Asymmetric synthesis of pyrido[1,2-c]pyrimidinones

Article abstract of DOI:10.1515/znb-2009-0610

"Asymmetric Electrophilic α-Amidoalkylation" reactions with a chiral alkylaminocarbonyl unit as chiral auxiliary are used for the stereoselective synthesis of 2-substituted piperidine derivatives. Intramolecular condensation of the nitrogen of the aminoca

Full text of DOI:10.1515/znb-2009-0610

Asymmetric Synthesis of Pyrido[1,2-c]pyrimidinones
Jo¨rg Pabela, Elmar Wadenstorferb, and Klaus T. Wannera
a Department of Pharmacy, Center of Drug Research, Ludwig-Maximilians-University Munich,
Butenandtstraße 5 – 13, 81377 Munich, Germany
b Daiichi Sankyo Europe GmbH, Luitpoldstr. 1, 85276 Pfaffenhofen, Germany
Reprint requests to Prof. Dr. K. T. Wanner. Fax: +49 89 2180 77247.
E-mail: Klaus.Wanner@cup.uni-muenchen.de
Z. Naturforsch. 2009, 64b, 653 – 661; received April 16, 2009
Dedicated to Professor Gerhard Maas with best wishes on the occasion of his 60th birthday
“Asymmetric Electrophilic α-Amidoalkylation” reactions with a chiral alkylaminocarbonyl unit
as chiral auxiliary are used for the stereoselective synthesis of 2-substituted piperidine derivatives.
Intramolecular condensation of the nitrogen of the aminocarbonyl group with the keto function
present in the newly introduced side chain of the amidoalkylation products results in the formation
of hexahydropyrido[1,2-c]pyrimidinones. After reduction and removal of the N-alkyl moiety of the
chiral auxiliary the target compounds, enantiopure octahydro-1H-pyrido[1,2-c]pyrimidin-1-ones, are
obtained.
Key words: α-Amidoalkylation, Asymmetric Synthesis, Heterocycles, N-Acyliminium Ion,
Pyridopyrimidinone
Introduction
The piperidine ring is a common structure in many
natural products [1] and is found in numerous biologi-
cally active compounds [2]. Accordingly, the synthesis
of isolated as well as fused piperidine derivatives has
represented a field of intense research efforts for many
decades with increasing attention being paid to meth-
ods providing access to enantiopure compounds [3].
Previously, we reported on a cationic type of
asymmetric synthesis involving chiral N-acyliminium
ions provided with an N-acyl group as chiral auxil-
iary [4]. This methodology, which we termed “Asym-
metric Electrophilic α-Amidoalkylation” (AEαA),
has been successfully employed in the stereoselec-
tive synthesis of α-substituted piperidines [5], pyrro-
lidines [6], 1,2,3,4-tetrahydroisoquinolines [7], and
1,2,3,4-tetrahydro-β-carbolines [8]. Further efforts
aimed at extending this concept to iminium ions 1
(Scheme 1) in which a chiral N-alkylaminocarbonyl
Fig. 1. Tetraponerines T3, T4, T7 and T8.
substituent instead of a chiral N-acyl group serves as
a chiral auxiliary. The successful implementation of
this plan was expected to give access to the alkylation
products 2 (Scheme 1) which in turn should be suitable
starting materials for the preparation of stereoisomeric
pyrido[1,2-c]pyrimidinones 3 and 4 in enantiopure
form (Scheme 1). As pyrido[1,2-c]pyrimidinones 3
and 4 are structurally related to the tetraponerines
T3, T4, T7 and T8 (Fig. 1), toxic alkaloids found in
the New Guinean ant Tetraponera sp., the realization of
Scheme 1.
c
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J. Pabel et al. · Asymmetric Synthesis of Pyrido[1,2-c]pyrimidinones
Scheme 2.
the aforementioned synthetic concept seemed highly
rewarding [9].
Interestingly, amidoalkylation reactions of this type
with the asymmetric induction arising from acyclic
stereocontrol utilizing an alkylaminocarbonyl group
are still unprecedented for piperidine so far. The
only related study has been published by Streith et
al. [10]. They successfully used the oxazolidine 5
to generate the chiral pyridinium ion 6, which when
treated with RMgBr yielded the dihydropyridone 7
(Scheme 2).
Results and Discussion
We selected the piperidine derivatives 13 and 16 as
amidoalkylation reagents for this study (Scheme 4).
The enamide moiety present in 13 and 16 was in-
tended to serve as a precursor for the generation of
acyliminium ions, for which purpose it had often been
used in previous studies [11]. The (S)-1-pheny-1-ethyl-
aminocarbonyl and the (S)-1-naphthyl-1-ethylamino-
carbonyl moieties in 13 and 16 had been chosen as
chiral auxiliaries as the commercial availability of the
isocyanates (S)-1-(1-isocyanatoethyl)benzene (8) and
(S)-1-(1-isocyanatoethyl)naphthalene (11) (Scheme 3)
was expected to facilitate the synthesis of the required
piperidine derivatives.
The synthesis of the enamides 13 and 16 was per-
formed as outlined in Scheme 3. Upon treatment
of 1,2,3,6-tetrahydripyridine 9 with either (S)-1-(1-
isocyanatoethyl)benzene (8) or (S)-1-(1-isocyanato-
ethyl)naphthalene (11) the tetrahydropyridine deriva-
tives 10 and 12 were obtained, in 91 % and 94 % yield,
respectively.
Scheme 3.
on γ-Al2O3 instead of Pd on carbon was employed as
catalyst.
For the amidoalkylation reactions, enamides 13
and 16 were activated following a common procedure
developed for related compounds. Thus CH2Cl2 was
saturated with a large excess of HCl gas, and the enam-
ides 13 and 16 were added to this solution. Then, af-
ter vacuum had been applied to remove unbound HCl,
TiCl4 was added to transform the presumed interme-
diates, the α-chloroamides 14 and 17, into the corre-
sponding N-acyliminium ions 15 and 18 (Scheme 4).
When silylenolether 19 selected as trapping reagent
was added to the reaction mixture that had been gener-
ated as described above, the expected addition prod-
ucts, 20/21 and 22/23, were indeed formed, but the
yields for the addition products 20/21 (34%) and 22/23
Subsequent isomerization of the allyl amides 10 (50 %) were far from being satisfying, and also the
and 12 employing Pd on γ-Al2O3 as catalyst in the stereoselectivity was low (20/21 = 60/40; 22/23 =
presence of triethylamine led to the corresponding 78/22). For both the poor yield and low selectivity HCl
enamides 13 and 16 in 82 % and 68 % yield, respec- gas was blamed that despite evacuation might have re-
tively (Scheme 4). For analogous isomerization reac- mained in the reaction solution. Therefore, in further
tions reported previously [11a] Pd on carbon had been experiments in contrast to the original procedure in-
used as a catalyst. In the case of 10 and 12, how- stead of a large excess a definite amount of HCl gas
ever, distinctly higher yields were reached when Pd (4.5 equivalents) was introduced into the reaction mix-
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J. Pabel et al. · Asymmetric Synthesis of Pyrido[1,2-c]pyrimidinones
655
Scheme 4.
Scheme 5.
Scheme 6.
ture by means of a gas-tight syringe. Keeping every- to the chiral auxiliary which might positively influence
thing else the same, the yields for the addition prod- the extent of its asymmetric induction.
ucts 20/21 and 22/23 then rose to 75 % and 58 %,
and the diastereoselectivity to 71/29 (20/21) and 84/16
(22/23), respectively (Scheme 5). Obviously, exces-
sive HCl gas (or its complex with TiCl4) that had re-
mained in the reaction mixture had partly decomposed
the silylenolether 19 in the first reaction thus leading
to a lower yield. The formation of a complex between
In order to assign the stereochemistry at the newly
created stereocenter in 2-position of the piperidine
ring, the major diastereomer 22 was transformed into
the known aminoalcohol 26 [12]. Reduction of 22 with
NaBH4 yielded the alcohols 24 and 25 (diastereoselec-
tivity 66/34). Finally, treatment of the stereoisomer 24
with LiOH led to the known amino alcohol 26 [12]
TiCl4 and HCl could also explain why, when excessive (Scheme 6). Comparison of the optical rotation and the
1H NMR data of 26 with those of an authentic sam-
ple [11a] allowed the assignment of the relative and the
absolute configuration of this compound. In this way,
HCl is absent, a higher diastereoselectivity is reached.
Free TiCl4 (or TiCl5− after abstraction of Cl− from the
substrate) will have a higher capability to coordinate
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J. Pabel et al. · Asymmetric Synthesis of Pyrido[1,2-c]pyrimidinones
Scheme 7.
compound 26 turned out to be of (R,R)-configuration (27), 25 % (31), 37 % (29), and 13 % (33), respectively
which, of course, must apply to the corresponding (Scheme 7). As the compounds turned out to be unsta-
stereocenters in the amidoalcohol 24 as well. Finally, ble at r. t., which was likely to be a result of the enam-
according to these results the main product of the trap- ide moiety present, they were quickly transformed to
ping reaction of the N-acyliminium ion 18 with the the saturated compounds which, indeed, appeared to
silylenolether 19, 22 must have (R)-configurationat the be stable.
newly created stereocenter at 2-position of the piperi-
Interestingly, the reductions that had been accom-
plished by means of NaBH4 in acetic acid must have
dine ring (Scheme 6) as well.
1
The H NMR spectra of the major isomer 20 and proceeded with high asymmetric induction, as in each
the minor isomer 21 from the trapping reaction of the case only a single diastereomer could be isolated,
N-acyliminium ion 15 with 19 were very similar to the their yields amounting to 72 % (28), 43 % (32), 72 %
major and minor isomer 22 and 23, respectively, that (30), and 67 % (34), respectively. The last step of our
had resulted from the corresponding reaction with the synthetic sequence to pyrido[1,2-c]pyrimidinones re-
N-acyliminium ion 18. Only the 1H NMR signals aris- quired the removal of the chiral auxiliary from the ni-
ing from the aryl groups, the phenyl and the naphthyl trogen atom in 2-position of the ring system. This last
moiety, present in the chiral auxiliaries of 20/21 and step was only performed for compounds 28 and 32
22/23, differed, of course, significantly. Accordingly, which upon hydrogenation over Pd/C provided the
the newly created stereocenter of the major isomer 20 desired target compounds 35 and 36 in 76 % and
and the minor isomer 21 was assigned (R)- and (S)- 68 % yield, respectively (Scheme 7).
stereochemistry, respectively, based on the similarities
with the major and minor isomers 22 and 23.
The stereochemistry of the new stereocenter in the
reduction products 28, 30, 32, and 34 was assigned
1
In the next step, the amidoalkylation products 20/21 by means of H coupling constants observed in the
and 22/23 were transformed to the bicyclic enam- 1H NMR spectra for the protons in positions 3, 4 and 4a
ides 27/31 and 29/33. As starting materials, the mix- in the bicyclic ring system. In addition, this assignment
tures of the diastereomeric amidoalkylation products was further verified by NO experiments performed for
were employed since the diastereomers of the cyclized the enantiopure target compound 35. These experi-
products turned out to be easier to separate than those ments revealed positive NO effects between the pro-
of the precursors. The cyclization was effected by heat- tons in positions 3, 4a and 8 as indicated in Fig. 2. Of
ing the starting materials in the presence of molecu- course, such effect would not be found in the (R,S)-
lar sieve and catalytic amounts of p-toluenesulfonic configurated isomer 37 as the distance between the
acid for 8 h to reflux. The pure diastereomers of the protons in 3- and 4a-position is too large (Fig. 2). Tak-
thus formed cyclic enamides 27/31 and 29/33 were ob- ing into account the stereochemistry of the 4a-position
tained after column chromatography in yields of 21 % identified by correlation with the aminoalcohol 26,
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J. Pabel et al. · Asymmetric Synthesis of Pyrido[1,2-c]pyrimidinones
N-[(1S)-1-Phenylethyl]-3,6-dihydropyridine-1(2H)-
657
carboxamide (10)
(S)-1-(1-Isocyanatoethyl)benzene (8) (4.9◦1 g, 33.3 mmol)
dissolved in THF (18 mL) was cooled to 0 C, and 1,2,3,6-
tetrahydropyridine (9) (5.54 g, 66.7 mmol) was added with
stirring. After 10 min the mixture was warmed to r. t. and
stirred for 13 h. The solvent was removed from the result-
ing mixture, and the remaining residue was dissolved in
EtOAc and washed with aqueous NaHSO4 solution (3×)
and H2O (3×). The organic phase was dried over MgSO4
and concentrated in vacuo. The resulting residue was puri-
fied by CC on silica gel (EtOAc / n-heptane◦1 : 1). Color-
−2.7◦ (c = 0.075, CHCl3). – IR (KBr): ν = 3029, 2969,
2971, 2834, 1615, 1534, 1446, 1409, 1340, 1254, 762, 702,
653, 567, 532 cm−1. – 1H NMR (400 MHz, CDCl3): δ =
1.50 (d, J = 6.7 Hz, 3 H, HCCH3), 2.13 – 2.19 (m, 2 H,
NCH2CH2), 3.47 – 3.52 (m, 2 H, NCH2CH2), 3.80 – 3.83 (m,
Fig. 2. NOE experiments.
compound 35 must be of (R,R)- and its enantiomer 36
self-evidently of (S,S)-configuration.
less crystals, 7.44 g (91 %). – M. p. 96 – 98 C. – [α]D20
=
Conclusion
In the work presented, we demonstrated that “Asym-
metric Electrophilic α-Amidoalkylation”reactions can
also be performed with piperidine derivatives provided
with a carboxamide unit as a chiral auxiliary. The C-2 2 H, NCH2CH), 4.59 (d, J = 6.7 Hz, 1 H, NH), 5.06 (quin, J =
6.7 Hz, 1 H, HCCH3), 5.62 – 5.59 (m, 1 H, HC=CH), 5.84 –
5.92 (m, 1 H, HC=CH), 7.22 – 7.29 (m, 1 H, Har), 7.29 –
7.37 (m, 4 H, Har). – MS (EI): m/z = 230 [M]+, 125, 105. –
C14H18N2O (230.31): calcd. C 73.01, H 7.88, N 12.16; found
C 73.01, H 8.00, N 12.02.
substituted piperidine derivatives obtained by utilizing
this new type of asymmetric amidoalkylation reactions
turned out to be well suited for the preparation of enan-
tiopure pyrido[1,2-c]pyrimidones, compounds with a
core structure analogous to that of the natural products
tetraponerines.
N-[(1S)-Naphthylethyl]-3,6-dihydropyridine-1(2H)-
carboxamide (12)
Experimental Section
Preparation according to 10 from (S)-1-(1-
isocyanatoethyl)naphthalene (11) (0.473 mg, 2.39 mmol)
All reactions were performed using dried glassware un-
der N2 atmosphere. All solvents were freshly dried using
standard [13] procedures. Melting points were determined
on a Bu¨chi melting point 510 apparatus and are uncorrected.
1H spectra were recorded in CDCl3 or CD2Cl2 at 400 MHz.
Infrared spectra were obtained on a Perkin-Elmer Paragon
1000 FTIR spectrometer. Microanalytical data for carbon,
hydrogen and nitrogen were determined on a Heraeus Rapid
Analyzer. Commercially obtained reagents were used with-
out further purification. Flash chromatography was carried
out using silica gel 60 (0.032 – 0.063 mm). HPLC: Merck Hi-
tachi Series 6000, column: LiChrospher 250-4/250-25 Si 60
(5 µm).
in THF (20 mL) and 9 (0.397 mg, 4.80 mmol). Colorless
◦
crystals, 630 mg (94 %). – M. p. 153 – 155 C. – [α]578
=
35.0◦ (c = 0.915, CHCl3). – IR (KBr): ν = 3320, 3050,
2981, 2917, 2833, 1610, 1534, 1407, 1252, 1214, 774,
665 cm−1. – 1H NMR (400 MHz, CDCl3): δ = 1.67 (d,
J = 6.8 Hz, 3 H, HCCH3), 2.14 – 2.17 (m, 2 H, NCH2CH2),
3.47 – 3.50 (m, 2 H, NCH2), 3.70 – 3.85 (m, 2 H, NCH2),
4.63 (d, J = 7.3 Hz, 1 H, NH), 5.59 (m, 1 H, HC=CH),
5.82 – 5.89 (m, 2 H, HCCH3, HC=CH), 7.43 – 7.56 (m, 4 H,
Har), 7.77 – 7.79 (m, 1 H, Har), 7.84 – 7.85 (m, 1 H, Har),
817 – 8.19 (m, 1 H, Har). – MS (EI): m/z = 280 [M]+, 155,
127, 115. – C18H20N2O (280.36): calcd. C 77.11, H 7.19,
N 9.99; found C 77.18, H 7.20, N 9.91.
General procedure for the reduction of the cyclic enamides
(GP1)
N-[(1S)-1-Phenylethyl]-3,4-dihydropyridine-1(2H)-
carboxamide (13)
The corresponding enamide was dissolved in glacial
acetic acid, and NaBH4 was added at 0 ◦C. After 10 min the
reaction mixture was allowed to warm to r. t. and stirred over
In a pressure tube under N2, a mixture of 10 (997 mg,
night (16 h). The resulting solution was laced with H2O and 4.33 mmol) in THF (4 mL), NEt3 (◦1 mL) and Pd on γ-Al2O3
HCl (0.1 M) and extracted with CH2Cl2. The combined or- (85 mg; 5 %) was heated to 105 C for 4 h. After cooling
ganic layers were dried (MgSO4) and concentrated in vacuo. to r. t., filtration and evaporation of the solvent the resulting
The resulting crude product was purified by CC on silica gel residue was purified by CC on silica gel (EtOAc / n-heptane /
(EtOAc / n-heptane 1 : 1).
CH2Cl2 1 : 2 : 2). Colorless crystals, 813 mg (82 %). – M. p.
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658
J. Pabel et al. · Asymmetric Synthesis of Pyrido[1,2-c]pyrimidinones
121 – 125 ◦C. – [α]D20 = 43.4◦ (c = 2.015, CHCl3). – IR (KBr): HPLC (EtOAc / n-heptane 4 : 6; 1.0 mL/min): d. s. 20/21 =
ν = 2972, 1625, 1535, 13,76, 1270, 986, 758, 698 cm−1. – 28.7/71.3.
1H NMR (400 MHz, CDCl3): δ = 1.51 (d, J = 6.9 Hz,
20: Colorless crystals, 168 mg (43 %). – M. p. 84 –
85 ◦C. – [α]2D0 = 51.2◦ (c = 0.44, CHCl3). – IR (KBr):
3 H, HCCH3), 1.81 – 1.88 (m, 2 H, NCH2CH2), 2.01 – 2.08
(m, 2 H, NCH2CH2CH2), 3,46 – 3.57 (m, 2 H, NCH2), 4.72
(d, J = 6.8 Hz, 1 H, NH), 4.88 (td, J = 4.0/8.2 Hz, 1 H,
NCH=CH), 5.05 (quin, J = 6.9 Hz, 1 H, HCCH3), 6.70 (d,
J = 8.2 Hz, 1 H, NHC=CH), 7.25 – 7.27 (m, 1 H, Har), 7.32 –
7.37 (m, 4 H, Har). – MS (EI): m/z = 230 [M]+, 105. –
C14H18N2O (230.31): calcd. C 73.01, H 7.88, N 12.16; found
C 72.85, H 8.06, N 12.15.
ν = 3409, 3026, 2933, 2863, 1674, 1622, 1506, 1448, 1372,
1264, 1016, 752, 703 cm−1. – 1H NMR (400 MHz, CDCl3):
δ = 1.44 – 1.80 (m, 6 H, CH2), 1.48 (d, J = 7.0 Hz, 3 H,
HCCH3), 2.71 (dt, J = 3.0/13.3 Hz, 1 H, NCH2ax.), 3.00 (dd,
J = 4.6/17.2 Hz, 1 H, CH2CO), 3.65 (dd, J = 8.0/17.2 Hz,
1 H, CH2CO), 4.20 (dbr, J = 13.7 Hz, 1 H, NCH2eq.), 4.49 –
4.76 (m, 1 H, NCH), 4.97 (quin, J = 7.0 Hz, 1 H, HCCH3),
6.07 (d, J = 7 Hz, 1 H, NH), 7.22 – 7.28 (m, 1 H, Har), 7.33 –
7.38 (m, 2 H, Har), 7.40 – 7.44 (m, 2 H, Har), 7.47 – 7.53 (m,
2 H, Har), 7.59 – 7.64 (m, 1 H, Har), 7.99 – 8.03 (m, 2 H,
Har). – MS (EI): m/z = 350 [M]+, 231, 202. – C22H26N2O2
(350.46): calcd. C 75.40, H 7.48, N 7.99; found C 75.44,
H 7.46, N 7.97.
N-[(1S)-1-Naphthylethyl]-3,4-dihydropyridine-1(2H)-
carboxamide (16)
Preparation according to 13 from 12 (720 mg, 2.57 mmol)
in THF (4 mL), NEt3 (1 mL) and Pd on γ-Al2O3 (85 mg;
5 %). Purification by CC on silica gel (EtOAc / n-heptane
1 : 1). Colorless crystals, 485 mg (68 %). – M. p. 148 –
21: Colorless crystals, 69 mg (18 %). – M. p. 85 – 87 ◦C. –
[α]2D0 = −8.1 (c = 0.51, CHCl3). – IR (KBr): ν = 3340, 3062,
2929, 2858, 1681, 1633, 1520, 1448, 1373, 1266, 1018, 755,
◦
151 C. – [α]2D0 = +109.3◦ (c = 0.45, HCCl3). – IR (KBr):
ν = 3049, 2932 2872, 1634, 1538, 1454, 1373, 1353, 1268,
1254, 1188, 1070, 988, 800, 778, 736, 717 cm−1. – 1H NMR
(400 MHz, CDCl3): δ = 1.69 (d, J = 6.9 Hz, 3 H, HCCH3),
1.82 (quin, J = 6.0 Hz, 2 H, NCH2CH2), 2.00 – 2.06 (m, 2 H,
NCH=CHCH2), 3.49 (t, J = 5.6 Hz, 2 H, NCH2), 4.76 (d, J =
7.2 Hz, 1 H, NH), 4.84 (td, J = 4.0/8.0 Hz, 1 H, NCH=CH),
5.86 (quin, J = 7.0 Hz, 1 H, HCCH3), 6.69 (d, J = 8.0 Hz,
1 H, NCH), 7.43 – 7.58 (m, 4 H, Har), 7.78 – 7.82 (m, 1 H,
Har), 7.85 – 7.89 (m, 1 H, Har), 8.14 – 8.18 (m, 1 H, Har). –
MS (EI): m/z = 280 [M]+, 155, 125, 105. – C18H20N2O
(280.36): calcd. C 77.11, H 7.19, N 9.99; found C 77.19,
H 7.33, N 9.78.
1
698 cm−1. – H NMR (400 MHz, CDCl3): δ = 1.36 – 1.76
(m, 6 H, CH2), 1.44 (d, J = 6.8 Hz, 3 H, HCCH3), 2.62 (dt,
J = 3.1/13.1 Hz, 1 H, NCH2ax.), 2.95 (dd, J = 5.2/16.8 Hz,
1 H, CH2CO), 3.46 (dd, J = 7.3/16.8 Hz, 1 H, CH2CO), 4.04
(dbr, J = 13.1 Hz, 1 H, NCH2eq.), 4.64 – 4.71 (m, 1 H, NCH),
4.86 (quin, J = 6.8 Hz, 1 H, HCCH3), 5.86 (d, J = 6.8 Hz,
1 H, NH), 7.08 – 7.13 (m, 1 H, Har), 7.16 – 7.21 (m, 2 H, Har),
7.23 – 7.27 (m, 2 H, Har), 7.38 – 7.44 (m, 2 H, Har), 7.50 –
7.55 (m, 1 H, Har), 7.88 – 7.92 (m, 2 H, Har). – MS (EI):
m/z = 350 [M]+, 231, 202. – C22H26N2O2 (350.46): calcd.
C 75.40, H 7.48, N 7.99; found C 75.36, H 7.40, N 7.99.
(2R)-N-[(1S)-1-Naphthylethyl]-2-(2-oxo-2-phenylethyl)-
piperidine-1-carboxamide (22) and (2S)-N-[(1S)-1-naphth-
ylethyl]-2-(2-oxo-2-phenylethyl)piperidine-1-carboxamide
(23)
(2R)-2-(2-Oxo-2-phenylethyl)-N-[(1S)-1-phenylethyl]piper-
idine-1-carboxamide (20) and (2S)-2-(2-oxo-2-phenylethyl)-
N-[(1S)-1-phenylethyl]piperidine-1-carboxamide (21)
HCl gas (175 mL, 7.81 mmol) was dissolved in CH2Cl2
(8 mL) at −87 ◦C using a gas-tight syringe. A solution of 13
(400 mg, 1.73 mmol) in CH2Cl2 (4.5 mL) was slowly added
over a period of 30 min. The excess of HCl was removed
Preparation according to 20/21 from 16 (430 mg,
1.53 mmol) in CH2Cl2 (4.5 mL), HCl gas (175 mL,
7.81 mmol) in CH2Cl2 (8 mL), TiCl4 (387 mg, 2.04 mmol)
and 19 (556 mg, 2.89 mmol). Purification by CC on sil-
ica gel (EtOAc / n-heptane 1 : 1) yielded 395 mg (58 %) of
the mixture of diastereomers 22 and 23, which were sepa-
rated by prep. HPLC (EtOAc / n-heptane 4 : 6; 15 mL/min).
Analytical HPLC (EtOAc / n-heptane 4 : 6; 1.0 mL/min):
d. s. 22/23 = 15.7/84.3.
◦
◦
at 10−2 mbar and −60 C (2 h). After cooling to −87 C,
TiCl4 (386 mg, 1.91 mmol) was added, and the resulting yel-
low solution was stirred for 50 min. Afterwards trimethyl(1-
phenylvinyloxy)silane (19) (501 mg, 2.61 mmol) in CH2Cl2
(2 mL) was added over a period of 15 min. The resulting
◦
mixture was stirred for 16 h at −87 C and quenched with
◦
22: Colorless crystals. – M. p. 163 C. – [α]578 = 120.8◦
H2O (10 mL). After neutralization with NaHCO3 solution
the aqueous layer was extracted with CH2Cl2 (3×). The (c = 0.625, CHCl3). – IR (KBr): ν = 3350, 2940, 1680, 1630,
combined organic layers were dried over MgSO4 and con- 1510 cm−1. – 1H NMR (400 MHz, CDCl3): δ = 1.40 – 1.75
centrated in vacuo. Purification by CC on silica gel (EtOAc / (m, 6 H, CH2), 1.64 (d, J = 6.9 Hz, 3 H, HCCH3), 2.72 (dt,
n-heptane 4 : 6) yielded 450 mg (74 %) of the mixture of J = 2.7/13.6 Hz, 1 H, NCH2), 2.97 (dd, J = 4.4/17.2 Hz, 1 H,
diastereomers 20 and 21, which were separated by prep. CH2CO), 3.66 (dd, J = 8.1/17.2 Hz, 1 H, CH2CO), 4.18 (dbr,
HPLC (EtOAc / n-heptane 4 : 6; 15 mL/min). Analytical J = 13.6 Hz, 1 H, NCH2), 4.66 – 4.75 (m, 1 H, NCH), 5.81
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659
(quin, J = 6.9 Hz, 1 H, HCCH3), 6.09 (d, J = 6.9 Hz, 1 H, 5.13 (sbr, 1 H, NH), 5.92 (quint, J = 6.6 Hz, 1 H, CH-CH3),
NH), 7.47 – 8.02 (m, 11 H, Har), 8.21 – 8.23 (m, 1 H, Har). – 7.25 – 7.37 (m, 5 H, Har), 7.43 – 7.55 (m, 4 H, Har), 7.78 –
MS (EI): m/z = 400 [M]+, 202, 155, 105. – C26H28N2O2 7.80 (m, 1 H, Har), 7.83 – 7.87 (m, 1 H, Har), 8.15 – 8.17
(400.52): calcd. C 77.97, H 7.05, N 6.99; found C 78.08, (m, 1 H, Har). – MS (EI): m/z = 402 [M]+. – C22H26N2O
H 7.18, N 6.84.
(402.54): calcd. C 77.58, H 7.51, N 6.96; found C 77.56,
H 7.59, N 6.88.
23: Colorless crystals. – M. p. 43 ◦C. – [α]578 = 52.6◦ (c =
0.38, CHCl3). – IR (KBr): ν = 3350, 2930, 2850, 1730, 1680,
1530 cm−1. – 1H NMR (400 MHz, CDCl3): δ = 1.40 – 1.80
(m, 6 H, CH2), 1.67 (d, J = 6.8 Hz, 3 H, HCCH3), 2.73 (dt,
J = 2.7/14.3 Hz, 1 H, NCH2), 3.02 (dd, J = 5.7/16.7 Hz, 1 H,
CH2CO), 3.45 (dd, J = 7.1/16.7 Hz, 1 H, CH2CO), 4.10 (dbr,
J = 14.3 Hz, 1 H, NCH2), 4.66 – 4.75 (m, 1 H, NCH), 5.78
(quin, J = 7.0 Hz, 1 H, HCCH3), 5.88 (d, J = 7.0 Hz, 1 H,
NH), 7.37 – 7.82 (m, 11 H, Har), 8.12 – 8.15 (m, 1 H, Har). –
MS (EI): m/z = 400 [M]+, 202, 155, 105. – C26H28N2O2
(400.52): calcd. C 77.97, H 7.05, N 6.99; found C 78.15,
H 7.21, N 6.79.
(1R)-1-Phenyl-2-[(2R)-piperidin-2-yl]ethanol (26) [12]
To a solution of 24 (80.5 mg, 0.2 mmol) in dioxane
(10 mL) was added LiOH·H2O (209 mg, 5.00 mmol) in H2O
◦
(1 mL) and the mixture stirred for 72 h at 150 C in a pres-
sure tube. After evaporation of the solvent the residue was
laced with HCl solution and washed with Et2O. The remain-
ing aqueous solution was brought to pH = 9 with KOH and
extracted with Et2O. The combined organic layers were dried
(MgSO4), concentrated in vacuo and recrystallized from n-
hexane. Colorless crystals, 25.2 mg (61 %). – [α]546 = 40.0◦
(c = 0.175, CHCl3). – [α]578 = 34.3◦ (c = 0.15, CHCl3). –
1H NMR (400 MHz, CDCl3): δ = 1.09 – 1.19 (m, 1 H),
1.28 – 1.39 (m, 1 H), 1.48 – 1.73 (m, 5 H), 1.81 – 1.87 (m,
1 H), 2.67 (ddd, J = 2.9/12.1/13.6 Hz, 1 H, NCH2ax.), 2.92
(tt, J = 2.5/10.7 Hz, 1 H, NCH), 3.09 (d, J = 13.6 Hz, 1 H,
NCH2eq.), 4.95 (dd, J = 2.6/10.6 Hz, 1 H, CH-OH), 7.21 –
7.38 (m, 5 H, Har).
(2R)-2-[(2R)-2-Hydroxy-2-phenylethyl]-N-[(1S)-1-naphth-
ylethyl]piperidine-1-carboxamide (24) and (2R)-2-[(2S)-2-
hydroxy-2-phenylethyl]-N-[(1S)-1-naphthylethyl]piperidine-
1-carboxamide (25)
NaBH4 (56.8 mg, 1.5 mmol) was added to a solution of 23
(120.2 mg, 0.3 mmol) in EtOH (25 mL) at 0 C and the
◦
mixture stirred for 15 h at r. t. and subsequently laced with
HCl (2 M) and H2O and extracted with Et2O (3×). The com-
bined organic layers were dried (MgSO4) and concentrated
in vacuo. The resulting residue was purified by CC on silica
gel (EtOAc / n-heptane 6 : 4). Separation with prep. HPLC
(EtOAc / n-heptane 4 : 1; 13 mL/min) yielded 24 and 25. An-
alytical HPLC (EtOAc / n-heptane 3 : 7; 2.0 mL/min; 35 ◦C):
d. s. 24/25 = 66/34.
(4aR)-3-Phenyl-2-[(1S)-1-phenylethyl]-2,4a,5,6,7,8-hexa-
hydro-1H-pyrido[1,2-c]pyrimidin-1-one (27) and (4aS)-3-
phenyl-2-[(1S)-1-phenylethyl]-2,4a,5,6,7,8-hexahydro-1H-
pyrido[1,2-c]pyrimidin-1-one (31)
A mixture of 20 and 21 (450 mg, 1.28 mmol) in toluene
(10 mL) together with some crystals of p-toluenesulfonic
acid and molecular sieve (600 mg) was heated to reflux
for 8 h. After filtration the solution was washed with aque-
ous NaHCO3 solution (1×) and H2O (3×) and dried over
MgSO4. Evaporation of the solvent gave a crude product
which was purified by CC on silica gel (EtOAc / n-heptane
2 : 8). The diastereomers 27 and 31 were obtained by prep.
HPLC (EtOAc / n-heptane 1 : 9; 14.4 mL/min).
27: Colorless oil (decomposition at r. t.), 89 mg (21 %). –
IR (film): ν = 3060, 2934, 2857, 1706, 1660, 1446, 1265,
1250, 1074, 1028, 756, 699 cm−1. – 1H NMR (400 MHz,
CDCl3): δ = 1.16 – 1.94 (m, 6 H, CH2), 1.73 (d, J = 7.1 Hz,
3 H, HCCH3), 2.43 (dt, J = 2.5/13.2 Hz, 1 H, NCH2ax.),
4.82 – 4.85 (m, 1 H, NCH), 4.35 (d, J = 13.2 Hz, 1 H,
NCH2eq.), 4.64 (q, J = 7.1 Hz, 1 H, HCCH3), 4.69 (d, J =
4.6 Hz, 1 H, NC=CH), 7.14 – 7.32 (m, 10 H, Har). – MS (EI):
m/z = 332 [M]+, 227, 105. – C22H24N2O (332.45): calcd.
C 79.48, H 7.28, N 8.43; found C 79.37, H 7.38, N 7.84.
31: Colorless oil (decomposition at r. t.), 107 mg (25 %). –
24: Colorless crystals, 63.3 mg (51.6 %). – M. p. 96 ◦C. –
[α]578 = 142.2◦ (c = 0.225, CHCl3). – IR (KBr): ν =
3320, 2930, 2860, 1620, 1540 cm−1. – 1H NMR (400 MHz,
CDCl3): δ = 1.25 – 1.66 (m, 6 H), 1.66 (d, J = 6.9 Hz, 3 H,
CH3), 1.90 (ddd, J = 4.2/10.1/14.3 Hz, 1 H, CH2CHOH),
2.00 (ddd, J = 3.4/7.7/14.3 Hz, 1 H, CH2CHOH), 2.66 (dt,
J = 2.8/12.9 Hz, 1 H, NCH2ax.), 3.17 (sbr, 1 H, CHOH),
3.83 (d, J = 12.9 Hz, 1 H, NH2eq.), 4.20 – 4.23 (m, 1 H,
NCH), 4.68 (d, J = 7.7 Hz, 1 H, CHOH), 5.43 (d, J = 6.9 Hz,
1 H, NH), 5.87 (quint, J = 6.9 Hz, 1 H, CHCH3), 7.24 – 7.37
(m, 4 H, Har), 7.75 – 7.77 (m, 1 H, Har), 7.84 – 7.86 (m, 1 H,
Har), 8.19 – 8.21 (m, 1 H, Har). – MS (EI): m/z = 402 [M]+. –
C22H26N2O (402.54): calcd. C 77.58, H 7.51, N 6.96; found
C 77.63, H 7.64, N 6.81.
◦
25: Colorless crystals, 27.8 mg (23 %). – M. p. 165 C. –
[α]578 = 186.7◦ (c = 0.15, CHCl3). – IR (KBr): ν = 3270,
2930, 2860, 1610, 1540 cm−1. – 1H NMR (400 MHz,
CDCl3): δ = 1.39 – 1.82 (m, 7 H), 1.69 (d, J=6.6 Hz, 3 H,
CH3), 2.19 (ddd, J = 2.2/12.1/14.3 Hz, 1 H), 2.80 (t, J = IR (film): ν = 3060, 2937, 2857, 1710, 1660, 1446, 1268,
12.5 Hz, 1 H, NCH2ax.), 3.52 – 3.72 (mbr, 1 H, NCH2eq.), 1250, 1074, 1028, 735, 699 cm−1. – 1H NMR (400 MHz,
4.51 (d, J = 11.0 Hz, 1 H, CH-OH), 4.68 (m, 1 H, NCH), CDCl3): δ = 1.21 – 1.92 (m, 6 H, CH2), 1.72 (d, J = 6.8 Hz,
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J. Pabel et al. · Asymmetric Synthesis of Pyrido[1,2-c]pyrimidinones
3 H, HCCH3), 2.45 (dt, J = 3.1/12.7 Hz, 1 H, NCH2ax.), 3.94 1 H, CH2), 0.88 (d, J = 13.1 Hz, 1 H, CH2), 1.08 –
(td, J = 2.8/10.9 Hz, 1 H, NCH), 4.37 (dbr, J = 13.0 Hz, 1 H, 1.23 (m, 2 H, CH2), 1.27 (d, J = 7.2 Hz, 3 H, HCCH3),
NCH2eq.), 4.67 (d, J = 3.1 Hz, 1 H, NC=CH), 4.74 (q, J = 1.45 – 1.58 (m, 2 H, CH2), 1.73 (ddd, J = 1.7/3.2/13.5 Hz,
7.1 Hz, 1 H, HCCH3), 7.14 – 7.36 (m, 10 H, Har). – MS (EI): 1 H, NCH(Ph)CH2), 1.98 (ddd, J = 5.4/8.3/13.4 Hz, 1 H,
m/z = 332 [M]+, 227, 105. – C22H24N2O (332.45): calcd. NCH(Ph)CH2), 2.53 (dt, J = 2.4/13.0 Hz, 1 H, NCH2ax.),
C 79.48, H 7.28, N 8.43; found C 79.88, H 7.58, N 7.73.
3.10 (ddt, J = 2.1/8.2/12.2, 1 H, NCH), 4.24 (dd, J =
3.3/5.4 Hz, 1 H, NCH(Ph)), 4.51 (td, J = 2.2/13.2 Hz, 1 H,
NCH2eq.), 5.93 (q, J = 7.2 Hz, 1 H, HCCH3), 7.13 – 7.31 (m,
10 H, Har). – MS (EI): m/z = 334 [M]+, 229, 215, 132, 105. –
C22H26N2O (334.46): calcd. C 79.01, H 7.84, N 8.38; found
C 79.01, H 7.91, N 8.31.
(4aR)-2-[(1S)-1-Naphthylethyl]-3-phenyl-2,4a,5,6,7,8-hexa-
hydro-1H-pyrido[1,2-c]pyrimidin-1-one (29) and (4aS)-2-
[(1S)-1-naphthylethyl]-3-phenyl-2,4a,5,6,7,8-hexahydro-
1H-pyrido[1,2-c]pyrimidin-1-one (33)
Preparation according to 27/31 from a mixture of 22
and 23 (361 mg, 0.90 mmol) in toluene (15 mL). Purifica-
tion by CC on silica gel (EtOAc / n-heptane 2 : 8) and sepa-
ration by prep. HPLC (EtOAc / n-heptane 4 : 6; 13.5 mL/min)
yielded the diastereomers 29 and 33.
(3S,4aS)-3-Phenyl-2-[(1S)-1-phenylethyl]octahydro-1H-
pyrido[1,2-c]pyrimidin-1-one (32)
According to GP1 from 31 (56 mg, 0.17 mmol) in AcOH
(5 mL) and NaBH4 (127 mg, 3.37 mmol). Colorless crys-
tals, 168 mg (43 %). – M. p. 77 – 73. – [α]2D0 = −111.9◦ (c =
0.45, CHCl3). – IR (KBr): ν = 3030, 2934, 2853, 1633,
1470, 1445, 1365, 1329, 1278, 1095, 1029, 736, 699 cm−1. –
1H NMR (400 MHz, CDCl3): δ = 0.87 – 1.00 (m, 1 H, CH2),
1.29 – 1.51 (m, 3 H, CH2), 1.72 – 1.80 (m, 2 H, CH2), 1.78
(d, J = 7.2 Hz, 3 H, HCCH3), 2.12 (ddd, J = 5.8/6.7/13.6 Hz,
1 H, NCH(Ph)CH2), 2.43 (ddd, J = 5.1/6.0/13.6 Hz, 1 H,
NCH(Ph)CH2), 2.66 (t, J = 12.9 Hz, 1 H, NCH2ax.), 3.23
(dtd, J = 2.6/5.7/11.9 Hz, 1 H, NCH), 4.62 (dbr, J = 12.9 Hz,
1 H, NCH2eq.), 4.73 (dd, J = 5.2/6.7 Hz, 1 H, NCH(Ph)),
5.41 (q, J = 7.2 Hz, 1 H, HCCH3), 7.19 – 7.31 (m, 8 H,
Har), 7.37 – 7.52 (m, 2 H, Har). – MS (EI): m/z = 334 [M]+,
229, 215, 132, 105. – C22H26N2O (334.46): calcd. C 79.01,
H 7.84, N 8.38; found C 79.08, H 7.84, N 8.32.
29: Colorless oil (decomposition at r. t.), 127 mg (37 %). –
IR (KBr): ν = 3056, 2918, 2850, 1634, 1446, 1403, 1265,
1
1250, 738, 704 cm−1. – H NMR (400 MHz, CDCl3): δ =
1.10 – 1.85 (m, 6 H, CH2), 1.78 (d, J = 7.4 Hz, 3 H, HCCH3),
2.46 (dt, J = 3.6/12.8 Hz, 1 H, NCH2ax.), 3.70 (td, J =
3.7/10.5 Hz, 1 H, NCH), 4.39 (d, J = 3.9 Hz, 1 H, NC=CH),
4.45 (dbr, J = 12.8 Hz, 1 H, NCH2eq), 5.92 (q, J = 7.4 Hz,
1 H, HCCH3), 6.64 – 6.80 (m, 2 H, Har), 6.86 – 6.92 (m, 1 H,
Har), 6.93 – 7.03 (m, 3 H, Har), 7.05 – 7.12 (m, 1 H, Har),
7.34 – 7.45 (m, 2 H, Har), 7.53 – 7.58 (m, 1 H, Har), 7.72 –
7.76 (m, 1 H, Har), 7.89 – 7.94 (m, 1 H, Har). – MS (EI):
m/z = 382 [M]+, 227, 155. – C26H26N2O (382.51): calcd.
C 81.64, H 6.85, N 7.32; found C 81.93, H 6.85, N 7.03.
33: Colorless oil (decomposition at r. t.), 45 mg (13 %). –
IR (KBr): ν = 3052, 2935, 2854, 1658, 1644, 1446, 1403,
1263, 1250, 779, 761, 735, 703 cm−1. – 1H NMR (400 MHz,
CDCl3): δ = 1.04 (dt, J = 3.7/11.8 Hz, 1 H, CH2), 1.23-1.78
(m, 5 H, CH2), 1.89 (d, J = 6.9 Hz, 3 H, HCCH3), 2.64 (dt,
J = 3.0/12.8 Hz, 1 H, NCH2ax.), 3.74 (td, J = 3.2/11.8 Hz,
1 H, NCH), 4.46 (dbr, J = 13.1 Hz, 1 H, NCH2eq), 4.50 (d,
J = 3.5 Hz, 1 H, NC=CH), 5.92 (q, J = 6.9 Hz, 1 H, HCCH3),
6.71 – 6.87 (m, 2 H, Har), 6.97 – 7.02 (m, 1 H, Har), 7.03 –
7.11 (m, 3 H, Har), 7.14 – 7.21 (m, 1 H, Har), 7.43 – 7.53 (m,
2 H, Har), 7.61 – 7.67 (m, 1 H, Har), 7.80 – 7.85 (m, 1 H, Har),
7.91 – 7.97 (m, 1 H, Har). – MS (EI): m/z = 382 [M]+, 227,
155. – C26H26N2O (382.51): calcd. C 81.64, H 6.85, N 7.32;
found C 81.99, H 6.94, N 6.89.
(3R,4aR)-2-[(1S)-1-Naphthylethyl]-3-phenyloctahydro-1H-
pyrido[1,2-c]pyrimidin-1-one (30)
According to GP1 from 29 (80 mg, 0.21 mmol) in
AcOH (7 mL) and NaBH4 (180 mg, 4.18 mmol). Color-
less crystals, 58 mg (72 %). – M. p. 137 – 139. – [α]D20
=
5.8◦ (c = 0.09, CHCl3). – IR (KBr): ν = 3050, 2936, 2854,
1622, 1472, 1447, 1277, 1228, 1191, 806, 783, 731, 701,
1
644 cm−1. – H NMR (400 MHz, CDCl3): δ = 0.51 – 0.63
(m, 1 H, NCHCH2), 0.86 – 0.95 (m, 1 H, NCHCH2), 1.13 –
1.32 (m, 2 H, CH2), 1.47 – 1.63 (m. 2 H, CH2), 1.69 (d,
J = 7.1, Hz, 3 H, HCCH3), 1.92 (ddd, J = 1.6/3.0/13.5 Hz,
1 H, NCH(Ph)CH2), 2.37 (ddd, J = 5.7/8.2/13.5 Hz, 1 H,
NCH(Ph)CH2), 2.63 (dt, J = 3.0/13.2 Hz, 1 H, NCH2ax.),
3.21 (ddt, 2.1/8.2/11.9 Hz, 1 H, NCH), 4.55 (dd, J =
3.1/5.4 Hz, 1 H, NCH(Ph)), 4.60 (, J = 13.2 Hz, 1 H,
NCH2eq.), 6.58 – 6.62 (m, 4 H, Har), 6.65 – 6.72 (m, 1 H,
(3R,4aR)-3-Phenyl-2-[(1S)-1-phenylethyl]octahydro-1H-
pyrido[1,2-c]pyrimidin-1-one (28)
According to GP1 from 27 (50 mg, 0.15 mmol) in AcOH Har), 6.77 (q, J = 7.1, 1 H, HCCH3), 7.13 – 7.19 (m, 1 H,
(4.5 mL) and NaBH4 (136 mg, 3.60◦mmol). Colorless crys- Har), 7.35 – 7.41 (m, 2 H, Har), 7.42 – 7.47 (m, 1 H, Har),
tals, 36 mg (72 %). – M. p. 76 – 81 C. – [α]D20 = 76.7 (c = 7.55 – 7.63 (m, 2 H, Har), 8.63 – 8.68 (m, 1 H, Har). – MS
0.08, CHCl3). – IR (KBr): ν = 2932, 2852, 1627, 1470, (EI): m/z = 384 [M]+, 229, 153, 127. – C26H28N2O (384.52):
1445, 1362, 1321, 1275, 1229, 1095, 1029, 747, 700 cm−1. – calcd. C 81.21, H 7.34, N 7.29; found C 81.13, H 7.33,
1H NMR (400 MHz, CDCl3): δ = 0.50 (dq, J = 3.8/12.6 Hz, N 7.20.
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661
(3S,4aS)-2-[(1S)-1-Naphthylethyl]-3-phenyloctahydro-1H-
pyrido[1,2-c]pyrimidin-1-one (34)
vacuo the residue was purified by CC on silica gel (EtOAc /
n-heptane 3 : 7). Colorless crystals, 15 mg (68 %). – M. p.
176 – 178 ◦C. – [α]D20 = −64.3◦ (c = 0.3, CHCl3). – IR
(KBr): ν = 3192, 2920, 2852, 1644, 1472, 1453, 1362,
According to GP1 from 33 (25 mg, 0.07 mmol) in AcOH
(3 mL) and NaBH4 (49 mg, 1.31 mmol). Colorless oil, 18 mg
(67 %). – [α]2D0 = 66.5◦ (c = 1.24, CHCl3). – IR (KBr): ν =
3050, 2936, 2854, 1622, 1472, 1447, 1277, 1228, 1191, 806,
783, 731, 701, 644 cm−1. – 1H NMR (400 MHz, CDCl3):
δ = 0.43 (dq, J = 3.7/12.3 Hz, 1 H, CH2), 0.71 – 0.83 (m, 1 H,
CH2), 1.01 – 1.27 (m, 2 H, CH2), 1.40 – 1.48 (m, 3 H, CH2),
1.45 (d, J = 7.0 Hz, 3 H, HCCH3), 1.52 (dbr, J = 13.4 Hz,
1 H, CH2), 2.58 (dt, J = 2.7/12.9 Hz, 1 H, NCH2ax.), 2.88
(tt, J = 3.6/6.3 Hz, 1 H, NCH), 4.01 (t, J = 4.4 Hz, 1 H,
NCH(Ph)CH2), 4.55 (dbr, J = 12.9 Hz, 1 H, NCH2eq), 6.51
(q, J = 7.0 Hz, 1 H, HCCH3), 7.05 – 7.10 (m, 2 H, Har), 7.12 –
7.24 (m, 3 H, Har), 7.25 – 7.29 (m, 1 H, Har), 7.32 – 7.37 (m,
1 H, Har), 7.40 – 7.52 (m, 2 H, Har), 7.72 – 7.77 (m, 1 H,
Har), 7.78 – 7.83 (m, 1 H, Har), 8.01 – 8.06 (m, 1 H, Har). –
MS (EI): m/z = 384 [M]+, 229, 153, 127. – C26H28N2O
(384.52): calcd. C 81.21, H 7.34, N 7.29; found C 81.23,
H 7.26, N 7.25.
1
1333, 1289, 1264, 1131, 1100, 757, 698 cm−1. – H NMR
(400 MHz, CDCl3): δ = 1.15 – 1.29 (m, 1 H, CH2), 1.29 –
1.51 (m, 2 H, CH2), 1.69 – 1.87 (m, 4 H, CH2), 2.13 (dtd,
J = 2.2/3.5/13.3 Hz, 1 H, NCH(Ph)CH2), 2.58 (dt, J =
3.3/13.1 Hz, 1 H, NCH2ax.), 3.30 (ddt, J = 3.0/3.9/11.2 Hz,
1 H,. NCH), 4.47 (dd, J = 3.0/11.5 Hz, 1 H, NCH(Ph)),
4.50 – 4.58 (m, 1 H, NCH2eq.), 4.70 (s, 1 H, NH), 7.28 – 7.40
(m, 5 H, Har). – MS (CI): m/z = 231 [M+1]+. – C22H26N2O
(230.31): calcd. C 73.01, H 7.88, N 12.16; found C 73.15,
H 7.93, N 12.28.
(3S,4aS)-3-Phenyloctahydro-1H-pyrido[1,2-c]pyrimidin-1-
one (36)
A mixture of 32 (0.38 mg, 0.11 mmol) and Pd/C (10 mg;
10 %) in MeOH (20 mL) was stirred at r. t. under hydro-
gen for 14 h. After filtration and removal of the solvent in
vacuo the residue was purified by CC on silica gel (EtOAc /
n-heptane 3 : 7). The spectroscopic data were identical with
those of 35. Colorless crystals, 19 mg (76 %). – M. p. 176 –
(3R,4aR)-3-Phenyloctahydro-1H-pyrido[1,2-c]pyrimidin-1-
one (35)
◦
178 C. – [α]2D0 = 64.3 (c = 0.35, CHCl3). – C22H26N2O
A mixture of 28 (0.32 mg, 0.10 mmol) and Pd/C (10 mg;
10 %) in MeOH (25 mL) was stirred at r. t. under hydro-
gen for 14 h. After filtration and removal of the solvent in
(230.31): calcd. C 73.01, H 7.88, N 12.16; found C 73.18,
H 7.97, N 11.90.
[1] a) For recent examples, see: D. R. Ijzendoorn, P. N. M.
Botman, R. H. Blaauw, Org. Lett. 2006, 8, 239 – 242;
b) B. Dhudshia, B. F. T. Cooper, C. L. B. Macdonald,
A. N. Thadani, Chem. Commun. (Camb) 2009, 4, 463 –
465; c) C. Yue, I. Gauthier, J. Royer, H.-P. Husson,
J. Org. Chem. 1996, 61, 4949 – 4954.
[8] U. Weber, C. Hoesl, W. Ponikwar, M. Suter,
H. No¨th, K. T. Wanner, Heterocycles 2004, 63, 2747 –
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