Synthesis of regioisomeric pyrido[c]azocanones from azaindanone derivatives

Article abstract of DOI:10.1002/ejoc.201301736

A ring enlargement reaction with methylamine gave new pyrido[2,3-c]-, pyrido[3,4-c]- and pyrido[3,2-c]azocanone derivatives from cyclic β-oxo esters with a cyclopentapyridine skeleton and a 1,4-diketone moiety. The starting materials for this ring transformation were either prepared from halogenopyridine carboxylates by Heck reaction and subsequent hydrogenation, or (halogenomethyl)pyridine carboxylates were submitted to S_N reaction with diethyl malonate. Both routes were completed by Dieckmann condensation to build the cyclic β-oxo ester structure and alkylation with phenacylbromide to install the 1,4-diketone motif. Copyright

Full text of DOI:10.1002/ejoc.201301736

FULL PAPER
DOI: 10.1002/ejoc.201301736
Synthesis of Regioisomeric Pyrido[c]azocanones from Azaindanone Derivatives
Miriam Penning[a] and Jens Christoffers*[a]
Keywords: Synthetic methods / Ring expansion / Heterocycles / Medium-ring compounds / Lactams
A ring enlargement reaction with methylamine gave new
pyrido[2,3-c]-, pyrido[3,4-c]- and pyrido[3,2-c]azocanone de-
rivatives from cyclic β-oxo esters with a cyclopentapyridine
skeleton and a 1,4-diketone moiety. The starting materials
hydrogenation, or (halogenomethyl)pyridine carboxylates
were submitted to SN reaction with diethyl malonate. Both
routes were completed by Dieckmann condensation to build
the cyclic β-oxo ester structure and alkylation with phenacyl-
for this ring transformation were either prepared from halo- bromide to install the 1,4-diketone motif.
genopyridine carboxylates by Heck reaction and subsequent
substitutions,[7] electrophilic cyclizations,[8] 2,3-sigmatropic
Introduction
rearrangements of N-benzylammonium ylides (Sommelet–
Hauser rearrangements),[9] radical chain insertions,[10] and
ring closing metatheses.[11] However, one area that remains
poorly developed is the synthesis of heterocycle-fused ring
systems, in particular those that contain a pyridine ring,
which is one of the key molecular binding sites in medicinal
chemistry.[12]
The efficient construction of medium sized nitrogen-con-
taining rings is an ongoing challenge for synthetic chemists,
as the entropic penalty for ring closure is typically higher
than for five- and six-membered systems. Nevertheless,
fused nitrogen-containing eight-membered ring systems
(azocines) are common in nature, being found in a number
of bioactive molecules and pharmaceuticals. These include
natural products such as apparicine (1),[1] uleine (2),[2] dasy-
carpidone (3),[3] and cycloechinulin (4)[4] (Figure 1) as well
as other compounds that are promising for medicinal chem-
istry.[5]
In 2006 we discovered a transformation of 1,4-diketones
with primary amines that furnished eight-membered ring
lactams, i.e., hexahydroazocinones, which defined new scaf-
folds for combinatorial chemistry.[13] This transformation
was subsequently used for the preparation of a library of
almost five thousand compounds for the discovery of new
lead structures.[14] Furthermore, we have used pyrrolidine
and tetrahydrothiophene derivatives in the ring-expansion
reaction to form eight-membered ring lactams with a
second N-heteroatom (diazocanones)[15] or an additional S-
heteroatom (thiazocanones).[16] The latter have been used
for the preparation of a combinatorial library consisting of
more than one hundred compounds. Finally, we recently
introduced a benzo[c] annulation at the azocanone ring.[17]
Since the pyridine moiety is one of the privileged structural
motifs in medicinal chemistry,[18] we report herein on an
extension of our investigations towards the preparation of
pyrido[c] annulated azocanones 5–8 as part of our continu-
ing efforts to provide new heterocyclic scaffolds for combi-
natorial chemistry (Scheme 1).[19] The retrosynthetic ap-
proach to all four target structures 5–8 is the same and can
therefore be exemplified for the pyrido[2,3-c] congener 5.
Our key reaction for eight-membered lactam formation is
actually the ring enlargement of the 1,4-diketone 9 with
MeNH2. Compound 9 should be obtained by alkylation of
azaindanone carboxylate 10 with phenacylbromide (11).
The cyclic β-oxo ester moiety of 10 can be derived from
di- (n = 1; 13a) or triesters (n = 2; 13b) by Dieckmann
condensation.[20] The synthesis of 13 was actually the major
Figure 1. Examples of natural products with annulated azocine
moieties.
Due to their attractive structures, fused benzo[c]azocines
have previously been prepared through the application of
methods such as nucleophilic[6] and electrophilic (aromatic)
[a] Institut für Chemie, Carl von Ossietzky Universität Oldenburg,
26111 Oldenburg, Germany
E-mail: jens.christoffers@uni-oldenburg.de
www.christoffers.chemie.uni-oldenburg.de
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301736.
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Synthesis of Regioisomeric Pyrido[c]azocanones
Scheme 1. Target structures and their retrosynthetic approach.
challenge of this project. For n = 1, diester 13a is available detail.[17] Finally, the tert-butyl ester function was smoothly
by Heck reaction of halo (X = Cl, Br) pyridine 12 followed cleaved under acidic conditions to furnish carboxylic acid
by hydrogenation. When n = 2, triester 13b could be ob- 17 (73%).
tained by substitution of (halomethyl)pyridines 14 with ma-
lonates.
Results and Discussion
Synthesis of pyrido[2,3-c]azocanone 5 was accomplished
through the Heck route and started with commercially
available 3-bromopicolinic acid (15), which was esterified
according to a published procedure (92% yield of product
12; Scheme 2).[21] The subsequent Heck reaction was ac-
complished according to a standard protocol[22] with an ex-
cess of tert-butyl acrylate (68% of product 16), which was
followed by catalytic hydrogenation (92%). Actually, in ini-
tial experiments, two ethyl ester functions were present in
the intermediate product, which led to very low yield in the
Dieckmann condensation. With the tert-butyl methyl dies-
ter 13a this step still gave moderate, but preparatively use-
ful, yield of β-oxo ester 10. The latter could be alkylated
with α-bromoketone 11 to give 1,4-diketone 9 (31%). The
yield-limiting process was competing O-alkylation, which is
well-known for sterically congested β-dicarbonyl com-
pounds.[23] Ring enlargement reaction with MeNH2 in
tetrahydrofuran (THF) was performed at 100 °C in a tightly
closed reaction vial. Compound 5 was obtained with good
yield. In the NMR spectra of the latter, a doubled signal set
was observed, which was due to two slowly interconverting
diastereoisomeric conformers. Whereas C-6 is clearly a
Scheme 2. Synthesis of pyrido[2,3-c]azocanones 5 and 17. Reagents
stereogenic center, a second stereogenic element is defined
by the plane of the pyridine ring, which becomes a chirality
plane due to the restricted torsion of the folded boat con-
formation of the eight-membered ring (for structural details
see below). This stereochemical issue was previously ob-
and conditions: (a) SOCl2 (4 equiv.), MeOH, 0–85 °C, 24 h;
(b) CH2=CHCO2tBu (10 equiv.), Pd(OAc)2 (0.1 equiv.), PPh3
(0.2 equiv.), NEt3 (5 equiv.), DMF, 110 °C, 18 h; (c) Pd–C (cat.), H2
(1 atm), iPrOH, 23 °C, 22 h; (d) NaH (2.5 equiv.), THF, 0–50 °C,
1 h; (e) PhCOCH2Br (11; 1.2 equiv.), K2CO3 (1.2 equiv.), acetone,
40 °C, 2 h; (f) MeNH2 (2 equiv.), THF, 100 °C, 16 h; (g) TFA,
served for the benzo-annulated analogues and discussed in CH2Cl2, 23 °C, 19 h.
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M. Penning, J. Christoffers
FULL PAPER
Synthesis of pyrido[3,4-c]azocanone 6 was accomplished
through the malonate route and started with nitrile 19,
which was prepared in three steps from commercially avail-
able cyano acetamide and ethyl acetoacetate according to a
published procedure.[24] The nitrile function was first solvo-
lyzed to give ethyl ester 18 (Scheme 3).[25] Since all attempts
at direct α-halogenation of the 4-Me group failed, we fol-
lowed a literature report[26] and achieved the synthesis via
the N-oxide 20 (74% with mCPBA), which could be con-
verted with TosCl to give 4-chloromethyl derivative 21. Nu-
cleophilic displacement with diethyl malonate gave triester
23 (54%), which was submitted to Dieckmann condensa-
tion to furnish β-oxo ester 22 (50%).[27] The last two steps
proceeded analogously to the preparation of compound 5:
Alkylation with bromoketone 11 (59% yield of 1,4-diketone
24) and ring transformation with MeNH2 (36%). As ob-
served in the previous case, product 6 showed doubled sig-
nal sets in the NMR spectra.
Scheme 4. Attempts at the synthesis of pyrido[4,3-c]azocanone 7.
Reagents and conditions: (a) SOCl2 (4 equiv.), MeOH, 0–80 °C,
24 h; (b) CH2=CHCO2tBu (20 equiv.), Pd(OAc)2 (0.1 equiv.), PPh3
(0.2 equiv.), NEt3 (5 equiv.), DMA, 120 °C, 18 h; (c) Pd–C (cat.),
H2 (1 atm), iPrOH, 23 °C, 3 d; (d) KOtBu (2.5 equiv.), THF, 0 °C,
0.5 h.
Scheme 3. Synthesis of pyrido[3,4-c]azocanone 6. Reagents and
conditions: (a) 1. H2SO4/H2O, 130 °C, 17 h; 2. EtOH, 80 °C, 4 h;
(b) mCPBA (2 equiv.), CHCl3, 0–23 °C, 19 h; (c) TosCl (2 equiv.),
1,4-dioxane, 100 °C, 1.5 h; (d) Na (3 equiv.) in EtOH, CH2-
(CO2Et)2 (3 equiv.), THF, 0–23 °C, 2 h; (e) Na (4 equiv.) in EtOH,
65 °C, 2 h; (f) PhCOCH2Br (11; 1.2 equiv.), K2CO3 (1.2 equiv.),
acetone, 40 °C, 3 h; (g) MeNH2 (2 equiv.), THF, 100 °C, 17 h.
Scheme 5. Synthesis of pyrido[3,2-c]azocanone 8. Reagents and
conditions: (a) 1. NH4OAc (1.1 equiv.), toluene, 110 °C, 2 h;
2. CH2=CHCHO (3 equiv.), 110 °C, 2.5 h; (b) DMF (0.1 equiv.),
trichloroisocyanuric acid (1.5 equiv.), CH2Cl2, 23 °C, 16 h; (c) Na
(3 equiv.) in EtOH, CH2(CO2Et)2 (3 equiv.), THF, 0–23 °C, 4 h;
(d) NaH (1.5 equiv.), THF, 65 °C, 1 h; (e) PhCOCH2Br (11;
1.2 equiv.), K2CO3 (1.2 equiv.), acetone, 56 °C, 3 h; (f) MeNH2
(2 equiv.), THF, 100 °C, 15 h; (g) NaOH (10 equiv.), H2O, EtOH,
Attempts at the preparation of pyrido[4,3-c]azocanone 7
were made by using both the malonate and Heck routes.
The latter actually started with commercially available
chloro isonicotinic acid 26, which was first esterified to give
compound 25 (Scheme 4).[28] However, severe problems 23 °C, 1 h.
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Synthesis of Regioisomeric Pyrido[c]azocanones
then started with the Heck reaction. After tedious optimi- uric acid as the source of electrophilic chlorine,[31] which
zation (key was the change of solvent to DMA) product 27 was superior to N-chlorosuccinimide (NCS) or N-bromo-
could be obtained, but with only 20% yield. Even by fol- succinimide (NBS) (90% yield of product 33).[32] Nucleo-
lowing procedures developed particularly for the conversion philic substitution with diethyl malonate (67% of triester
of aryl chlorides,[29] no improvements were achieved. Cata- 34)[33] and Dieckmann condensation (74% of oxo ester 36)
lytic hydrogenation (69% of product 28) and Dieckmann were straightforward. The C-alkylation with bromoketone
condensation (39% of product 30) could be achieved, but 11 also worked well, giving 1,4-diketone 35 in 71% yield.
both showed problems with reproducibility. Finally, no con- Finally, ring enlargement with MeNH2 was achieved under
ditions for a successful SN2 reaction of oxo ester 30 with the previously established conditions, giving the target com-
phenacyl bromide (11) could be found. Along the malonate pound 8 (48%). After ester saponification (56%) the struc-
route, the β-oxo ethyl ester analogous to compound 30 tural features of the annulated ring system were established
could be obtained, however, alkylation with phenacyl brom- by X-ray crystallographic analysis of carboxylic acid 37.[34]
ide (11) could also not be achieved with this derivative. Figure 2 shows the structure in the solid state. The top view
Therefore, the third of our target compounds (i.e., 7) could gives an impression of the conformation of the eight-mem-
so far not be obtained.
bered ring. The amide moiety is planar, as expected (di-
Synthesis of pyrido[3,2-c]azocanone 8 was successfully hedral angle O1–C5–N6–C11 0.7°), with a formal C–N
accomplished through the malonate route, starting with the double bond (C5–N6 135 pm). The enamine C–C double
synthesis of nicotinic acid derivative 31, which was obtained bond is not in conjugation with the amide moiety (dihedral
in one step from ethyl acetoacetate (32), ammonia, and ac- angle C11–N6–C7–Ph 71°). The eight-membered ring is in
roleine according to a published procedure (Scheme 5).[30] a folded, boat-shaped conformation. It can be clearly seen
For side chain α-halogenation, we chose trichloroisocyan- from Figure 2 (bottom view) that the pyridine ring becomes
a chirality plane, thus leading to the two slowly intercon-
verting diastereoisomeric conformations causing the
doubled signal sets in the NMR spectra. We had previously
determined the energy barrier for this ring inversion to be
about 70 kJmol–1 (in the case of benzo instead of pyrido
annulation).[17]
Conclusions
Three cyclopentapyridine derivatives 10, 22, and 36 with
β-oxo ester moieties were alkylated with phenacylbromide
(11) to 1,4-diketones 9, 24 and 35 as intermediate products
(31–71% yield). The latter three compounds were submitted
to ring-enlargement reactions with methylamine, furnishing
three new pyridoazocanone derivatives with 36–64% yield,
namely pyrido[2,3-c]azocanone 5, pyrido[3,4-c]azocanone 6
and pyrido[3,2-c]azocanone 8. The synthesis of a fourth re-
gioisomeric compound
7 with pyrido[4,3-c]azocanone
structure failed at the stage of the β-oxo ester 30. The prep-
aration of β-oxo esters 10, 22, 30 and 36 were accomplished
through two routes with a Dieckmann condensation in each
case as the last step. By following the Heck route, pyridine-
carboxylates 12 and 25, with a halogen atom in the α-posi-
tion to the ester function, were converted with tert-butyl-
acrylate (20–68%) and, after hydrogenation (69–92%), sub-
mitted to Dieckmann condensation (39–50%) to give β-oxo
esters 10 and 30. In the malonate route, (chloromethyl)pyr-
idinecarboxylates 21 and 33 were first prepared by side-
chain chlorination of the respective pyridinecarboxylates 18
and 31 with a methyl group α to the ester function and then
submitted to nucleophilic substitution with diethyl malon-
ate (54–67%). Dieckmann condensation (50–74%) gave β-
oxo esters 22 and 36.
Experimental Section
General: Preparative column chromatography was carried out using
Merck SiO2 (35–70 μm, type 60 A) with hexane, tert-butyl methyl
Figure 2. ORTEP representations of the structure of compound 37
in the solid state.
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M. Penning, J. Christoffers
FULL PAPER
ether (MTBE), ethyl acetate (EtOAc), CH2Cl2, or MeOH as el-
uents. TLC was performed on Merck aluminum plates coated with
166.40 (C), 172.05 (C) ppm. IR (ATR): ν = 2977 (w), 2952 (w),
˜
2932 (w), 1722 (vs), 1452 (m), 1429 (m), 1367 (m), 1301 (m), 1255
(m), 1233 (m), 1199 (m), 1147 (s), 1135 (s), 1091 (s), 845 (m), 804
(m), 753 (m), 717 (m), 660 (m) cm–1. HRMS (ESI): calcd. for
C14H19NNaO4 [M + Na+] 288.1212; found 288.1211.
1
SiO2 F254. H and 13C NMR spectra were recorded with a Bruker
Avance DRX 500 instrument. Multiplicities of carbon signals were
determined on the basis of DEPT experiments. MS and HRMS
spectra were obtained with a Finnigan MAT 95 (EI) and a Waters
Q-TOF Premier (ESI) spectrometer. IR spectra were recorded with
a Bruker Tensor 27 spectrometer equipped with a “GoldenGate”
diamond ATR unit. Elemental analyses were determined with a
Euro EA-CHNS instrument from HEKAtech.
tert-Butyl
7-Oxo-5,6-dihydrocyclopenta[b]pyridine-6-carboxylate
(10): NaH (60% in mineral oil, 45 mg, 1.13 mmol) was added under
an inert atmosphere (N2) to a cooled (ice-water bath) solution of
diester 13a (120 mg, 0.45 mmol) in anhydrous THF (1.4 mL) and
the mixture was stirred at 50 °C for 1 h. Water (10 mL) was added
and the solution was acidified with hydrochloric acid (1 M, 5 mL)
to pH 1. The aqueous layer was extracted with CH2Cl2 (3ϫ 10 mL)
Methyl 3-Bromopicolinate (12): SOCl2 (16.7 g, 140 mmol) was
added to a cooled (ice-water bath) solution of acid 15 (7.10 g,
35.1 mmol) in MeOH (10 mL) and the mixture was stirred at 85 °C and the combined organic extracts were dried (MgSO4), filtered,
for 24 h. All volatile materials were then removed in vacuo and the
residue dissolved in satd. aqueous NaHCO3 solution (75 mL). The
aqueous layer was extracted with CH2Cl2 (3ϫ 40 mL) and the
combined organic extracts were dried (MgSO4), filtered, and the
solvent was evaporated. Ester 12 (6.99 g, 32.4 mmol, 92%) was iso-
lated as a colorless solid; mp. 37–38 °C. 1H NMR (500 MHz,
CDCl3): δ = 3.99 (s, 3 H), 7.29 (dd, J = 4.6, 8.2 Hz, 1 H), 7.99 (dd,
and the solvents were evaporated. β-Oxo ester 10 (52 mg,
0.22 mmol, 50%) was isolated after column chromatography (SiO2;
CH2Cl2/MeOH = 20:1; Rf = 0.38) as a colorless solid; m.p. 100–
101 °C. A doubled signal set is observed due to keto-enol tauto-
1
mers (ratio 1:5). H NMR (500 MHz, CDCl3): δ (ketone form) =
1.47 (s, 9 H), 3.31 (dd, J = 8.8, 18.2 Hz, 1 H), 3.49–3.53 (m, 1 H),
3.66 (dd, J = 3.7, 8.2 Hz, 1 H), 7.44 (dd, J = 4.5, 7.7 Hz, 1 H), 7.88
J = 1.4, 8.2 Hz, 1 H), 8.59 (dd, J = 1.2, 4.6 Hz, 1 H) ppm. 13C{1H} (d, J = 7.7 Hz, 1 H), 8.77 (d, J = 3.9 Hz, 1 H) ppm; δ (enol form)
NMR (125 MHz, CDCl3): δ = 53.31 (CH3), 119.45 (C), 126.73
(CH), 142.23 (CH), 147.95 (CH), 149.18 (C), 165.47 (C) ppm. IR (d, J = 7.6 Hz, 1 H), 8.61 (d, J = 4.6 Hz, 1 H), 10.16 (s, 1 H) ppm.
(ATR): ν = 3056 (w), 3002 (w), 2953 (w), 1735 (vs), 1570 (w),
13C{1H} NMR (125 MHz, CDCl3): δ (ketone form) = 28.23 (3
= 1.57 (s, 9 H), 3.43 (s, 2 H), 7.26 (dd, J = 5.0, 7.4 Hz, 1 H), 7.73
˜
1446 (w), 1419 (m), 1296 (s), 1206 (m), 1133 (m), 1058 (m), 1023 CH3), 29.92 (CH2), 53.24 (CH), 82.83 (C), 127.94 (CH), 135.33
(m), 959 (w), 837 (w), 794 (m), 723 (w), 635 (w) cm–1. HRMS (CH), 151.48 (CH), 152.78 (C), 155.46 (C), 167.00 (C), 205.23
(ESI): calcd. for C7H6BrNNaO2 [M + Na+] 237.9480; found
237.9485.
(C) ppm; δ (enol form) = 28.66 (3 CH3), 30.67 (CH2), 81.93 (C),
108.16 (C), 123.11 (CH), 132.28 (CH), 137.06 (C), 149.13 (CH),
152.78 (C), 155.46 (C), 168.64 (C) ppm. IR (ATR): ν = 3284 (w,
˜
(E)-Methyl 3-[2-(tert-Butoxycarbonyl)ethenyl]picolinate (16): tert-
Butyl acrylate (17.9 g, 139 mmol), Pd(OAc)2 (312 mg, 1.39 mmol),
PPh3 (729 mg, 2.78 mmol) and NEt3 (7.03 g, 69.5 mmol) were
added under an inert atmosphere (N2) to a solution of pyridine 12
(3.00 g, 13.9 mmol) in anhydrous DMF (35 mL) and the resulting
mixture was stirred at 110 °C for 18 h. Water (20 mL) was then
added and the aqueous layer was extracted with MTBE (3ϫ
20 mL). The combined organic extracts were dried (MgSO4), fil-
tered, and the solvents were evaporated to give 16 (2.48 g,
9.42 mmol, 68%) after column chromatography (SiO2; hexane/
br), 3010 (w), 2977 (w), 2932 (w), 2918 (w), 2900 (w), 1653 (m),
1610 (m), 1567 (m), 1393 (m), 1361 (m), 1279 (m), 1236 (m), 1206
(m), 1181 (m), 1157 (s), 1130 (s), 1121 (s), 1098 (s), 781 (m), 759
(m), 714 (m) cm–1. HRMS (ESI): calcd. for C13H15NNaO3 [M +
Na+] 256.0950; found 256.0957.
tert-Butyl 7-Oxo-6-(2-oxo-2-phenylethyl)-5,6-dihydrocyclopenta[b]-
pyridine-6-carboxylate (9): Phenacylbromide (11; 58 mg,
0.29 mmol) and K2CO3 (40 mg, 0.29 mmol) were added to a solu-
tion of β-oxo ester 10 (50 mg, 0.24 mmol) in acetone (0.5 mL) and
MTBE = 1:1; Rf = 0.17) as a yellow oil. 1H NMR (500 MHz, the mixture was stirred at 40 °C for 2 h. Water (10 mL) and brine
CDCl3): δ = 1.51 (s, 9 H), 3.99 (s, 3 H), 6.27 (d, J = 16.0 Hz, 1 H),
7.45 (dd, J = 4.6, 8.0 Hz, 1 H), 7.93 (dd, J = 1.4, 8.0 Hz, 1 H), 8.21
(5 mL) were added and the aqueous layer was extracted with
MTBE (3ϫ 10 mL). The combined organic extracts were dried
(d, J = 16.0 Hz, 1 H), 8.65 (dd, J = 1.3, 5.1 Hz, 1 H) ppm. 13C{1H} (MgSO4), filtered, and the solvent was evaporated. Diketone 9
NMR (125 MHz, CDCl3): δ = 28.33 (3 CH3), 53.27 (CH3), 81.25 (27 mg, 77 μmol, 31%) was isolated after column chromatography
(C), 125.13 (CH), 126.51 (CH), 132.49 (C), 135.93 (CH), 139.56 (SiO2; hexane/EtOAc = 1:1; Rf = 0.37) as a brownish resin. 1H
(CH), 147.18 (CH), 149.98 (C), 165.37 (C), 165.98 (C) ppm. IR NMR (500 MHz, CDCl3): δ = 1.30 (s, 9 H), 3.10 (d, J = 17.5 Hz,
(ATR): ν = 3004 (w), 2980 (w), 2956 (w), 2935 (w), 1710 (vs), 1638
1 H), 3.49 (d, J = 18.5 Hz, 1 H), 3.91 (d, J = 17.4 Hz, 1 H), 4.15
˜
(m), 1445 (m), 1424 (m), 1370 (m), 1293 (s), 1259 (m), 1241 (m), (d, J = 18.5 Hz, 1 H), 7.42–7.47 (m, 3 H), 7.55 (t, J = 7.3 Hz, 1
1197 (m), 1150 (vs), 1087 (s), 978 (m), 877 (m), 847 (m), 808 (m), H), 7.87 (d, J = 7.8 Hz, 1 H), 7.93 (d, J = 8.0 Hz, 2 H), 8.78 (d, J
770 (m), 707 (m), 667 (m) cm–1. HRMS (ESI): calcd. for
C14H17NNaO4 [M + Na+] 286.1055; found 286.1056.
= 4.5 Hz, 1 H) ppm. 13C{1H} NMR (125 MHz, CDCl3): δ = 27.82
(3 CH3), 36.34 (CH2), 43.86 (CH2), 58.01 (C), 82.90 (C), 127.87
(CH), 128.30 (2 CH), 128.91 (2 CH), 133.75 (CH), 134.92 (CH),
136.46 (C), 148.68 (C), 151.14 (CH), 152.91 (C), 168.34 (C), 197.08
Methyl 3-[2-(tert-Butoxycarbonyl)ethyl]picolinate (13a): A suspen-
sion of Pd/C (4 mg, 10% on charcoal), pyridine 16 (100 mg,
380 μmol) and iPrOH (1 mL) was degassed (three times freeze,
pump, thaw) and then stirred under an atmosphere of hydrogen
(1 bar) at 23 °C for 22 h. The mixture was then filtered and the
solvent was evaporated to give 13a (92 mg, 0.35 mmol, 92%) as a
(C), 201.01 (C) ppm. IR (ATR): ν = 3062 (w), 2977 (w), 2930 (w),
˜
2880 (w), 1742 (m), 1716 (s), 1684 (m), 1449 (w), 1369 (m), 1354
(w), 1289 (w), 1271 (m), 1256 (m), 1224 (m), 1149 (vs), 1050 (m),
1001 (m), 910 (m), 845 (w), 755 (w), 729 (s), 690 (m), 646 (m),
631 (m) cm–1. HRMS (ESI): calcd. for C21H21NNaO4 [M + Na+]
374.1368; found 374.1357.
1
colorless oil. H NMR (500 MHz, CDCl3): δ = 1.39 (s, 9 H), 2.59
(t, J = 7.5 Hz, 2 H), 3.20 (t, J = 7.5 Hz, 2 H), 3.98 (s, 3 H), 7.36
(dd, J = 4.6, 7.9 Hz, 1 H), 7.70 (dd, J = 0.9, 7.9 Hz, 1 H), 8.57 (dd,
J = 1.3, 4.6 Hz, 1 H) ppm. 13C{1H} NMR (125 MHz, CDCl3): δ =
28.31 (3 CH3), 28.58 (CH2), 36.42 (CH2), 52.95 (CH3), 80.83 (C),
tert-Butyl (Z)-9-Methyl-10-oxo-8-phenyl-5,6,9,10-tetrahydropyrido-
[2,3-c]azocine-6-carboxylate (5): A solution of MeNH2 (2 m in
THF, 0.34 mmol, 0.17 mL) was added to a solution of 1,4-diketone
126.29 (CH), 138.58 (C), 139.95 (CH), 147.22 (C), 147.53 (CH), 9 (60 mg, 0.17 mmol) in THF (0.7 mL) and the mixture was stirred
2144
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Eur. J. Org. Chem. 2014, 2140–2149

Synthesis of Regioisomeric Pyrido[c]azocanones
for 16 h at 100 °C in a closed reaction vial. Subsequently, the sol-
vent was evaporated and lactam 5 (40 mg, 0.11 mmol, 64%) was
isolated after column chromatography (SiO2; hexane/EtOAc = 1:3;
Rf = 0.47) as a yellowish oil. A doubled signal set is observed in the
NMR spectra (ratio 4:1). 1H NMR (500 MHz, CDCl3): δ (major
conformer) = 1.52 (s, 9 H), 2.93 (dd, J = 10.5, 16.0 Hz, 1 H), 3.10
(s, 3 H), 3.62 (dd, J = 8.1, 16.0 Hz, 1 H), 3.86 (dd, J = 8.6, 18.9 Hz,
1 H), 5.82 (d, J = 8.8 Hz, 1 H), 7.13 (dd, J = 4.8, 7.8 Hz, 1 H),
for 17 h. EtOH (210 mL) was added and stirring was continued for
4 h under reflux. The pH was adjusted to pH 8 with aqueous
NaOH (10 m, 240 mL) and the aqueous layer was extracted with
MTBE (3ϫ 75 mL). The combined organic layers were dried
(MgSO4), filtered, and the solvent was evaporated to give ester 18
(5.77 g, 34.9 mmol, 83%) as a colorless liquid, which did not re-
1
quire further purification. H NMR (500 MHz, CDCl3): δ = 1.38
(t, J = 7.1 Hz, 3 H), 2.59 (s, 3 H), 4.36 (q, J = 7.1 Hz, 2 H), 7.14
7.27–7.31 (m, 4 H), 7.35 (d, J = 7.8 Hz, 1 H), 7.37–7.39 (m, 1 H), (d, J = 4.9 Hz, 1 H), 8.52 (d, J = 4.8 Hz, 1 H), 9.04 (s, 1 H) ppm.
8.43 (d, J = 4.6 Hz, 1 H) ppm; δ (minor conformer) = 1.51 (s, 9
H), 3.00–3.04 (m, 1 H), 3.02 (s, 3 H), 3.37–3.43 (m, 1 H), 3.48–3.53
(m, 1 H), 5.59 (d, J = 8.6 Hz, 1 H), 7.19 (dd, J = 4.8, 7.7 Hz, 1 H),
13C{1H} NMR (125 MHz, CDCl3): δ = 14.47 (CH3), 21.38 (CH3),
61.34 (CH2), 126.24 (C), 126.56 (CH), 149.51 (C), 151.78 (CH),
152.28 (CH), 166.36 (C) ppm. IR (ATR): ν = 2982 (w), 2933 (w),
˜
7.37–7.39 (m, 5 H), 7.42 (d, J = 7.9 Hz, 1 H), 8.49 (d, J = 4.8 Hz, 2907 (w), 1718 (s), 1592 (m), 1443 (m), 1366 (m), 1307 (m), 1274
1 H) ppm. 13C{1H} NMR (125 MHz, CDCl3): δ (major conformer)
(s), 1222 (m), 1171 (m), 1104 (s), 1063 (m), 1018 (m), 857 (m), 839
= 28.10 (3 CH3), 33.09 (CH3), 35.29 (CH2), 45.52 (CH), 82.18 (C),
(m), 773 (m) cm–1. HRMS (ESI): calcd. for C9H11NNaO2 [M +
123.02 (CH), 124.00 (CH), 126.82 (2 CH), 128.98 (2 CH), 129.30 Na+] 188.0687; found 188.0688.
(CH), 130.58 (C), 134.82 (C), 137.57 (CH), 144.01 (C), 147.88
3-(Ethoxycarbonyl)-4-methylpyridine 1-Oxide (20): mCPBA (70%,
(CH), 154.07 (C), 170.33 (C), 172.32 (C) ppm; δ (minor conformer)
= 28.10 (3 CH3), 32.83 (CH2), 33.46 (CH3), 46.57 (CH), 82.06 (C),
121.52 (CH), 124.59 (CH), 126.52 (2 CH), 128.80 (2 CH), 128.94
(CH), 132.06 (C), 137.21 (C), 135.60 (CH), 144.54 (C), 148.73
5.61 g, 22.8 mmol) was added while stirring to a cooled (ice-water
bath) solution of ester 18 (1.89 g, 11.4 mmol) in CHCl3 (12 mL)
and the mixture was stirred at 23 °C for 19 h. CHCl3 (40 mL) and
K2CO3 (6.30 g, 45.6 mmol) were added and stirring was continued
for 10 min. The mixture was filtered and the filtrate was dried
(MgSO4), filtered, and the solvent was removed in vacuo to give
N-oxide 20 (1.53 g, 8.44 mmol, 74%) as a colorless solid (mp 67–
69 °C), which did not require further purification. 1H NMR
(500 MHz, CDCl3): δ = 1.37 (t, J = 7.2 Hz, 3 H), 2.58 (s, 3 H),
4.36 (q, J = 7.2 Hz, 2 H), 7.16 (d, J = 6.6 Hz, 1 H), 8.20 (dd, J =
1.8, 6.6 Hz, 1 H), 8.73 (d, J = 1.7 Hz, 1 H) ppm. 13C{1H} NMR
(125 MHz, CDCl3): δ = 14.31 (CH3), 20.65 (CH3), 62.27 (CH2),
128.82 (C), 129.11 (CH), 140.53 (CH), 140.82 (CH), 141.11 (C),
(CH), 154.98 (C), 168.89 (C), 170.60 (C) ppm. IR (ATR): ν = 3057
˜
(w), 2978 (w), 2931 (w), 2874 (w), 1727 (s), 1663 (s), 1449 (m), 1371
(s), 1325 (m), 1315 (m), 1291 (m), 1258 (m), 1208 (m), 1151 (vs),
1108 (m), 1051 (m), 1033 (m), 848 (m), 774 (m), 735 (m), 700
(m) cm–1. HRMS (ESI): calcd. for C22H24N2NaO3 [M + Na+]
387.1685; found 387.1672.
(Z)-9-Methyl-10-oxo-8-phenyl-5,6,9,10-tetrahydropyrido[2,3-c]-
azocine-6-carboxylic Acid (17): TFA (812 mg, 7.12 mmol) was
added to a solution of ester 5 (65 mg, 0.18 mmol) in CH2Cl2
(0.9 mL) and the mixture was stirred at 23 °C for 19 h. All volatile
materials were removed in vacuo and the residue was dissolved in
water (10 mL). The aqueous layer was extracted with CH2Cl2 (3ϫ
10 mL) and the combined organic extracts were dried (MgSO4),
filtered, and the solvent was evaporated to give carboxylic acid 17
(40 mg, 0.13 mmol, 73%) after column chromatography (SiO2;
CH2Cl2/MeOH = 10:1; Rf = 0.16) as a colorless solid; m.p. 222–
224 °C. A doubled signal set is observed in the NMR spectra (ratio
3:1). 1H NMR (500 MHz, CDCl3): δ (major conformer) = 3.08 (dd,
J = 5.7, 16.1 Hz, 1 H), 3.13 (s, 3 H), 3.72 (dd, J = 8.1, 16.0 Hz, 1
H), 4.05 (dd, J = 8.6, 18.7 Hz, 1 H), 5.89 (d, J = 8.7 Hz, 1 H), 7.19
(dd, J = 4.8, 7.8 Hz, 1 H), 7.29–7.32 (m, 4 H), 7.40–7.42 (m, 2 H),
8.48 (d, J = 4.5 Hz, 1 H) ppm; δ (minor conformer) = 3.05 (s, 3
H), 3.58–3.64 (m, 3 H), 5.68 (d, J = 8.3 Hz, 1 H), 7.19 (dd, J =
4.8, 7.8 Hz, 1 H), 7.25–7.27 (m, 1 H), 7.35–7.37 (m, 1 H), 7.40–
7.42 (m, 3 H), 7.48 (d, J = 7.2 Hz, 1 H), 8.55 (d, J = 4.8 Hz, 1
H) ppm; no CO2H signal was observed. 13C{1H} NMR (125 MHz,
CDCl3): δ (major conformer) = 33.51 (CH3), 35.09 (CH2), 41.81
(CH), 122.57 (CH), 124.43 (CH), 126.80 (2 CH), 129.05 (2 CH),
129.50 (CH), 130.90 (C), 134.55 (C), 138.30 (CH), 144.23 (C),
147.45 (CH), 153.41 (C), 169.77 (C), 176.26 (C) ppm; δ (minor con-
former) = 33.19 (CH2), 33.69 (CH3), 45.36 (CH), 120.96 (CH),
125.01 (CH), 126.55 (2 CH), 129.05 (2 CH), 129.40 (CH), 132.13
(C), 136.43 (CH), 136.63 (C), 145.02 (C), 148.26 (CH), 154.30 (C),
163.52 (C) ppm. IR (ATR): ν = 3075 (w), 3031 (w), 2984 (w), 1704
˜
(s), 1480 (m), 1453 (m), 1363 (m), 1301 (s), 1278 (m), 1253 (m),
1217 (m), 1200 (m), 1094 (s), 1020 (m), 1008 (m), 890 (m), 866 (m),
782 (m), 768 (m), 551 (m) cm–1. MS (70 eV, EI): m/z (%) = 181
(100) [M+], 152 (44), 135 (47), 107 (31). HRMS (70 eV, EI): calcd.
for C9H11NO3 [M+] 181.0733; found 181.0727; C9H11NO3 (181.19):
calcd. C 59.66, H 6.12, N 7.73; found C 59.65; H 6.12; N 7.81.
Ethyl 4-(Chloromethyl)nicotinate (21): pTosCl (1.05 g, 5.52 mmol)
was added to a solution of N-oxide 20 (500 mg, 2.76 mmol) in diox-
ane (4.5 mL), the mixture was stirred for 1.5 h under reflux and
then acidified with hydrochloric acid (1 M, 15 mL) to pH 1. The
aqueous layer was washed with MTBE (2ϫ 20 mL) and the organic
extracts were discarded. Sat. aqueous NaHCO3 solution (20 mL)
was added to the aqueous layer to adjust to pH 8. The aqueous
phase was then extracted with MTBE (3ϫ 20 mL) and the com-
bined organic extracts were dried (MgSO4), filtered, and the solvent
was evaporated. After column chromatography (SiO2; hexane/
MTBE = 1:1; Rf = 0.33) compound 21 (261 mg, 1.31 mmol, 47%)
1
was obtained as a yellowish oil. H NMR (500 MHz, CDCl3): δ =
1.43 (t, J = 7.1 Hz, 3 H), 4.43 (q, J = 7.1 Hz, 2 H), 5.05 (s, 2 H),
7.61 (d, J = 5.1 Hz, 1 H), 8.76 (d, J = 5.1 Hz, 1 H), 9.16 (s, 1
H) ppm. 13C{1H} NMR (125 MHz, CDCl3): δ = 14.33 (CH3),
43.20 (CH2), 61.90 (CH2), 124.12 (C), 124.58 (CH), 147.68 (C),
151.82 (CH), 153.29 (CH), 165.38 (C) ppm. IR (ATR): ν = 3053
˜
168.34 (C), 175.00 (C) ppm. IR (ATR): ν = 2924 (w), 2899 (w),
˜
(w), 2984 (w), 2940 (w), 2911 (w), 2875 (w), 1717 (vs), 1592 (m),
1564 (w), 1447 (w), 1408 (w), 1394 (w), 1369 (m), 1312 (m), 1280
(s), 1233 (m), 1221 (m), 1207 (m), 1175 (m), 1146 (w), 1108 (s),
1057 (m), 1018 (m), 860 (w), 846 (w), 772 (m), 737 (m), 693
(m) cm–1. HRMS (ESI): calcd. for C9H10ClNNaO2 [M + Na+]
222.0298; found 222.0305. C9H10ClNO2 (199.63): calcd. C 54.15,
H 7.02, N 5.05; found C 54.10, H 7.03, N 5.03.
2853 (w), 1709 (s), 1656 (vs), 1579 (m), 1434 (m), 1414 (m), 1379
(s), 1338 (m), 1303 (m), 1241 (m), 1186 (s), 1130 (m), 1108 (m),
1080 (m), 1051 (m), 925 (m), 881 (m), 801 (m),
771 (s), 743 (m), 700 (s), 682 (m), 660 (m), 635 (m) cm–1. HRMS
(ESI): calcd. for C18H16N2NaO3 [M + Na+] 331.1059; found
331.1066.
Ethyl 4-Methylnicotinate (18): A solution of nitrile 19 (5.00 g, Diethyl 2-{[3-(Ethoxycarbonyl)-4-pyridyl]methyl}malonate (23): Di-
42.3 mmol) in 75% aqueous H2SO4 (85 mL) was stirred at 130 °C ethyl malonate (241 mg, 1.50 mmol) was added to a cooled (ice-
Eur. J. Org. Chem. 2014, 2140–2149
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2145

M. Penning, J. Christoffers
FULL PAPER
water bath) solution of Na (35 mg, 1.5 mmol) in EtOH/THF (1:1;
2 mL). Subsequently, a solution of 21 (100 mg, 501 μmol) in THF
(1 mL) was added and the resulting mixture was stirred while cool-
ing for 1 h and then at 23 °C for 1 h. All volatile materials were
removed in vacuo and the residue was diluted with water (10 mL)
and extracted with MTBE (3ϫ 10 mL). The combined organic ex-
tracts were dried (MgSO4), filtered, and the solvent was evaporated
to give malonate 23 (88 mg, 0.28 mmol, 54%) after column
chromatography (SiO2; hexane/MTBE = 1:1; Rf = 0.29) as a yellow
oil. 1H NMR (500 MHz, CDCl3): δ = 1.22 (t, J = 7.1 Hz, 6 H),
132 °C. 1H NMR (500 MHz, CDCl3): δ = 1.15 (t, J = 7.1 Hz, 3 H),
3.17 (d, J = 18.2 Hz, 1 H), 3.58 (d, J = 18.5 Hz, 1 H), 4.00 (d, J =
18.2 Hz, 1 H), 4.14 (q, J = 7.11 Hz, 2 H), 4.16 (d, J = 18.5 Hz, 1
H), 7.45–7.48 (m, 2 H), 7.50 (d, J = 5.2 Hz, 1 H), 7.57–7.60 (m, 1
H), 7.94–7.96 (m, 2 H), 8.77 (d, J = 5.2 Hz, 1 H), 9.06 (s, 1 H) ppm.
13C{1H} NMR (125 MHz, CDCl3): δ = 14.02 (CH3), 38.19 (CH2),
43.74 (CH2), 58.24 (C), 62.41 (CH2), 121.89 (CH), 128.26 (2 CH),
128.89 (2 CH), 131.35 (C), 133.91 (CH), 136.03 (C), 147.27 (CH),
154.14 (CH), 161.72 (C), 169.40 (C), 196.81 (C), 200.63 (C) ppm.
IR (ATR): ν = 2963 (w), 2909 (w), 1737 (vs), 1702 (s), 1682 (vs),
˜
1.42 (t, J = 7.1 Hz, 3 H), 3.57 (d, J = 7.7 Hz, 2 H), 3.87 (t, J = 1620 (w), 1597 (vs), 1478 (w), 1449 (m), 1416 (m), 1397 (m), 1353
7.7 Hz, 1 H), 4.16 (dq, J = 10.8, 7.1 Hz, 2 H), 4.17 (dq, J = 10.8,
7.1 Hz, 2 H), 4.42 (q, J = 7.1 Hz, 2 H), 7.27 (s, 1 H), 8.60 (d, J =
(m), 1326 (w), 1292 (s), 1224 (s), 1207 (s), 1180 (vs), 1157 (s), 1096
(m), 1066 (m), 1044 (m), 1033 (m), 1020 (m), 999 (m), 943 (w), 909
5.1 Hz, 1 H), 9.15 (s, 1 H) ppm. 13C{1H} NMR (125 MHz, CDCl3): (s), 859 (m), 850 (m), 749 (s), 689 (s), 600 (m), 561 (m), 536
δ = 14.12 (2 CH3), 14.30 (CH3), 33.08 (CH2), 52.26 (CH), 61.84 (2 (m) cm–1. HRMS (ESI): calcd. for C19H17NNaO4 [M + Na+]
CH2), 61.90 (CH2), 126.22 (CH), 127.01 (C), 150.26 (CH), 151.22 346.1055; found 346.1054.
(CH), 151.24 (C), 165.32 (C), 168.55 (2 C) ppm. IR (ATR): ν =
˜
Ethyl
9-Methyl-10-oxo-8-phenyl-5,6,9,10-tetrahydropyrido[3,4-c]-
2983 (w), 2940 (w), 2907 (w), 1718 (vs), 1591 (w), 1558 (w), 1466
(w), 1446 (w), 1406 (w), 1392 (w), 1368 (m), 1328 (w), 1303 (m),
1275 (s), 1247 (m), 1216 (m), 1175 (m), 1147 (m), 1107 (s), 1052
(m), 1030 (m), 858 (m), 787 (m), 728 (w), 701 (w), 602 (w), 580 (w),
549 (m) cm–1. HRMS (ESI): calcd. for C16H21NNaO6 [M + Na+]
346.1267; found 346.1262.
azocine-6-carboxylate (6): A solution of MeNH2 (2 M in THF,
0.45 mmol, 0.25 mL) was added to a solution of 1,4-diketone 24
(73 mg, 0.23 mmol) in THF (0.25 mL) and the mixture was stirred
for 17 h at 100 °C in a closed reaction vial. The solvent was evapo-
rated and lactam 6 (27 mg, 81 μmol, 36%) was isolated after col-
umn chromatography (SiO2; hexane/EtOAc = 1:2; Rf = 0.36) as a
yellowish resin. A doubled signal set is observed in the NMR spec-
Ethyl 7-Oxo-5,6-dihydrocyclopenta[c]pyridine-6-carboxylate (22): A
solution of malonate 23 (250 mg, 773 μmol) in abs. EtOH (1.5 mL)
was added under an inert atmosphere (N2) to a solution of Na
(71 mg, 3.1 mmol) in abs. EtOH (1.5 mL) and the mixture was
stirred at 65 °C for 2 h. Water (10 mL) was added and the solution
was acidified with hydrochloric acid (1 M, 5 mL) to pH 3. The
aqueous layer was extracted with CH2Cl2 (3ϫ 10 mL) and the
combined organic extracts were dried (MgSO4), filtered, and the
solvent was evaporated. β-Oxo ester 22 (80 mg, 0.39 mmol, 50%)
was obtained after column chromatography (SiO2; CH2Cl2/MeOH
= 20:1; Rf = 0.41) as a colorless solid; m.p. 92–93 °C. A doubled
signal set is observed due to keto-enol tautomers (ratio 4:3). 1H
NMR (500 MHz, CDCl3): δ (ketone form) = 1.29 (t, J = 7.1 Hz, 3
H), 3.37 (dd, J = 18.1, 8.4 Hz, 1 H), 3.58 (dd, J = 18.1, 4.0 Hz, 1
1
tra (ratio 5:1). H NMR (500 MHz, CDCl3): δ (major conformer)
= 1.34 (t, J = 7.2 Hz, 3 H), 3.05 (dd, J = 11.3, 16.6 Hz, 1 H), 3.12
(s, 3 H), 3.64 (dd, J = 7.5, 16.4 Hz, 1 H), 3.95 (ddd, J = 7.5, 9.2,
11.3 Hz, 1 H), 4.24–4.31 (m, 2 H), 5.94 (d, J = 9.2 Hz, 1 H), 6.98
(d, J = 5.2 Hz, 1 H), 7.28–7.35 (m, 5 H), 8.41 (d, J = 5.1 Hz, 1 H),
8.64 (s, 1 H) ppm; δ (minor conformer) = 1.33 (t, J = 7.9 Hz, 3 H),
3.03 (s, 3 H), 3.05 (dd, J = 16.6, 11.3 Hz, 1 H), 3.52–3.59 (m, 1 H),
3.64 (dd, J = 16.4, 7.5 Hz, 1 H), 4.23–4.32 (m, 2 H), 5.70 (d, J =
8.3 Hz, 1 H), 7.08 (d, J = 5.0 Hz, 1 H), 7.22–7.24 (m, 2 H), 7.28–
7.35 (m, 3 H), 8.52 (d, J = 5.0 Hz, 1 H), 8.74 (s, 1 H) ppm. 13C{1H}
NMR (125 MHz, CDCl3): δ (major conformer) = 14.35 (CH3),
33.77 (CH3), 36.56 (CH2), 41.32 (CH), 61.83 (CH2), 122.31 (CH),
124.17 (CH), 126.20 (2 CH), 129.09 (2 CH), 129.52 (CH), 132.86
H), 3.72 (dd, J = 8.4, 4.1 Hz, 1 H), 4.21–4.25 (m, 2 H), 7.47 (d, J (C), 134.08 (C), 143.78 (C), 143.98 (C), 148.74 (CH), 149.83 (CH),
= 5.1 Hz, 1 H), 8.73 (d, J = 5.2 Hz, 1 H), 8.99 (s, 1 H) ppm; δ (enol
form) = 1.34 (t, J = 7.1 Hz, 3 H), 3.55 (s, 2 H), 4.31 (q, J = 7.1 Hz,
2 H), 7.42 (d, J = 5.0 Hz, 1 H), 8.61 (d, J = 4.9 Hz, 1 H), 8.88 (s,
1 H), 10.32 (br. s, 1 H) ppm. 13C{1H} NMR (125 MHz, CDCl3): δ
(ketone form) = 14.25 (CH3), 30.33 (CH2), 53.03 (CH), 62.18
169.87 (C), 172.62 (C) ppm; δ (minor conformer) = 14.38 (CH3),
33.95 (CH3), 34.08 (CH2), 44.89 (CH), 61.88 (CH2), 120.82 (CH),
122.78 (2 CH), 125.92 (2 CH), 129.34 (2 CH), 133.33 (C), 136.51
(C), 144.93 (C), 145.41 (C), 147.51 (CH), 150.92 (CH), 168.91 (C),
171.29 (C) ppm. IR (ATR): ν = 3057 (w), 2934 (w), 1730 (s), 1641
˜
(CH2), 121.99 (CH), 131.25 (C), 147.40 (CH), 154.33 (CH), 161.57 (vs), 1590 (m), 1559 (w), 1465 (w), 1446 (m), 1428 (m), 1405 (m),
(C), 168.36 (C), 198.23 (C) ppm; δ (enol form) = 14.50 (CH3), 33.00 1372 (s), 1327 (m), 1255 (m), 1190 (s), 1117 (m), 1079 (m), 1028
(CH2), 60.56 (CH2), 103.26 (C), 120.24 (C), 133.64 (C), 142.56 (s), 950 (w), 919 (w), 892 (w), 856 (m), 769 (s), 731 (m), 697 (m),
(CH), 149.42 (CH), 151.45 (C), 167.59 (C), 168.87 (C) ppm. IR 648 (w), 635 (w), 585 (m), 552 (w) cm–1. HRMS (ESI): calcd. for
(ATR): ν = 2979 (m), 2913 (w), 1689 (vs), 1615 (s), 1584 (s), 1564 C20H20N2NaO3 [M + Na+] 359.1372; found 359.1373.
˜
(s), 1476 (w), 1458 (w), 1443 (m), 1414 (m), 1405 (m), 1384 (w),
1367 (w), 1320 (m), 1296 (m), 1253 (m), 1205 (s), 1175 (s), 1155 (s),
Methyl 3-Chloroisonicotinate (25): SOCl2 (4.53 g, 38.1 mmol) was
added to a cooled (ice-water bath) solution of acid 26 (1.50 g,
1119 (s), 1099 (s), 1027 (s), 925 (s), 863 (m), 839 (m), 826 (m), 766
9.52 mmol) in MeOH (50 mL) and the mixture was stirred for 24 h
(s), 729 (m), 669 (w), 646 (m), 580 (m) cm–1. HRMS (ESI): calcd.
at 80 °C. All volatile materials were removed in vacuo and the resi-
due was diluted with satd. aqueous NaHCO3 solution (50 mL). The
for C11H11NNaO3 [M + Na+] 228.0637; found 228.0643.
Ethyl 7-Oxo-6-(2-oxo-2-phenylethyl)-5,6-dihydrocyclopenta[c]pyrid- aqueous layer was extracted with CH2Cl2 (3ϫ 30 mL) and the
ine-6-carboxylate (24): Phenacylbromide (11; 84 mg, 0.42 mmol) combined organic extracts were dried (MgSO4), filtered, and the
and K2CO3 (58 mg, 0.42 mmol) were added to a solution of β-oxo
ester 22 (72 mg, 0.35 mmol) in acetone (0.7 mL) and the mixture
was stirred at 40 °C for 3 h. Water (10 mL) and brine (5 mL) were
added and the aqueous layer was extracted with CH2Cl2 (3ϫ
10 mL). The combined organic extracts were dried (MgSO4), fil-
tered, and the solvent was evaporated. Diketone 24 (67 mg,
0.21 mmol, 59%) was isolated after column chromatography (SiO2;
hexane/MTBE = 1:2; Rf = 0.21) as a brownish solid; m.p. 130–
solvent was evaporated to obtain ester 25 (1.28 g, 7.48 mmol, 79%)
as a colorless liquid. H NMR (500 MHz, CDCl3): δ = 3.95 (s, 3
H), 7.63 (d, J = 4.9 Hz, 1 H), 8.57 (d, J = 4.9 Hz, 1 H), 8.70 (s, 1
H) ppm. 13C{1H} NMR (125 MHz, CDCl3): δ = 53.17 (CH3),
124.27 (CH), 130.37 (C), 137.05 (C), 148.22 (CH), 151.60 (CH),
1
164.70 (C) ppm. IR (ATR): ν = 3047 (w), 3027 (w), 3014 (w), 2957
˜
(w), 1739 (s), 1437 (m), 1398 (m), 1305 (m), 1272 (vs), 1219 (m),
1196 (m), 1180 (m), 1132 (m), 1090 (m), 1040 (m), 961 (m), 851
2146
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 2140–2149

Synthesis of Regioisomeric Pyrido[c]azocanones
(m), 834 (m), 782 (m), 742 (m), 704 (m), 665 (m) cm–1. HRMS 1 h at the same temperature. The solvents were evaporated and the
(ESI): calcd. for C7H7ClNO2 [M + H+] 172.0165; found 172.0161. residue was purified by chromatography (SiO2; hexane/MTBE =
1:1; Rf = 0.35) to give ester 31 (4.27 g, 25.8 mmol, 34%) as a yellow
Methyl (E)-3-[(2-tert-Butoxycarbonyl)ethenyl]isonicotinate (27):
oil. 1H NMR (500 MHz, CDCl3): δ = 1.39 (t, J = 7.1 Hz, 3 H),
tert-Butyl acrylate (1.49 g, 11.7 mmol), Pd(OAc)2 (13 mg, 58 μmol),
2.85 (s, 3 H), 4.37 (q, J = 7.1 Hz, 2 H), 7.22–7.25 (m, 1 H), 8.22
PPh3 (31 mg, 0.12 mmol) and NEt3 (295 mg, 2.92 mmol) were
(d, J = 7.4 Hz, 1 H), 8.60 (dd, J = 1.5, 4.8 Hz, 1 H) ppm. 13C{1H}
added under an inert atmosphere (N2) to a solution of pyridine 25
NMR (125 MHz, CDCl3): δ = 14.47 (CH3), 24.64 (CH2), 61.64
(100 mg, 0.583 mmol) in anhydrous DMA (1.5 mL) and the mix-
(CH3), 121.31 (CH), 126.26 (C), 139.18 (CH), 151.27 (CH), 159.75
ture was stirred at 120 °C for 18 h. Water (10 mL) was added and
(C), 166.52 (C) ppm. IR (ATR): ν = 2982 (w), 2934 (w), 1720 (s),
˜
the aqueous layer was extracted with MTBE (3ϫ 10 mL). The
combined organic extracts were dried (MgSO4), filtered, and the
solvents were evaporated to give 27 (31 mg, 0.12 mmol, 20%) after
column chromatography (SiO2; hexane/MTBE = 1:1; Rf = 0.39) as
1584 (m), 1571 (m), 1439 (m), 1296 (m), 1275 (s), 1243 (s), 1140
(m), 1081 (s), 754 (s) cm–1. MS (70 eV, EI): m/z (%) = 165 (27)
[M+], 120 (40), 86 (62), 84 (98), 49 (100). HRMS (70 eV, EI): calcd.
for C9H11NO2 [M+] 165.1790; found 165.0782.
1
a yellow oil. H NMR (500 MHz, CDCl3): δ = 1.53 (s, 9 H), 3.95
Ethyl 2-(Chloromethyl)nicotinate (33):[32] DMF (263 mg,
3.60 mmol) and trichloroisocyanuric acid (12.6 g, 54.0 mmol) were
added to a solution of ester 31 (5.95 g, 36.0 mmol) in CH2Cl2
(36 mL) and the resulting mixture was stirred for 16 h at 23 °C.
The mixture was then filtered, the residue was washed with CH2Cl2
(2ϫ 40 mL) and the combined filtrates were washed with satd.
aqueous NaHCO3 solution (2ϫ 50 mL) and brine (50 mL) and
dried (MgSO4). After filtration, the solvents were evaporated to
give 33 (6.45 g, 32.3 mmol, 90%) as a yellow oil, which did not
require further purification. 1H NMR (500 MHz, CDCl3): δ = 1.41
(t, J = 7.2 Hz, 3 H), 4.41 (q, J = 7.1 Hz, 2 H), 5.10 (s, 2 H), 7.34
(dd, J = 4.8, 7.9 Hz, 1 H), 8.26 (d, J = 7.9 Hz, 1 H), 8.70 (d, J =
4.8 Hz, 1 H) ppm. 13C{1H} NMR (125 MHz, CDCl3): δ = 14.34
(CH3), 45.74 (CH2), 62.10 (CH2), 123.40 (CH), 126.02 (C), 139.34
(s, 3 H), 6.32 (d, J = 16.0 Hz, 1 H), 7.72 (d, J = 5.0 Hz, 1 H), 8.19
(d, J = 16.0 Hz, 1 H), 8.68 (d, J = 4.6 Hz, 1 H), 8.86 (s, 1 H) ppm.
13C{1H} NMR (125 MHz, CDCl3): δ = 28.40 (3 CH3), 53.11
(CH3), 81.28 (C), 123.45 (CH), 124.94 (CH), 130.76 (C), 136.48
(C), 139.10 (CH), 149.61 (CH), 150.80 (CH), 165.44 (C), 166.03
(C) ppm. IR (ATR): ν = 2977 (w), 2933 (w), 2872 (w), 1722 (s),
˜
1480 (w), 1454 (w), 1439 (w), 1367 (m), 1319 (w), 1274 (m), 1257
(m), 1222 (w), 1145 (s), 1101 (m), 980 (w), 845 (m), 702 (w), 671
(m), 628 (m) cm–1. HRMS (ESI): calcd. for C14H17NNaO4 [M +
Na+] 286.1055; found 286.1057.
Methyl 3-[(2-tert-Butoxycarbonyl)ethyl]isonicotinate (28): A suspen-
sion of Pd/C (6 mg, 10% on charcoal), pyridine 27 (30 mg,
0.11 mmol) and iPrOH (0.5 mL) was degassed (three times freeze,
pump, thaw) and then stirred under an atmosphere of hydrogen
(1 bar) at 23 °C for 3 d. Subsequently, the mixture was filtered and
the solvent was evaporated to give 28 (21 mg, 79 μmol, 69%) after
column chromatography (SiO2; hexane/MTBE = 1:1; Rf = 0.36) as
a colorless oil. 1H NMR (500 MHz, CDCl3): δ = 1.39 (s, 9 H), 2.55
(t, J = 7.6 Hz, 2 H), 3.20 (t, J = 7.6 Hz, 2 H), 3.92 (s, 3 H), 7.65
(d, J = 5.0 Hz, 1 H), 8.56 (d, J = 5.0 Hz, 1 H), 8.60 (s, 1 H) ppm.
13C{1H} NMR (125 MHz, CDCl3): δ = 27.18 (CH2), 28.29 (3
CH3), 36.69 (CH2), 52.73 (CH3), 80.84 (C), 123.58 (CH), 136.20
(C), 136.70 (C), 148.64 (CH), 153.02 (CH), 166.56 (C), 171.90
(CH), 152.34 (CH), 157.39 (C), 165.66 (C) ppm. IR (ATR): ν =
˜
2983 (w), 2940 (w), 1719 (s), 1583 (m), 1572 (m), 1442 (m), 1300
(m), 1262 (s), 1129 (m), 1081 (s), 1058 (m), 740 (m), 692 (m) cm–1.
MS (70 eV, EI): m/z (%) = 199 (53) [M+], 171 (23), 164 (46), 154
(56), 136 (100), 126 (24), 84 (48), 49 (47). HRMS (70 eV, EI): calcd.
for C9H10ClNO2 [M+] 199.0400; found 199.0399.
Ethyl 2-[2,2-Bis(ethoxycarbonyl)ethyl]nicotinate (34):[33] Diethyl ma-
lonate (6.00 g, 37.5 mmol) was added to a cooled (ice-water bath)
solution of Na (862 mg, 37.5 mmol) in EtOH/THF (1:1, 26 mL).
Subsequently, a solution of compound 33 (2.50 g, 12.5 mmol) in
THF (13 mL) was added and the mixture was further stirred with
cooling for 2 h and then at 23 °C for 2 h. All volatile materials were
removed in vacuo and the residue was diluted with water (60 mL)
and extracted with MTBE (3ϫ 50 mL). The combined organic ex-
tracts were dried (MgSO4), filtered, and the solvent was evaporated
to give malonate 34 (2.69 g, 8.32 mmol, 67%) after column
chromatography (SiO2; hexane/MTBE = 2:1; Rf = 0.28) as a yellow
oil. 1H NMR (500 MHz, CDCl3): δ = 1.22 (t, J = 7.1 Hz, 6 H),
1.38 (t, J = 7.1 Hz, 3 H), 3.82 (d, J = 7.6 Hz, 2 H), 4.35–4.39 (m,
5 H), 4.37 (q, J = 7.1 Hz, 2 H), 7.20 (dd, J = 4.1, 8.4 Hz, 1 H),
8.19 (d, J = 7.9 Hz, 1 H), 8.56 (d, J = 4.8 Hz, 1 H) ppm. 13C{1H}
NMR (125 MHz, CDCl3): δ = 14.26 (2 CH3), 14.44 (CH3), 35.29
(CH), 50.49 (CH2), 61.50 (2 CH2), 61.69 (CH2), 121.50 (CH),
125.90 (C), 138.74 (CH), 151.45 (CH), 158.93 (C), 166.33 (C),
(C) ppm. IR (ATR): ν = 2977 (w), 2955 (w), 2930 (w), 2850 (w),
˜
1727 (vs), 1453 (w), 1436 (w), 1408 (w), 1367 (w), 1275 (m), 1231
(w), 1209 (w), 1150 (m), 1103 (w), 673 (m), 631 (s) cm–1. HRMS
(ESI): calcd. for C14H19NNaO4 [M + Na+] 288.1212; found
288.1209.
tert-Butyl
5-Oxo-6,7-dihydrocyclopenta[c]pyridine-6-carboxylate
(30): KOtBu (37 mg, 0.33 mmol) was added under an inert atmo-
sphere (N2) at 0 °C to a solution of diester 28 (35 mg, 0.13 mmol)
in anhydrous THF (0.4 mL) and the mixture was stirred for 30 min
at this temperature. Water (10 mL) was added and the solution was
acidified with hydrochloric acid (1 M, 4 mL) to pH 1 and then ex-
tracted with CH2Cl2 (3ϫ 10 mL). The combined organic extracts
were dried (MgSO4), filtered, and the solvent was evaporated to
give β-oxo ester 30 (12 mg, 51 μmol, 39%) as a colorless oil. A
doubled signal set is observed due to keto-enol tautomerism (ratio
1:6). 1H NMR (500 MHz, CDCl3): δ (ketone form) = 1.46 (s, 9 H),
3.39 (dd, J = 8.4, 17.2 Hz, 1 H), 3.55 (dd, J = 3.8, 17.6 Hz, 1 H),
3.72–3.80 (m, 1 H), 7.56 (d, J = 4.9 Hz, 1 H), 8.69 (d, J = 5.1 Hz,
1 H), 8.94 (s, 1 H) ppm; δ (enol form) = 1.56 (s, 9 H), 3.63 (s, 2
H), 7.68 (d, J = 5.3 Hz, 1 H), 8.65 (d, J = 5.3 Hz, 1 H), 8.77 (s, 1
H), 9.03 (br. s, 1 H) ppm.
169.82 (2 C) ppm. IR (ATR): ν = 2982 (w), 2939 (w), 2907 (w),
˜
1746 (m), 1721 (s), 1571 (m), 1442 (m), 1368 (m), 1277 (m), 1253
(m), 1174 (m), 1136 (m), 1089 (m), 1055 (m), 1033 (m), 1019 (m),
858 (m), 758 (m) cm–1. MS (70 eV, EI): m/z (%) = 323 (4) [M+], 278
(60), 250 (90), 232 (83), 204 (100), 176 (73), 148 (27). HRMS (70 eV,
EI): calcd. for C16H21NO6 [M+] 323.1369; found 323.1370.
C16H21NO6 (323.34): calcd. C 59.43, H 6.55, N 4.33; found C
59.35, H 6.51, N 4.47.
Ethyl 2-Methylnicotinate (31): A solution of ethyl acetoacetate 32
(10.0 g, 76.8 mmol) and NH4OAc (6.64 g, 86.2 mmol) in toluene
(310 mL) was heated to reflux for 2 h in a Dean–Stark trap. Sub-
sequently, freshly distilled acroleine (12.9 g, 230 mmol) was slowly
added over 1.5 h under reflux and the mixture was then stirred for
Ethyl 5-Oxo-6,7-dihydrocyclopenta[b]pyridine-6-carboxylate (36):
Under an inert atmosphere (N2), a solution of malonate 34 (3.83 g,
11.8 mmol) in anhydrous THF (24 mL) was added to a suspension
Eur. J. Org. Chem. 2014, 2140–2149
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2147

M. Penning, J. Christoffers
FULL PAPER
of NaH (60% in mineral oil, 708 mg, 17.7 mmol) in anhydrous
THF (35 mL), while heating to reflux. The mixture was further
stirred at this temperature for 1 h, then acidified with hydrochloric
acid (1 M, 18 mL) to pH 5 and the aqueous layer was extracted
with CH2Cl2 (3ϫ 50 mL). The combined organic extracts were
dried (MgSO4), filtered, and the solvent was evaporated to give β-
oxo ester 36 (1.78 g, 8.68 mmol, 74%) after column chromatog-
raphy (SiO2; hexane/MTBE = 1:5; Rf = 0.40) as a yellow solid;
m.p. 53–55 °C. A doubled signal set is observed due to keto-enol
tautomers (ratio 2:1). 1H NMR (500 MHz, CDCl3): δ (ketone
form) = 1.28 (t, J = 7.1 Hz, 3 H), 3.49 (dd, J = 8.5, 18.0 Hz, 1 H),
3.66 (dd, J = 4.6, 17.4 Hz, 1 H), 3.79 (dd, J = 4.1, 8.5 Hz, 1 H),
4.21–4.25 (m, 2 H), 7.34 (dd, J = 4.8, 7.8 Hz, 1 H), 8.02 (dd, J =
spectra (ratio 2:1). 1H NMR (500 MHz, CDCl3): δ (major con-
former) = 1.27 (t, J = 7.1 Hz, 3 H), 3.05 (s, 3 H), 3.30 (dd, J =
11.7, 16.7 Hz, 1 H), 3.72 (dd, J = 7.6, 16.6 Hz, 1 H), 3.92 (ddd, J
= 7.7, 9.1, 11.7 Hz, 1 H), 4.16–4.25 (m, 2 H), 6.02 (d, J = 9.1 Hz,
1 H), 7.08 (dd, J = 4.9, 7.4 Hz, 1 H), 7.21–7.27 (m, 5 H), 7.65 (dd,
J = 1.7, 7.8 Hz, 1 H), 8.39 (dd, J = 1.7, 4.8 Hz, 1 H) ppm; δ (minor
conformer) = 1.26 (t, J = 7.0 Hz, 3 H), 2.97 (s, 3 H), 3.21–3.23 (m,
1 H), 3.65–3.68 (m, 2 H), 4.16–4.25 (m, 2 H), 5.70 (d, J = 7.7 Hz,
1 H), 7.11 (dd, J = 4.9, 7.7 Hz, 1 H), 7.14–7.16 (m, 2 H), 7.21–7.27
(m, 3 H), 7.76 (dd, J = 1.7, 7.7 Hz, 1 H), 8.44 (dd, J = 1.7, 4.9 Hz,
1 H) ppm. 13C{1H} NMR (125 MHz, CDCl3): δ (major conformer)
= 14.43 (CH3), 33.74 (CH3), 39.98 (CH2), 41.43 (CH), 61.73 (CH2),
121.76 (CH), 125.95 (CH), 126.19 (2 CH), 129.11 (2 CH), 129.41
1.6, 7.8 Hz, 1 H), 8.82 (dd, J = 1.6, 4.8 Hz, 1 H) ppm; δ (enol form) (CH), 132.48 (C), 134.41 (C), 136.46 (CH), 143.38 (C), 150.03 (C),
= 1.35 (t, J = 7.1 Hz, 3 H), 3.65 (s, 2 H), 4.32 (q, J = 7.1 Hz, 2 H),
7.31 (dd, J = 5.0, 7.7 Hz, 1 H), 7.90 (dd, J = 1.1, 7.7 Hz, 1 H), 8.58
(dd, J = 1.1, 5.0 Hz, 1 H), 10.47 (s, 1 H) ppm. 13C{1H} NMR
(125 MHz, CDCl3): δ (ketone form) = 14.37 (CH3), 33.33 (CH2),
154.30 (CH), 170.89 (C), 172.62 (C) ppm; δ (minor conformer) =
14.47 (CH3), 34.13 (CH3), 37.21 (CH2), 44.51 (CH), 61.73 (CH2),
121.76 (2 CH), 121.84 (CH), 122.33 (CH), 129.11 (2 CH), 129.24
(CH), 132.52 (C), 134.86 (CH), 137.01 (C), 144.69 (C), 150.70 (C),
53.24 (CH), 61.97 (CH2), 123.13 (CH), 133.06 (CH), 131.33 (C), 156.02 (CH), 170.05 (C), 171.75 (C) ppm. IR (ATR): ν = 3058 (w),
˜
156.66 (CH), 168.72 (C), 173.18 (C), 198.10 (C) ppm; δ (enol form) 2980 (w), 2937 (w), 2907 (w), 1730 (s), 1461 (s), 1446 (m), 1420
= 14.61 (CH3), 35.02 (CH2), 60.54 (CH2), 102.86 (C), 122.19 (CH),
(m), 1372 (s), 1264 (m), 1186 (m), 1161 (m), 1102 (m), 1029 (m),
128.89 (CH), 133.42 (C), 149.43 (CH), 163.50 (C), 167.22 (C), 770 (m), 734 (m), 698 (m), 632 (m) cm–1. MS (70 eV, EI): m/z (%)
169.43 (C) ppm. IR (ATR): ν = 3067 (w), 2989 (w), 2976 (w), 2900 = 336 (1) [M+], 260 (100), 245 (47), 195 (28), 165 (17), 105 (35), 91
˜
(w), 1694 (s), 1650 (s), 1623 (s), 1608 (m), 1575 (s), 1563 (s), 1403
(6), 77 (6). HRMS (70 eV, EI): calcd. for C20H20N2O3 [M+]
(m), 1342 (m), 1324 (m), 1280 (m), 1244 (m), 1214 (s), 1183 (s), 336.1468; found 336.1460.
1161 (m), 1102 (m), 1088 (s), 1039 (m), 1024 (m), 923 (m), 814 (m),
765 (s), 726 (m) cm–1. MS (70 eV, EI): m/z (%) = 205 (100) [M+],
193 (33). HRMS (70 eV, EI): calcd. for C11H11NO3 [M+] 205.0739;
found 205.0734. C11H11NO3 (205.21): calcd. C 64.38, H 5.40, N
6.83; found C 64.36, H 5.40, N 6.77.
(Z)-6-Methyl-5-oxo-7-phenyl-5,6,9,10-tetrahydropyrido[3,2-c]-
azocine-9-carboxylic Acid (37): A solution of NaOH (512 mg,
12.8 mmol) in water (6.5 mL) was added to a solution of ester 8
(430 mg, 1.28 mmol) in EtOH (1.5 mL) and the mixture was stirred
at 23 °C for 1 h. Subsequently, water (10 mL) was added and the
mixture was acidified with hydrochloric acid (1 M, 15 mL) to pH 1.
The aqueous layer was extracted with CH2Cl2 (3ϫ 20 mL) and the
combined organic extracts were dried (MgSO4), filtered, and the
solvents were evaporated to give carboxylic acid 37 (220 mg,
710 μmol, 56%) after column chromatography (SiO2; CH2Cl2/
MeOH = 10:1; Rf = 0.03) as a brown solid; m.p. 201–205 °C. A
Ethyl 5-Oxo-6-(2-oxo-2-phenylethyl)-6,7-dihydrocyclopenta[b]pyrid-
ine-6-carboxylate (35): Phenacylbromide (11; 1.28 g, 6.43 mmol)
and K2CO3 (889 mg, 6.43 mmol) were added to a solution of β-
oxo ester 36 (1.10 g, 5.36 mmol) in acetone (11 mL) and the mix-
ture was heated for 3 h at reflux. Water (15 mL) and brine (15 mL)
were added and the aqueous layer was extracted with MTBE (3ϫ
20 mL). The combined organic extracts were dried (MgSO4), fil-
tered, and the solvent was evaporated. Diketone 35 (1.23 g,
3.80 mmol, 71%) was isolated after column chromatography (SiO2;
hexane/MTBE = 1:2; Rf = 0.23) as a brownish resin. 1H NMR
(500 MHz, CDCl3): δ = 1.12 (t, J = 7.1 Hz, 3 H), 3.25 (d, J =
18.1 Hz, 1 H), 3.70 (d, J = 18.6 Hz, 1 H), 4.00 (d, J = 18.1 Hz, 1
H), 4.10–4.14 (m, 2 H), 4.12 (d, J = 18.5 Hz, 1 H), 7.37 (dd, J =
5.2, 7.2 Hz, 1 H), 7.43 (t, J = 7.7 Hz, 2 H), 7.55 (t, J = 7.4 Hz, 1
H), 7.92 (d, J = 8.0 Hz, 2 H), 8.07 (d, J = 7.7 Hz, 1 H), 8.82–8.83
(m, 1 H) ppm. 13C{1H} NMR (125 MHz, CDCl3): δ = 14.09 (CH3),
40.83 (CH2), 43.83 (CH2), 58.13 (C), 62.37 (CH2), 123.01 (CH),
128.33 (2 CH), 128.91 (2 CH), 129.11 (C), 133.04 (CH), 133.88
(CH), 136.13 (C), 156.04 (CH), 169.84 (C), 172.93 (C), 196.76 (C),
1
doubled signal set is observed in the NMR spectra (ratio 3:1). H
NMR (500 MHz, CDCl3): δ (major conformer) = 2.99 (s, 3 H),
3.26 (dd, J = 11.1, 16.5 Hz, 1 H), 3.68 (dd, J = 7.9, 16.4 Hz, 1 H),
3.88 (dt, J = 8.3, 11.0 Hz, 1 H), 6.06 (d, J = 8.8 Hz, 1 H), 7.30–
7.38 (m, 6 H), 7.90–7.94 (m, 1 H), 8.47 (dd, J = 1.6, 4.9 Hz, 1 H),
12.89 (br. s, 1 H) ppm; δ (minor conformer) = 2.87 (s, 3 H), 3.26
(dd, J = 11.1, 16.5 Hz, 1 H), 3.68 (dd, J = 7.9, 16.4 Hz, 1 H), 3.88
(dt, J = 8.3, 11.0 Hz, 1 H), 5.98 (d, J = 8.9 Hz, 1 H), 7.25–7.27 (m,
2 H), 7.30–7.38 (m, 3 H), 7.43–7.51 (m, 1 H), 7.90–7.94 (m, 1 H),
8.51 (dd, J = 1.6, 4.9 Hz, 1 H), 12.89 (br. s, 1 H) ppm. 13C{1H}
NMR (125 MHz, CDCl3): δ (major conformer) = 33.03 (CH3),
38.44 (CH2), 40.56 (CH), 121.92 (CH), 123.59 (C), 125.72 (2 CH),
128.29 (CH), 129.00 (2 CH), 132.20 (C), 133.97 (C), 136.66 (CH),
142.38 (C), 149.01 (CH), 153.61 (C), 169.17 (C), 173.47 (C) ppm; δ
(minor conformer) = 32.96 (CH3), 36.22 (CH2), 43.13 (CH), 122.32
(CH), 123.07 (CH), 125.39 (2 CH), 127.04 (CH), 129.06 (2 CH),
132.40 (C), 134.79 (CH), 136.02 (C), 142.79 (CH), 149.79 (CH),
200.56 (C) ppm. IR (ATR): ν = 3060 (w), 2977 (w), 2938 (w), 1740
˜
(s), 1713 (vs), 1698 (s), 1596 (m), 1578 (s), 1470 (m), 1449 (m), 1417
(m), 1406 (m), 1354 (m), 1284 (m), 1258 (m), 1237 (m), 1215 (s),
1196 (vs), 1096 (m), 1040 (m), 1001 (m), 914 (m), 753 (m), 690 (m),
625 (m) cm–1. HRMS (ESI): calcd. for C19H17NNaO4 [M + Na+]
346.1055; found 346.1066.
155.24 (C), 168.62 (C), 172.71 (C) ppm. IR (ATR): ν = 2915 (w,
˜
br), 2477 (w, br), 1656 (m), 1638 (s), 1582 (m), 1444 (m), 1419 (m),
1379 (m), 1322 (m), 1248 (m), 1198 (m), 1186 (m), 1165 (m), 1110
(m), 815 (m), 769 (s), 752 (m), 695 (m) cm–1. MS (70 eV, EI): m/z
(%) = 308 (4) [M+], 264 (9), 246 (13), 235 (8), 118 (100), 91 (8), 77
(10). HRMS (70 eV, EI): calcd. for C18H16N2O3 [M+] 308.1155;
found 308.1146.
Ethyl (Z)-6-Methyl-5-oxo-7-phenyl-5,6,9,10-tetrahydropyrido[3,2-
c]azocine-9-carboxylate (8): A solution of MeNH2 (2 M in THF,
1.24 mmol, 0.62 mL) was added to a solution of 1,4-diketone 35
(200 mg, 0.62 mmol) in THF (0.62 mL) and the mixture was stirred
for 15 h at 100 °C in a closed reaction vial. The solvent was then
evaporated and lactam 8 (101 mg, 300 μmol, 48%) was isolated af-
ter column chromatography (SiO2; hexane/EtOAc = 1:2; Rf = 0.25)
as a yellowish resin. A doubled signal set is observed in the NMR
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C{1H} NMR spectra of all products.
2148
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 2140–2149

Synthesis of Regioisomeric Pyrido[c]azocanones
[15] M. Penning, J. Christoffers, Eur. J. Org. Chem. 2012, 1809–
1818.
Acknowledgments
[16] R. Pflantz, J. Sluiter, M. Kricˇka, W. Saak, C. Hoenke, J.
Christoffers, Eur. J. Org. Chem. 2009, 5431–5436.
[17] F. Behler, F. Habecker, W. Saak, T. Klüner, J. Christoffers, Eur.
J. Org. Chem. 2011, 4231–4240.
The authors gratefully acknowledge Torben Alpers for assistance
and Nicola Matthieu Mann for initial experiments. Marc
Schmidtmann and Wolfgang Saak are gratefully thanked for X-ray
crystallography. The Heinz Neumüller-Stiftung is acknowledged for
a fellowship to M. P.
[18] a) D. Blanco-Ania, P. H. H. Hermkens, L. A. J. M. Sliedregt,
H. W. Scheeren, F. P. J. T. Rutjes, J. Comb. Chem. 2009, 11,
547–555; b) N. M. Evdokimov, A. S. Kireev, A. A. Yakovenko,
M. Y. Antipin, I. V. Magedov, A. Kornienko, J. Org. Chem.
2007, 72, 3443–3453; c) For a review, see: D. A. Horton, G. T.
Bourne, M. L. Smythe, Chem. Rev. 2003, 103, 893–930.
[19] a) M. Würdemann, J. Christoffers, Eur. J. Org. Chem. 2013,
7421–7431; b) M. Penning, J. Christoffers, Eur. J. Org. Chem.
2013, 389–400; c) M. Bender, J. Christoffers, Z. Naturforsch. B
2011, 66, 1209–1218; d) M. Würdemann, J. Christoffers, Syn-
lett 2011, 2841–2843; e) A. Rosiak, W. Frey, J. Christoffers, Eur.
J. Org. Chem. 2006, 4044–4054; f) A. Rosiak, C. Hoenke, J.
Christoffers, Eur. J. Org. Chem. 2007, 4376–4382.
[20] J. Christoffers, T. Werner, W. Frey, A. Baro, Chem. Eur. J. 2004,
10, 1042–1045.
[21] F. Pierre, P. C. Chua, S. E. O’Brien, A. Siddiqui-Jain, P. Bour-
bon, M. Haddach, J. Michaux, J. Nagasawa, M. K. Schwaebe,
E. Stefan, A. Vialettes, J. P. Whitten, T. K. Chen, L. Darjania,
R. Stansfield, K. Anderes, J. Bliesath, D. Drygin, C. Ho, M.
Omori, C. Proffitt, N. Streiner, K. Trent, W. G. Rice, D. M.
Ryckman, J. Med. Chem. 2011, 54, 635–654.
[22] C. L. Diedrich, D. Haase, J. Christoffers, Synthesis 2008, 2199–
2210.
[23] J. Christoffers, Synth. Commun. 1999, 29, 117–122.
[24] E. Kiselev, K. A. Agama, Y. Pommier, M. Cushman, J. Med.
Chem. 2012, 55, 1682–1697.
[25] D. J. Wallace, A. D. Gibb, I. F. Cottrell, D. J. Kennedy, K. M. J.
Brands, U. H. Dolling, Synthesis 2001, 1784–1789.
[26] K. Clarke, J. Goulding, R. M. Scrowston, J. Chem. Soc. Perkin
Trans. 1 1984, 1501–1505.
[27] D. Binder, Monatsh. Chem. 1974, 105, 203–208.
[28] a) H. H. Fox, J. T. Gibas, J. Org. Chem. 1958, 23, 64–66; b) M.
Shahabi, E. Schirmer, K. Shanab, T. Leepasert, J. Ruzicka, W.
Holzer, H. Spreitzer, B. Aicher, P. Schmidt, L. Blumenstein, G.
Müller, E. Günther, Bioorg. Med. Chem. Lett. 2013, 23, 1846–
1852; c) J. Epsztajn, M. W. Plotka, A. Grabowska, Synth. Com-
mun. 1997, 27, 1075–1086.
[1] a) M.-L. Bennasar, E. Zulaica, D. Sole, T. Roca, D. Garcia-
Diaz, S. Alonso, J. Org. Chem. 2009, 74, 8359–8368; b) J. G.
Kettle, D. Roberts, J. A. Joule, Heterocycles 2010, 82, 349–370.
[2] G. Büchi, S. J. Gould, F. Näf, J. Am. Chem. Soc. 1971, 93,
2492–2501.
[3] L. J. Dolby, H. Biere, J. Am. Chem. Soc. 1968, 90, 2699–2700.
[4] L. K. Hansen, F. C. Størmer, D. Petersen, A. J. Aasen, Acta
Crystallogr. Sect. E 2001, 57, o909–o912.
[5] a) R. Ortega, E. Ravina, C. F. Masaguer, F. Areias, J. Brea,
M. I. Loza, L. Lopez, J. Selent, M. Pastor, F. Sanz, Bioorg.
Med. Chem. Lett. 2009, 19, 1773–1778; b) M. Hellal, G. D.
Cuny, J. Org. Chem. 2010, 75, 3465–3568; c) A. Hölemann, H.-
U. Reissig, Synlett 2004, 2732–2735; d) M. T. McKenna, G. R.
Proctor, L. C. Young, A. L. Harvey, J. Med. Chem. 1997, 40,
3516–3523.
[6] a) D. A. Alonso, L. R. Falvello, B. Mancheno, C. Najera, M.
Tomas, J. Org. Chem. 1996, 61, 5004–5012; b) D. A. Alonso,
C. Najera, Tetrahedron Lett. 1994, 35, 8867–8870.
[7] a) J. B. Bremner, E. J. Browne, P. E. Davies, C. L. Raston, A. H.
White, Aust. J. Chem. 1980, 33, 1323–1334; b) O. O. Orazi,
R. A. Corral, H. Giaccio, J. Chem. Soc. Perkin Trans. 1 1986,
1977–1982; c) A. Rabi-Barakay, D. Ben-Ishai, Tetrahedron
1994, 50, 10771–10782; d) H. J. Kim, U. C. Yoon, Y.-S. Jung,
N. S. Park, E. M. Cederstrom, P. S. Mariano, J. Org. Chem.
1998, 63, 860–863; e) M. Mizukami, H. Saito, T. Higuchi, M.
Imai, H. Bando, N. Kawahara, S. Nagumo, Tetrahedron Lett.
2007, 48, 7228–7231; f) S. Nagumo, M. Mizukami, K. Wada,
T. Miura, H. Bando, N. Kawahara, Y. Hashimoto, M. Miyash-
ita, H. Akita, Tetrahedron Lett. 2007, 48, 8558–8561.
[8] F. Homsi, G. Rousseau, J. Org. Chem. 1998, 63, 5255–5258.
[9] a) G. C. Jones, C. R. Hauser, J. Org. Chem. 1962, 27, 3572–
3576; b) F. Sumiya, N. Shirai, Y. Sato, Chem. Pharm. Bull.
1991, 39, 36–40.
[10] a) S. Kim, G. H. Joe, J. Y. Do, J. Am. Chem. Soc. 1993, 115,
3328–3329; b) K. J. Blackall, D. Hendry, R. J. Pryce, S. M. Ro-
berts, J. Chem. Soc. Perkin Trans. 1 1995, 2767–2771; c) L.
Benati, D. Nanni, C. Sangiorgi, P. Spagnolo, J. Org. Chem.
1999, 64, 7836–7841.
[11] a) C. Lane, V. Snieckus, Synlett 2000, 1294–1296; b) J.-L.
Panayides, R. Pathak, H. Panagiotopoulos, H. Davids, M. A.
Fernandes, C. B. de Koning, W. A. L. van Otterlo, Tetrahedron
2007, 63, 4737–4747.
[29] W. A. Herrmann, C. Brossmer, C.-P. Riesinger, T. H. Riermeier,
K. Öfele, M. Beller, Chem. Eur. J. 1997, 3, 1357–1364.
[30] N. Ueyama, T. Yanagisawa, T. Kawai, M. Sonegawa, H. Baba,
S. Mochizuki, K. Kosakai, T. Tomiyama, Chem. Pharm. Bull.
1994, 42, 1841–1849.
[31] E. C. Juenge, D. A. Beal, W. P. Duncan, J. Org. Chem. 1970,
35, 719–722.
[32] R. F. Doehner Jr. (American Cyanamid Company), Eur. Pat.
Appl. 0325730 A2, 1988.
[12] a) J. Adachi, K. Nomura, K. Shiraki, K. Mitsuhashi, Chem.
Pharm. Bull. 1974, 22, 658–662; b) T. A. Moss, Tetrahedron
Lett. 2013, 54, 4254–4258.
[13] M. Rössle, J. Christoffers, Synlett 2006, 106–108.
[14] a) R. Pflantz, P. Tielmann, M. Rössle, C. Hoenke, J. Christof-
fers, Eur. J. Org. Chem. 2007, 3227–3238; b) For a review, see:
J. Christoffers, Catal. Today 2011, 159, 96–99.
[33] J. Hurst, D. G. Wibberley, J. Chem. Soc. 1962, 119–122.
[34] CCDC-988848 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Received: November 19, 2013
Published Online: February 3, 2014
Eur. J. Org. Chem. 2014, 2140–2149
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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