): δ ϭ 12.47 (CH3), 14.12 (CH3), 19.58 (CH3), 20.80 (CH3),
21.02 (CH2), 23.85 (CH3), 26.64 (CH2), 27.71 (CH2), 31.09 (CH2),
31.86 (CH), 34.86 (CH2), 39.53 (CH2), 40.56 (CH2), 42.11 (CH2),
54.92 (C), 72.92 (CH), 115.34 (CH), 150.06 (C), 168.46 (C), 171.28
(C), 213.01 (C) ppm. IR (ATR): ν˜ ϭ 2966 (m), 2934 (s), 2969 (m),
1657 (s), 1637 (vs) cmϪ1. HRMS for C21H34N2O2 (70 eV, EI): calcd.
346.2621, found 346.2620.
(R)-3-Methylspiro[5.5]undec-2-ene-1,7-dione (ent-10b): ent-10b was
prepared as described for rac-10b (vide supra). GC: Bondex unα/
β, tR(R-10b) ϭ 28.90 min, 96% ee.
rac-2-Benzyl-9-methyl-2-azaspiro[5.5]undec-8-ene-1,7-dione
(rac-
10d): Ice-cold concd. H2SO4 (3 mL) was added to rac-11d (350 mg,
1.16 mmol), the reaction mixture was stirred at 23 °C for 16 h, and
then hydrolyzed with ice (11 g). The aqueous layer was extracted
with CH2Cl2 (3 ϫ 20 mL). The combined extracts were washed
with satd. NaHCO3 solution (10 mL), dried (MgSO4) and the sol-
vents evaporated. The residue was chromatographed (SiO2, PE/EA,
1:1, Rf ϭ 0.14) to yield rac-10d (79.1 mg, 0.279 mmol, 24%) as a
colorless oil. 1H NMR (500 MHz, CDCl3): δ ϭ 1.72Ϫ1.82 (m, 2
H), 1.90Ϫ1.99 (m, 2 H), 2.01 (s, 3 H), 2.22Ϫ2.28 (m, 1 H),
2.37Ϫ2.48 (m, 2 H), 2.90Ϫ2.97 (m, 1 H), 3.20Ϫ3.27 (m, 1 H),
3.28Ϫ3.35 (m, 1 H), 4.50 (d, J ϭ 14.8 Hz, 1 H), 4.86 (d, J ϭ
14.8 Hz, 1 H), 5.90 (sext., J ϭ 1.2 Hz, 1 H), 7.28Ϫ7.40 (m, 5 H)
ppm. 13C{1H} NMR (125 MHz, CDCl3): δ ϭ 19.01 (CH2), 24.59
(CH3), 28.07 (CH2), 29.91 (CH2), 32.64 (CH2), 47.56 (CH2), 50.88
(CH2), 53.00 (C), 125.25 (CH), 127.57 (CH), 128.14 (CH), 128.99
(CH), 137.50 (C), 161.74 (C), 170.56 (C), 199.12 (C) ppm. IR
(ATR): ν˜ ϭ 1661 (vs), 1626 (vs), 1492 (m), 1452 (m), 1436 (m),
1355 (m), 1284 (m), 1220 (m), 1290 (s) cmϪ1. HRMS for
C18H21NO2 (70 eV, EI): calcd. 283.1572, found 283.1572. GC: Bon-
dex unα/β, temperature program: 3 min at 150 °C, then 2.5 K
minϪ1 gradient to 220 °C, tR(S-10d) ϭ 30.94 min, tR(R-10d) ϭ
31.06 min.
(S)-N-(8-Benzyl-3-methyl-7-oxo-8-azaspiro[5.5]undec-2-en-1-
ylidene)-L-valine Diethylamide (9d): Cu(OAc)2·H2O (46.4 mg,
0.232 mmol) and 8 (245 mg, 3.50 mmol) were added to a solution
of 4d (900 mg, 2.33 mmol) in acetone (4 mL), and the reaction mix-
ture was stirred at 23 °C for 16 h. After evaporation of all volatile
materials, the residue was chromatographed [SiO2, gradient elution
from PE/EA, 2:1 to EA, Rf (SiO2, PE/EA, 1:1) ϭ 0.29] to give 9d
(375 mg, 0.859 mmol, 37%) as a yellow oil, [α]2D0 ϭ ϩ115 (c ϭ 4.15,
1
CHCl3). H NMR (500 MHz, CDCl3): δ ϭ 0.93 (d, J ϭ 6.4 Hz, 3
H), 1.02 (t, J ϭ 7.0 Hz, 3 H), 1.04 (t, J ϭ 7.0 Hz, 3 H), 1.06 (d,
J ϭ 6.4 Hz, 3 H), 1.64Ϫ1.73 (m, 2 H), 1.76 (ddd, J ϭ 13.4, J ϭ
5.1, J ϭ 2.2 Hz, 1 H), 1.89 (s, 3 H), 2.02Ϫ2.34 (m, 5 H), 2.76 (ddd,
(S)-2-Benzyl-9-methyl-2-azaspiro[5.5]undec-8-ene-1,7-dione (10d):
J ϭ 13.4, J ϭ 12.1, J ϭ 6.4 Hz, 1 H), 3.05Ϫ3.14 (m, 1 H), Hydrochloric acid (1.5 mL, 3 mol/L) was added to a solution of 9d
3.16Ϫ3.26 (m, 2 H), 3.27Ϫ3.32 (m, 1 H), 3.34Ϫ3.42 (m, 1 H), (99.0 mg, 0.226 mmol) in acetone (1 mL), and the reaction mixture
3.68Ϫ3.79 (m, 1 H), 3.85 (d, J ϭ 15.3 Hz, 1 H), 3.92 (d, J ϭ was stirred at 23 °C for 20 h. After extraction with CH2Cl2 (3 ϫ
10.2 Hz, 1 H), 5.43 (d, J ϭ 15.3 Hz, 1 H), 6.26 (s, 1 H), 7.25Ϫ7.45 2 mL), the combined organic layers were washed with NaHCO3
(m, 5 H) ppm. 13C{1H} NMR (125 MHz, CDCl3): δ ϭ 12.36
solution (1 mL), dried (MgSO4) and the solvents evaporated. The
(CH3), 14.00 (CH3), 17.84 (CH2), 19.32 (CH3), 20.95 (CH3), 23.86 residue was chromatographed [SiO2, gradient elution from PE/EA,
Eur. J. Org. Chem. 2003, 2845Ϫ2853
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2851

J. Christoffers, B. Kreidler, S. Unger, W. Frey
FULL PAPER
Table 1. X-ray single-crystal analysis data for compounds 2c, 2d, and 2f
2c
2d
2f
Empirical formula
Formula mass (g molϪ1
Crystal system
C9H13BF2O2
202.00
monoclinic
P21/n
7.8825(10)
10.5116(13)
11.8363(11)
90
92.324(8)
90
4
979.9(2)
1.369
293
C14H16BF2NO2
279.09
monoclinic
P21/c
14.5604(5)
9.3357(5)
10.3842(4)
90
101.586(4)
90
C9H13BF2O3
218.00
monoclinic
P21/c
8.9963(5)
11.9601(5)
10.2611(6)
90
109.618(4)
90
4
1039.97(9)
1.392
293
)
Space group
˚
a (A)
˚
b (A)
˚
c (A)
α (deg)
β (deg)
γ (deg)
Z
4
3
˚
V (A )
1382.78(10)
1.341
293
1.54178
0.893
0.2551
dcalcd. (g cmϪ3
T (K)
)
˚
λ (A)
0.71073
0.117
0.1324
0.0527
1.035
1.54178
1.064
0.2622
0.0758
1.156
µ (mmϪ1
)
Rw (F2)
R(F) [I Ͼ 2σ(I)]
0.0721
1.151
Goodness-of-fit on F2
2:1 to EA, Rf (PE/EA) ϭ 0.14] to yield 10d in analytical amounts 14.6 Hz, 1 H), 7.23Ϫ7.34 (m, 5 H) ppm. 13C{1H} NMR (125 MHz,
only. GC: Bondex unα/β, tR(S-10d) ϭ 30.94 min, Ͼ95% ee.
CDCl3): δ ϭ 19.65 (CH2), 26.79 (CH3), 29.25 (CH2), 29.26 (CH2),
29.99 (CH3), 39.10 (CH2), 47.39 (CH2), 50.65 (CH2), 59.14 (C),
127.54 (CH), 128.07 (CH), 128.67 (CH), 136.94 (C), 169.58 (C),
206.99 (C), 207.97 (C) ppm. IR (ATR): ν˜ ϭ 1714 (vs), 1633 (vs),
1494 (m), 1453 (m), 1356 (s), 1168 (m) cmϪ1. HRMS for
C18H23NO3 (70 eV, EI): calcd. 301.1678, found 301.1676.
(S)-2-Acetyl-2-(3-oxobutyl)cyclopentanone (11a): Cu(OAc)2·H2O
(10 mg, 0.05 mmol) was added to 5a (150 mg, 0.53 mmol) in ace-
tone (2 mL), and the reaction mixture was stirred at 23 °C for 1 h.
Then 8 (112 mg, 1.60 mmol) was added, and the mixture stirred at
23 °C for 20 h. After all volatile materials were evaporated, hydro-
chloric acid (2 mL, 2 mol/L) was added to the residue and stirred
for 3 h. The reaction mixture was extracted with CH2Cl2 (3 ϫ
5 mL), dried (MgSO4) and concentrated. Chromatography on SiO2
with PE/EA, 1:1 (Rf ϭ 0.34) gave 11a (36 mg, 0.18 mmol, 35%) as a
pale yellow oil. GC: Lipodex E, temperature program: 20 K minϪ1
gradient from 40 °C to 100 °C, then 120 min isothermic, finally 1 K
minϪ1 gradient to 120 °C, tR(S-11a) ϭ 156.22 min, tR(R-11a) ϭ
157.46 min, 87% ee.
2-Benzyl-7-methyl-1,9-dioxo-2-azaspiro[5.5]undec-7-ene (12): To
rac-11d (200 mg, 0.66 mmol) were successively and dropwise added
pyrrolidine (40 mg, 0.56 mmol) and glacial acetic acid (34 mg,
0.56 mmol), the reaction mixture stirred at 23 °C for 16 h, and then
directly chromatographed on SiO2 (EA, Rf ϭ 0.36) to give 12
(170 mg, 0.59 mmol, 89%) as a yellow oil. 1H NMR (500 MHz,
CDCl3): δ ϭ 1.86Ϫ2.09 (m, 4 H), 1.94 (s, 3 H), 2.17 (ddd, J ϭ
13.5, J ϭ 5.0, J ϭ 3.8 Hz, 1 H), 2.43 (ddd, J ϭ 17.5, J ϭ 13.0, J ϭ
4.9 Hz, 1 H), 2.48 (ddd, J ϭ 17.5, J ϭ 5.3, J ϭ 3.8 Hz, 1 H), 2.61
(dddd, J ϭ 13.4, J ϭ 13.1, J ϭ 5.4, J ϭ 1.1 Hz, 1 H), 3.24Ϫ3.37
(m, 2 H), 4.55 (d, J ϭ 14.6 Hz, 1 H), 4.71 (d, J ϭ 14.6 Hz, 1 H),
5.93 (q, J ϭ 1.4 Hz, 1 H), 7.25Ϫ7.34 (m, 5 H) ppm. 13C{1H} NMR
(125 MHz, CDCl3): δ ϭ 19.83 (CH2), 20.82 (CH3), 28.72 (CH2),
31.36 (CH2), 32.44 (CH2), 47.53 (C), 48.27 (CH2), 50.94 (CH2),
127.65 (CH), 128.21 (CH), 128.63 (CH), 128.74 (CH), 137.02 (C),
163.63 (C), 171.79 (C), 197.82 (C) ppm. IR (ATR): ν˜ ϭ 1665 (s),
1620 (vs), 1492 (m), 1452 (m), 1352 (m), 1265 (m), 1232 (m), 1196
(s), 737 (m), 608 (m) cmϪ1. HRMS for C18H21NO2 (70 eV, EI):
calcd. 283.1572, found 283.1572.
(S)-2-Acetyl-2-(3-oxobutyl)cyclohexanone (11b): Cu(OAc)2·H2O
(13.4 mg, 0.07 mmol) was added to 5b (395 mg, 1.34 mmol) in ace-
tone (5 mL), and the reaction mixture was stirred at 23 °C for 1 h.
Then 8 (212 mg, 2.68 mmol) was added, and the mixture stirred at
23 °C for 16 h. After all volatile materials were evaporated, hydro-
chloric acid (5 mL, 0.5 mol/L) was added to the residue and stirred
for 1 h. The reaction mixture was extracted with CH2Cl2 (3 ϫ
5 mL), dried (MgSO4) and concentrated. Chromatography on SiO2
with PE/EA, 1:1 (Rf ϭ 0.42) gave 11b (188 mg, 0.89 mmol, 67%)
as a colorless oil, 96% ee (determined by GLC after derivatization
to 10).
Single-Crystal X-ray Analysis: Single-crystal X-ray diffraction data
were collected for difluoroborates 2c, 2d and 2f (Table 1). For each
structure the data were collected either on a Nicolet P3 dif-
fractometer by using a graphite monochromator with Mo-Kα radi-
rac-3-Acetyl-1-benzyl-3-(3-oxobutyl)-2-piperidone
(rac-11d):
Cu(OAc)2·H2O (10 mg, 0.050 mmol) and 8 (105 mg, 1.50 mmol)
were added to a solution of 1d (231 mg, 1.00 mmol) in acetone
(1 mL), and the reaction mixture was stirred at 23 °C for 16 h. All
volatile materials were removed under vacuum, and the residue was
chromatographed on Al2O3 (PE/EA, 1:1, Rf ϭ 0.37) to yield rac-
11d (255 mg, 0.85 mmol, 85%) as a colorless oil. 1H NMR
(500 MHz, CDCl3): δ ϭ 1.56 (ddd, J ϭ 13.3, J ϭ 9.5, J ϭ 3.5 Hz,
1 H), 1.65Ϫ1.74 (m, 1 H), 1.79Ϫ1.87 (m, 1 H), 2.11 (s, 3 H),
2.12Ϫ2.19 (m, 3 H), 2.21 (s, 3 H), 2.47 (ddd, J ϭ 17.8, J ϭ 9.5,
˚
ation (λ ϭ 0.71073 A) (2c) or on a Siemens P4 diffractometer by
˚
using Cu-Kα radiation (λ ϭ 1.54178 A). The structures were solved
by direct methods and refined[20] against F2.
Acknowledgments
J ϭ 6.0 Hz, 1 H), 2.56 (ddd, J ϭ 17.8, J ϭ 9.5, J ϭ 6.0 Hz, 1 H), This work was generously supported by the Deutsche Forschungs-
3.19Ϫ3.27 (m, 2 H), 4.40 (d, J ϭ 14.6 Hz, 1 H), 4.76 (d, J ϭ gemeinschaft and the Fonds der Chemischen Industrie. B. K.
2852
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2003, 2845Ϫ2853

Regioselective Enamine Formation from Oxonia-Boranuida-Betaines
FULL PAPER
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www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2853