Synthesis of densely substituted trans-configured 4-acylated piperidine-2,4-diones as 3:1 Adducts of imines and ketenes

Article abstract of DOI:10.1021/jo100709y

An operationally simple method is described to form densely substituted diastereomerically pure trans-configured and potentially biologically interesting 5,6-dihydropyridone derivatives as 3:1 adducts of ketenes formed in situ from acyl bromides and aromatic imines.

Full text of DOI:10.1021/jo100709y

pubs.acs.org/joc
SCHEME 1. Proposed Formation of Piperidine-2,4-diones 4 as
2:1 Adducts of Dimethylketene (1) and Imines 2 As Reported by
Synthesis of Densely Substituted Trans-Configured
4-Acylated Piperidine-2,4-diones as 3:1 Adducts of
Imines and Ketenes
Staudinger
ꢀ
Jose Cabrera, Tina Hellmuth, and Rene Peters*
ꢀ
Institut fu€r Organische Chemie, Universita€t Stuttgart,
Pfaffenwaldring 55, D-70569 Stuttgart, Germany
observed that either a β-lactam or the 2:1 adduct can be
obtained in excess by variation of the reaction conditions.5
He concluded that a common 1,4-dipolar intermediate 6 is
involved6 that can either cyclize to form a β-lactam or undergo
a cycloaddition with a second ketene molecule.
rene.peters@oc.uni-stuttgart.de
Received April 13, 2010
In contrast to disubstituted ketenes, the parent ketene,
prepared in situ from acetyl chloride (7, 2 equiv), provided
1,3-oxazin-4-ones 9 (Scheme 2). This was explained by the
formation of diketene as the reactive intermediate and cata-
lysis by NEt3.7
During our ongoing investigations into the cycloadditions
of ketenes or related reactive species,8 we observed that acyl
bromides preferentially formed diastereomerically pure 3:1
adducts with aromatic imines and that piperidine-2,4-dione
products, related to those initially proposed by Staudinger,
are apparently intermediates in their formation.9 As a model
system we investigated the reaction of propionyl bromide
(11) and PMP-protected imine 10a (PMP = p-MeO-C6H4).
The ratio of 1:1, 2:1, and 3:1 adducts 12a, 13a, and 14a
mainly depended on the amounts of 11 and iPr2NEt and the
reaction temperature (Table 1).
An operationally simple method is described to form
densely substituted diastereomerically pure trans-config-
ured and potentially biologically interesting 5,6-dihydro-
pyridone derivatives as 3:1 adducts of ketenes formed in
situ from acyl bromides and aromatic imines.
An excess of propionyl bromide was required to obtain a
useful imine conversion. Use of 3 equiv of both 11 and
iPr2NEt at -50 °C resulted in only moderate conversion
(Table 1, entry 1). The product mixture contained 42% of the
known β-lactam 12a10 and 58% of piperidine-2,4-dione 13a,
while the 3:1 adduct 14a was not observed. Increasing the
amount of acyl bromide led to improved conversion and the
formation of 14a as the major product (entries 2 and 6). In
contrast, at 0 °C β-lactam 12a was formed with high selec-
tivity and 14a was detected only in trace amounts (entry 3).
A hundred years ago, Staudinger et al. reported that
benzaldehyde derived imines 2 carrying an N-Bn or N-Me
substituent behaved differently from aromatic N-aryl imines
on treatment with dimethylketene (1).1 In addition to the
expected β-lactam2 products 3 they observed the formation
of a product in which two ketene3 units were incorporated
and described them as piperidine-2,4-diones 4 (Scheme 1).
Similar 2:1 adducts were also reported by Staudinger for
quinoline.1
Half a century later reinvestigation by the Tennessee
Eastman Company (Martin, Hoyle, and Brannock) revealed
that the composition had been misassigned and that the 2:1
adducts are in fact 1,3-oxazin-6-ones 5 (Figure 1).4 Huisgen
later reported the related product with diphenylketene and
(6) Cossio, F. P.; Arrieta, A.; Sierra, M. A. Acc. Chem. Res. 2008, 41, 925.
(7) (a) Maujean, A.; Chuche, J. Tetrahedron Lett. 1976, 17, 2905.
(b) Formation of a piperidine-2,4-dione as side product, using dimeric tert-
butylcyanoketene: Schaumann, E.; Mrotzek, H. Chem. Ber. 1978, 111, 661.
(c) Daneshtalab, M.; Micetich, R. G.; Forghanifar, S. Heterocycles 1988,
27, 713.
(8) (a) Tiseni, P. S.; Peters, R. Chem.;Eur. J. 2010, 16, 2503. (b) Zajac,
M.; Peters, R. Chem.;Eur. J. 2009, 15, 8204. (c) Kull, T.; Peters, R. Angew.
Chem., Int. Ed. 2008, 47, 5461. (d) Tiseni, P. S.; Peters, R. Org. Lett. 2008, 10,
2019. (e) Kull, T.; Peters, R. Adv. Synth. Catal. 2007, 349, 1647. (f) Tiseni,
P. S.; Peters, R. Angew. Chem., Int. Ed. 2007, 46, 5325. (g) Zajac, M.; Peters,
R. Org. Lett. 2007, 9, 2007. (h) Koch, F. M.; Peters, R. Angew. Chem., Int. Ed.
2007, 46, 2685.
(9) The formation of a related 2:1 adduct has been observed as a side
product in a β-lactam formation: (a) Fetter, J.; Bertha, F.; Czuppon, T.;
Kajtar-Peredy, M.; Konkoly-Thege, M.; Lempert, K. J. Chem. Res., Synop.
1995, 11, 446. (b) For the formation of a 3:1 adduct as side product in a
β-lactam formation at 110 °C in toluene (no yield given) see: Afonso, A.;
Rosenblum, S. B.; Puar, M. S.; McPhail, A. T. Tetrahedron Lett. 1998, 39,
7431.
(10) The trans-configuration of 12a was assigned by comparison with
literature data: Townes, J. A.; Evans, M. A.; Queffelec, J.; Taylor, S. J.;
Morken, J. P. Org. Lett. 2002, 4, 2537.
(1) Staudinger, H.; Klever, H. W.; Kober, P. Annalen 1910, 374, 1.
(2) (a) Staudinger, H. Liebigs Ann. Chem. 1907, 356, 51. (b) Sheehan,
J. C.; Corey, E. J. Org. React. 1957, 9, 388. (c) Mukerjee, A. K.; Singh, A. K.
Tetrahedron 1978, 34, 1731. (d) Review on β-lactams: Georg, G. I.; Ravikumar,
V. T. In The Organic Chemistry of β-Lactams; Georg, G. I., Ed.; VCH:
New York, 1993; pp 295-368.
(3) Comprehensive reviews about ketene chemistry: (a) Ketenes; Tidwell,
T. T. Wiley: Hoboken, NJ, 2006. (b) Tidwell, T. T. Eur. J. Org. Chem. 2006, 563.
(c) Paull, D. H.; Weatherwax, A.; Lectka, T. Tetrahedron 2009, 65, 6771. (d) Orr,
R. K.; Calter, M. A. Tetrahedron 2003, 59, 3545. (e) Ketene history: Tidwell, T. T.
Angew. Chem., Int. Ed. 2005, 44, 5778.
(4) (a) Martin, J. C.; Hoyle, V. A., Jr.; Brannock, K. C. Tetrahedron Lett.
1965, 6, 3589. (b) Pratt, R. N.; Procter, S. A.; Taylor, G. A. Chem. Commun.
1965, 575. (c) Martin, J. C.; Brannock, K. C.; Burpitt, R. D.; Gott, P. G.;
Hoyle, V. A., Jr. J. Org. Chem. 1971, 36, 2211. (d) Moll, F.; Wieland, H. J.
Arch. Pharm. 1975, 308, 481.
(5) Huisgen, R.; Davis, B. A.; Morikawa, M. Angew. Chem., Int. Ed. Engl.
1968, 7, 826.
4326 J. Org. Chem. 2010, 75, 4326–4329
Published on Web 05/18/2010
DOI: 10.1021/jo100709y
r
2010 American Chemical Society

Cabrera et al.
JOCNote
at room temperature, the studies presented herein were all
carried out at considerably lower temperatures, still provid-
ing significant product quantities at -70 °C.
The relative configuration of the racemic reaction pro-
ducts is evident from NMR studies (Scheme 3). The slightly
puckered ring containing four sp2-hybridized ring atoms
should adopt the typical half-chair conformation. Since there
is no significant NOE interaction between the Me group at
C5 and the Ph at C6, a cis arrangement of these two sub-
stituents can be ruled out. This is confirmed by NOE inter-
actions between H(5) and the Ph substituent at C(6) and H(6)
and the Me at C(5). The coupling constants JH(5)/H(6) = ca.
1.2-1.5 Hz for all synthesized derivatives12 furthermore
reveal that both H atoms are in the equatorial position while
the substituents at C5 and C6 consequently adopt a trans-
diaxial orientation. This is not surprising as there are no sev-
ere 1,3-diaxial interactions in the otherwise flat ring.
FIGURE 1. Revised structure 5 of the 2:1 adducts obtained by
Staudinger and structure of the reactive 1,4-dipolar intermediate 6.
SCHEME 2. Formation of 1,3-Oxazin-4-ones 9 as 2:1 Adducts
of Ketene Prepared in Situ from Acetyl Chloride (7) and Imines 8
The different reactivity profile of acyl bromides as a source
of a mono- or unsubstituted ketene as compared to disub-
stituted ketenes may be explained by an enhanced steric acc-
essibility of the nucleophilic enolate C-atom of the ketene/
imine adduct 18 favoring the reaction of 18 as a C-nucleo-
phile (Scheme 4) while 6 acted as an O-nucleophile in the
formation of 2:1 adducts. Stepwise reaction with another
equivalent of the corresponding ketene rather than cycliza-
tion to β-lactam 12 would generate 1,6-dipole 19. This nucle-
ophilic attack is expected to occur selectively trans to the
ketene residue R3 to minimize repulsive interactions,3 thus
selectively forming the Z-configured enolate 19. Cyclization
via a half-chair-like transition state 20 would explain the
exclusive formation of trans-isomers which are subsequently
O-acylated by the third equivalent of a ketene. The different
reaction outcome, as compared to the results with acetyl chlo-
ride, might be explained by a lower concentration of ketene
dimers under the reaction conditions, i.e., at lower tempera-
ture and using a less nucleophilic base than NEt3.
In conclusion, an operationally simple new method was
found to form densely substituted diastereomerically pure
trans-configured piperidine-2,4-dione derivatives as 3:1 add-
ucts of monosubstituted ketenes, formed in situ from acyl bro-
mides and aromatic imines. Closely related heterocycles have
recently been actively investigated because of their interesting
biological properties.13 Moreover, related heterocycles, which
have often been plagued by laborious multistep syntheses
in the past, have been found to be useful intermediates in a
number of syntheses.14 Our results nicely complement the pre-
viously reported methods to form 2:1 adducts possessing
different ring atom patterns and might provide further impetus
in the search for new physiologically active dihydropyridones.
With a larger amount of base at -50 °C, the imine reacted
completely (entries 7 and 9). The optimized conditions make
use of 9 equiv of 11 and 6 equiv of iPr2NEt, with another 2
equiv of base added after 16 h to fully convert 13a into 14a.11
Reactions at -70 °C resulted in lower conversion and
product selectivity was not further improved (entries 5, 8,
and 10). No product was detected when 12a was treated with
11 under the reaction conditions in the absence of imine 10a.
Various imines provided similar results under the opti-
mized reaction conditions (Table 2). The imines were readily
formed by mixing the corresponding aromatic aldehydes 15
and amines 16 and were used directly after filtration (to re-
move Na2SO4) without any further purification. Product 14a
was isolated in 68% yield over two steps (entry 1). Better pro-
duct selectivity and higher yields were obtained for N-PMP-
imines derived from benzaldehyde derivatives carrying elec-
tron-withdrawing groups like cyanide (entry 2) or chloride
(entries 3-5). Ortho-, meta-, and para-substitution patterns
were all well-tolerated (entries 3-5). A similar result was also
obtained with a p-Me group as an example of a σ-donor
substituent (entry 6), while a p-MeO group as an example of a
π-donor-substituent impeded formation of 14g (entry 7)
despite full conversion of the imine. Changing the N sub-
stituent to phenyl resulted in slightly better product selecti-
vity (entry 8). In contrast, with nonaromatic N substituents
the reaction was found to be problematic. An iPr group still
allowed for product formation, albeit in a moderate yield of
46% (entry 9), whereas imines carrying a CH2R group (n-Pr,
n-Bu, and Bn) gave complex product mixtures but neither
products 12 nor 14. This is surprising given the fact that the
initial studies on 2:1 adduct formation with disubstituted
ketenes were limited to the use of N-CH2R substituted
aromatic imines.1,2,4,5 The special behavior of acyl bromides
is also evident from entry 10: in contrast to acetyl chlo-
ride, which formed a masked β-ketoamide protected as an N,
O-acetal (see Scheme 2), acetyl bromide (17) still provided
δ-lactam 14j as the major product. Compared to the result
with propionyl bromide both selectivity and yield were slightly
improved. Furthermore, in CH2Cl2 at -50 °C with propio-
nyl chloride only traces of 14a were detectable. While the
previously reported 2:1 adduct formations were performed
Experimental Section
General Procedure for the Formation of 4-Acylated Piperidine-
2,4-diones 14. To a stirred solution of the corresponding aldehyde
(12) Related monocyclic 5,6-dihydropyridones with a cis-configuration
show coupling constants JH(5)/H(6) of ca. 4-6 Hz, while the corresponding
trans-isomer gave singlets for H(6) (Ph substituent at C(6), Me at C(5)):
Bennett, D. M.; Okamoto, I.; Danheiser, R. L. Org. Lett. 1999, 1, 641.
(13) Selected examples: (a) Treatment of hepatitis C virus infections: Ellis,
D.; Li, L.; Tran, C. V.; Ruebsam, F.; Zhou, Y. U.S. Pat. Appl. Publ., US
2009062263, 2009. (b) Hypoglycemic activity: Xie, Y.; Raffo, A.; Ichise, M.;
Deng, S.; Harris, P. E.; Landry, D. W. Bioorg. Med. Chem. Lett. 2008, 18, 5111.
(c) Metabolism of strychnine: Mishima, M.; Tanimoto, Y.; Oguri, K.; Yoshimura,
H. Drug Metab. Dispos. 1985, 13, 716.
(11) Starting directly with 8 equiv of base, 13a was not completely
transformed into 14a and results very similar to entries 7 and 8 in Table 1
were obtained.
J. Org. Chem. Vol. 75, No. 12, 2010 4327

Cabrera et al.
JOCNote
TABLE 1. Optimization of the Synthesis of 3:1 Adduct 14a
entry no.
equiv of 11
equiv of iPr2NEt
T (°C)
conv of 10a (%)a
12a:13a:14a ratioa
1
2
3
4
5
6
7
8
9
10
3
6
6
6
6
9
9
9
9
10
3
3
3
4.5
3
3
6
6
-50
-50
0
-50
-70
-50
-50
-70
-50
-70
38
65
42/58/00
22/10/68
93/00/07
15/27/58
10/12/78
27/00/73
11/23/66
08/24/68
16/00/84
20/23/57
100b
90
40
70
100
78
100
100
6 (þ2c)
6 (þ2c)
aDetermined by 1H NMR. bReaction time 1 h. cAdded after 16 h.
TABLE 2. Investigation of Scope and Limitations for the Synthesis of Trans-Configured 4-Acylated Piperidine-2,4-diones 14
entry no.
R1
R2
R3
conv (%)a
12:14 ratioa
yield of 14 (%)b
dra of 14
1
2
3
4
5
6
7
8
9
10
Ph
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
100
100
100
100
100
100
100
100
100
100
16:84
06:94
08:92
12:88
11:89
10:90
14a: 68
14b: 82
14c: 76
14d: 80
14e: 74
14f: 65
14g: -c
14h: 70
14i: 46
14j: 77
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
-
>98:2
>98:2
>98:2
p-NCC6H4
p-ClC6H4
o-ClC6H4
m-ClC6H4
p-MeC6H4
p-MeOC6H4
Ph
10:90
12:88
10:90
Ph
Ph
iPr
p-MeOC6H4
aDetermined by 1H NMR. bYield of isolated product over 2 steps after column chromatography. cA complex mixture was formed.
15 (0.50 mmol) and amine 16 (0.50 mmol) in CH2Cl2 (4 mL) was
added anhydrous sodium sulfate. After the reaction mixture was
stirred for 4 h at room temperature, the solution was filtered
and the solvent was subsequently removed in vacuo. Anhydrous
CH2Cl2 (2 mL) was added and the mixture was cooled to -50 °C.
The corresponding acyl bromide (4.5 mmol) and diisopropylethy-
lamine (496.1 μL, 3.00 mmol) were successively added at -50 °C.
After the reaction mixture was stirred for 16 h at -50 °C, more
diisopropylethylamine (165.4 μL, 1.00 mmol) was added. The
mixture was stirred for an additional 4 h, poured into aqueous 1 M
HCl (10 mL), and extracted with CH2Cl2 (2 ꢀ 10 mL). The
combined organic phases were dried over MgSO4 and filtered
and the solvent was removed in vacuo. The crude product mix-
tures were purified by flash chromatography.
(14) Selected examples: (a) Padwa, A.; Danca, M. D. Org. Lett. 2002, 4,
715. (b) Padwa, A.; Danca, M. D.; Hardcastle, K. I.; McClure, M. S. J. Org.
Chem. 2003, 68, 929. (c) Sasaki, Y.; Niida, A.; Tsuji, T.; Shigenaga, A.; Fujii,
N.; Otaka, A. J. Org. Chem. 2006, 71, 4969. (d) Sasaki, Y.; Niida, A.; Tsuji,
T.; Fujii, N.; Otaka, A. Pept. Sci. 2006, 42, 89. (e) Menichincheri, M.;
Bargiotti, A.; Berthelsen, J.; Bertrand, J. A.; Bossi, R.; Ciavolella, A.; Cirla,
A.; Cristiani, C.; Croci, V.; D’Alessio, R.; Fasolini, M.; Fiorentini, F.; Forte,
B.; Isacchi, A.; Martina, K.; Molinari, A.; Montagnoli, A.; Orsini, P.; Orzi,
F.; Pesenti, E.; Pezzetta, D.; Pillan, A.; Poggesi, I.; Roletto, F.; Scolaro, A.;
Tato, M.; Tibolla, M.; Valsasina, B.; Varasi, M.; Volpi, D.; Santocanale, C.;
Vanotti, E. J. Med. Chem. 2009, 52, 293. (f) Chaloin, O.; Cabart, F.; Marin,
J.; Zhang, H.; Guichard, G.; Shibasaki, M.; Mihara, H. Org. Synth. 2008, 85,
147. (g) Kim, D.-I.; Deutsch, H. M.; Ye, X.; Schweri, M. M. J. Med. Chem.
2007, 50, 2718. (h) Marin, J.; Didierjean, C.; Aubry, A.; Casimir, J.-R.;
Briand, J.-P.; Guichard, G. J. Org. Chem. 2004, 69, 130. (i) Lee, Y.-g.;
McGee, K. F., Jr.; Chen, J.; Rucando, D.; Sieburth, S. J. Org. Chem. 2000,
65, 6676. (j) Padwa, A.; Coats, S. J.; Harring, S. R.; Hadjiarapoglou, L.;
Semones, M. A. Synthesis 1995, 973. (k) Rohloff, J. C.; Dyson, N. H.;
Gardner, J. O.; Alfredson, T. V.; Sparacino, M. L.; Robinson, J., III J. Org.
Chem. 1993, 58, 1935. (l) Akiba, K.; Nakatani, M.; Wada, M.; Yamamoto,
Y. J. Org. Chem. 1985, 50, 63.
trans-3,5-Dimethyl-1-(4-methoxyphenyl)-6-phenyl-4-propion-
yloxy-5,6-dihydro-1H-pyridin-2-one (14a): yield 68%, colorless
oil, EtOAc/petroleum ether 1:2; H NMR (300 MHz, CDCl3,
1
21 °C) δ 7.29-7.16 (m, 5H), 7.00 (d, J=9.0 Hz, 2H), 6.73 (d, J=
9.0 Hz, 2H), 4.54 (d, J=1.5 Hz, 1H), 3.67 (m, 3H), 2.70 (br q, J=
6.9 Hz, 1H), 2.35 (q, J=7.5 Hz, 2H), 1.74 (d, J=0.9 Hz, 3H),
1.40 (d, J = 6.9 Hz, 3 H), 1.09 (t, J = 7.5 Hz, 3 H); 13C NMR
(75 MHz, CDCl3, 21 °C) δ 170.8, 165.2, 157.9, 155.9, 140.4,
135.3, 128.5, 127.7, 127.5, 126.5, 118.9, 114.2, 68.8, 55.4, 40.7,
27.4, 18.6, 10.2, 9.0; IR (neat) ν 2932, 1760, 1643, 1509, 1240,
1135, 1061, 699; HRMS (EI) m/z calcd for C23H25NO4
379.1784, found 379.1763.
trans-3,5-Dimethyl-6-(4-cyanophenyl)-1-(4-methoxyphenyl)-
4-propionyloxy-5,6-dihydro-1H-pyridin-2-one (14b): yield 82%,
4328 J. Org. Chem. Vol. 75, No. 12, 2010

Cabrera et al.
JOCNote
SCHEME 3. Determination of the Relative Configuration and
the Preferred Trans-Diaxial Conformation by NOE Studies of
14ha
trans-3,5-Dimethyl-6-(3-chlorophenyl)-1-(4-methoxyphenyl)-
4-propionyloxy-5,6-dihydro-1H-pyridin-2-one (14e): yield 74%,
colorless oil, EtOAc/petroleum ether 1:3; 1H NMR (300 MHz,
CDCl3, 21 °C) δ 7.30-6.96 (m, 5H), 6.98 (d, J = 9.0 Hz, 2H),
6.74 (d, J=9.0 Hz, 2H), 4.51 (d, J=1.2 Hz, 1H), 3.68 (m, 3H),
2.67 (br q, J=6.9 Hz, 1H), 2.36 (q, J=7.5 Hz, 2H), 1.74 (d, J=
0.9 Hz, 3H), 1.41 (d, J=6.9 Hz, 3 H), 1.10 (t, J=7.5 Hz, 3 H);
13C NMR (75 MHz, CDCl3, 21 °C) δ 170.8, 165.0, 158.0, 155.7,
142.5, 134.9, 134.4, 129.8, 128.0, 127.5, 126.8, 124.7, 119.0,
114.3, 68.3, 55.3, 40.4, 27.4, 18.6, 10.1, 9.0; IR (neat) ν 2975,
1760, 1642, 1509, 1243, 1124, 1092, 829; HRMS (ESI) m/z calcd
for C23H25ClNO4 414.1472, found 414.1465.
aRelevant NOE interactions are indicated by the red arrows.
trans-3,5-Dimethyl-1-(4-methoxyphenyl)-6-(4-methylphenyl)-
4-propionyloxy-5,6-dihydro-1H-pyridin-2-one (14f): yield 65%,
colorless oil, EtOAc/petroleum ether 1:2); 1H NMR (300 MHz,
CDCl3, 21 °C) δ 7.13 (m, 4H), 7.06 (d, J=9.0 Hz, 2H), 6.80 (d, J=
9.0 Hz, 2H), 4.58 (d, J=1.5 Hz, 1H), 3.75 (m, 3H), 2.75 (br q, J=
6.9 Hz, 1H), 2.43 (q, J=7.5 Hz, 2H), 2.33 (s, 3H), 1.81 (d, J=
0.9 Hz, 3H), 1.46 (d, J=6.9 Hz, 3 H), 1.17 (t, J=7.5 Hz, 3 H);
13C NMR (75 MHz, CDCl3, 21 °C) δ 170.9, 165.2, 157.9, 155.9,
137.5, 137.4, 135.4, 129.2, 127.5, 126.4, 118.9, 114.2, 68.6, 55.4,
40.8, 27.4, 21.1, 18.6, 10.2, 9.0; IR (neat) ν 2929, 1761, 1642, 1509,
1242, 1123, 1091, 830; HRMS (EI) m/z calcd for C24H27NO4
393.1940, found 393.1940.
SCHEME 4. Mechanistic Rationale for the Formation of
Trans-Configured 4-Acylated Piperidine-2,4-diones 14
trans-3,5-Dimethyl-1,6-diphenyl-4-propionyloxy-5,6-dihydro-
1H-pyridin-2-one (14h): yield 70% colorless oil, EtOAc/petro-
leum ether 1:4; 1H NMR (300 MHz, CDCl3, 21 °C) δ 7.27-7.08
(m, 5H), 4.62 (d, J=1.2 Hz, 1H), 2.73 (br q, J=6.9 Hz, 1H), 2.35
(q, J=7.5 Hz, 2H), 1.74 (d, J=1.2 Hz, 3H), 1.41 (d, J=6.9 Hz, 3
H), 1.09 (t, J=7.5 Hz, 3 H); 13C NMR (75 MHz, CDCl3, 21 °C)
δ 170.8, 165.1, 156.0, 142.5, 140.4, 128.9, 128.5, 127.7, 126.4,
126.1, 119.0, 68.4, 40.9, 27.4, 18.5, 10.1, 9.0; IR (neat) ν 2975,
1761, 1644, 1122, 1093, 758, 694; HRMS (EI) m/z calcd for
C22H23NO3Na 372.1576, found 372.1578.
colorless oil, EtOAc/petroleum ether 1:2); 1H NMR (300 MHz,
CDCl3, 21 °C) δ 7.63 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.4 Hz,
2H), 7.02 (d, J=9.0 Hz, 2H), 7.82 (d, J=9.0 Hz, 2H), 4.67 (d,
J=1.2 Hz, 1H), 3.75 (m, 3H), 2.76 (br q, J=6.9 Hz, 1H), 2.43 (q,
J = 7.5 Hz, 2H), 1.81 (d, J = 1.2 Hz, 3H), 1.50 (d, J = 6.9 Hz,
3 H), 1.15 (t, J = 7.5 Hz, 3 H); 13C NMR (75 MHz, CDCl3,
21 °C) δ 171.1, 164.8, 158.2, 155.8, 145.8, 134.7, 132.4, 127.4,
127.4, 119.2, 118.5, 114.4, 111.9, 68.4, 55.4, 40.1, 27.4, 18.7, 10.0,
8.9; IR (neat) ν 2975, 2228, 1760, 1642, 1509, 1243, 1122, 1091,
728; HRMS (EI) m/z calcd for C24H24N2O4Na 427.1634, found
427.1637.
trans-3,5-Dimethyl-6-(4-chlorophenyl)-1-(4-methoxyphenyl)-
4-propionyloxy-5,6-dihydro-1H-pyridin-2-one (14c): yield 76%,
colorless oil, EtOAc/petroleum ether 1:2; 1H NMR (300 MHz,
CDCl3, 21 °C) δ 7.30 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 8.4 Hz,
2H), 7.03 (d, J=9.0 Hz, 2H), 6.81 (d, J=9.0 Hz, 2H), 4.58 (d,
J=1.5 Hz, 1H), 3.75 (m, 3H), 2.74 (br q, J=6.9 Hz, 1H), 2.44 (q,
J = 7.5 Hz, 2H), 1.81 (d, J = 0.6 Hz, 3H), 1.47 (d, J = 6.9 Hz,
3 H), 1.17 (t, J = 7.5 Hz, 3 H); 13C NMR (75 MHz, CDCl3,
21 °C) δ 171.0, 165.0, 158.0, 155.9, 140.0, 135.0, 133.6, 128.7,
127.9, 127.5, 118.9, 114.2, 68.3, 55.3, 40.4, 27.4, 18.6, 10.1, 9.0;
IR (neat) ν 2976, 1760, 1643, 1509, 1243, 1125, 1090, 830;
HRMS (EI) m/z calcd for C23H24ClNO4Na 436.1292, found
436.1286.
trans-3,5-Dimethyl-6-(2-chlorophenyl)-1-(4-methoxyphenyl)-
4-propionyloxy-5,6-dihydro-1H-pyridin-2-one (14d): yield 80%,
colorless oil, EtOAc/petroleum ether 1:3; 1H NMR (300 MHz,
CDCl3, 21 °C) δ 7.33-7.00 (m, 5H), 7.01 (d, J = 9.0 Hz, 2H),
6.74 (d, J=9.0 Hz, 2H), 4.96 (d, J=1.2 Hz, 1H), 3.68 (m, 3H),
2.71 (br q, J=6.9 Hz, 1H), 2.34 (q, J=7.5 Hz, 2H), 1.74 (d, J=
0.6 Hz, 3H), 1.45 (d, J=6.9 Hz, 3 H), 1.07 (t, J=7.5 Hz, 3 H);
13C NMR (75 MHz, CDCl3, 21 °C δ 170.9, 165.6, 158.0, 156.0,
137.2, 135.2, 132.1, 130.1, 129.0, 127.9, 127.2, 126.8, 118.7,
114.3, 65.4, 55.3, 38.5, 27.4, 18.2, 10.1, 9.0; IR (neat) ν 2943,
1754, 1645, 1509, 1239, 1125, 1079, 760; HRMS (ESI) m/z calcd
for C23H25ClNO4 414.1472, found 414.1471.
trans-3,5-Dimethyl-1-isopropyl-6-phenyl-4-propionyl-oxy-5,6-
dihydro-1H-pyridin-2-one (14i): yield 46%, colorless oil, EtOAc/
petroleum ether 1:4 (difficult purification); 1H NMR (300 MHz,
CDCl3, 21 °C) δ 7.26-7.08 (m, 5H), 4.85 (hept, J=6.9 Hz, 1H),
4.28 (br s, 1H), 2.50 (br q, J=6.9 Hz, 1H), 2.28 (q, J=7.5 Hz,
2H), 1.7 (d, J=0.6 Hz, 3H), 1.25 (d, J=6.9 Hz, 3H), 1.13 (d, J=
6.9 Hz, 3H), 1.04 (t, J=6.9 Hz, 3H), 0.77 (t, J=7.5 Hz, 3 H); 13
C
NMR (75 MHz, CDCl3, 21 °C) δ 170.8, 165.0, 154.4, 142.0,
128.2, 127.3, 126.1, 119.0, 59.5, 44.9, 40.8, 27.4, 20.5, 20.0, 19.9,
18.5, 18.6, 10.2, 9.0; IR (neat) ν 2975, 1761, 1626, 1434, 1114,
700; HRMS (ESI) m/z calcd for C19H25NO3Na 338.1732, found
338.1727.
4-Acetyloxy-1-(4-methoxyphenyl)-6-phenyl-5,6-dihydro-1H-
pyridin-2-one (14j): yield 77%, colorless oil, EtOAc/petroleum
ether 1:2); 1H NMR (300 MHz, CDCl3, 21 °C) δ 7.27-7.18 (m,
5H), 7.00 (d, J=9.0 Hz, 2H), 6.71 (d, J=9.0 Hz, 2H), 6.00 (d,
J=2.4 Hz, 1H), 4.97 (dd, J=7.2, 2.7 Hz, 1H), 3.66 (m, 3H), 3.49
(ddd, J=17.2, 7.2, 2.1 Hz, 1H), 2.57 (dd, J=17.2, 3.0 Hz, 1H),
2.06 (s, 3H); 13C NMR (75 MHz, CDCl3, 21 °C) δ 167.4, 164.8,
157.9, 157.1, 140.2, 134.2, 128.7, 127.9, 127.5, 126.6, 114.1,
111.6, 62.0, 55.3, 35.9, 21.0;IR (neat) ν 2934, 1765, 1634, 1509,
1242, 1180, 1128, 1030, 830, 699; HRMS (ESI) m/z calcd for
C20H19NO4Na 360.1212, found 360.1192.
Acknowledgment. This work was financially supported
by the Swiss National Science Foundation (SNF; postdoc-
toral fellowship to J.C.). We would like to thank Dr. Caroline
Scheuermann (University of Stuttgart) for reading the
manuscript.
Supporting Information Available: General experimental
information and copies of NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 12, 2010 4329