Formation of Bicyclic Cyclopentenone Derivatives by Robinson-Type Annulation of Cyclic β-Oxoesters Containing a 1,4-Diketone Moiety

Article abstract of DOI:10.1055/s-0036-1590812

Robinson-type cyclopentannulations of cyclic β-oxoesters possessing a 1,4-diketone moiety are accomplished under four different Bronsted basic reaction conditions. Using pyrrolidine/acetic acid in DMSO, an oxohexahydrocyclopenta[ a ]indene (42%) and an N

Full text of DOI:10.1055/s-0036-1590812

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–K
feature
A
en
I. Geibel et al.
Feature
Synthesis
Formation of Bicyclic Cyclopentenone Derivatives by Robinson-
Type Annulation of Cyclic β-Oxoesters Containing a 1,4-Diketone
Moiety
Irina Geibel
O
O
O
Me
O
Christoph Kahrs
AcOH
pyrrolidine
KOH
Jens Christoffers*
CO2Me
CO2Me
DMSO
H2O
80 °C, 18 h
60 °C, 2 h
N
N
N
Institut für Chemie, Carl von Ossietzky Universität Oldenburg,
26111 Oldenburg, Germany
jens.christoffers@uol.de
Boc
Boc
Boc
62%
100%
Received: 03.05.2017
Accepted: 31.05.2017
Published online: 25.07.2017
DOI: 10.1055/s-0036-1590812; Art ID: ss-2017-z0297-fa
B-ring. CORT 108297 (3) is a new and promising glucocorti-
coid receptor antagonist for the treatment of psychotic de-
pressions.5 The activity profile of compound 3 is compara-
ble to that of mifepristone (4) (RU 486), however, the main
advantage of CORT 108297 (3) is that it shows, in contrast
to mifepristone (4), no progesterone receptor antagonism.
Due to this adverse effect, mifepristone cannot be pre-
scribed to pregnant patients.
Abstract Robinson-type cyclopentannulations of cyclic β-oxoesters
possessing a 1,4-diketone moiety are accomplished under four differ-
ent Brønsted basic reaction conditions. Using pyrrolidine/acetic acid in
DMSO, an oxohexahydrocyclopenta[a]indene (42%) and an N-Boc-pro-
tected oxohexahydrocyclopenta[c]pyridine derivative (62%) are ob-
tained with retention of the ester moieties. The latter compound de-
fines an interesting new scaffold for medicinal chemistry with three
positions allowing further derivatizations. The use of KOtBu in DMSO or
NaH in toluene leads to cyclopentene derivatives with either partial es-
ter saponification and decarboxylation or displacement of the ester
moiety within the carbon skeleton. With aqueous KOH, the cyclopen-
tannulations are successful in almost all cases, but with the ester moi-
eties cleaved off. The respective bicyclic and tricyclic products are ob-
tained in good to excellent yields. The 1,4-diketone starting materials
are prepared by cerium-catalyzed oxidative coupling of β-oxoesters
with isopropenyl acetate. Alternatively, a two-step sequence consisting
of α-propargylation followed by palladium-catalyzed alkyne hydration is
used.
F
N
N
O
O
O
pyrrolidine
AcOH
Me
OEt
CO2Me
CO2Me
N
S
N
N
O
Boc
Boc
2 (70%)
O
1 (97% ee)
CF3
Me2N
Me
3
OH
Me
H
Keywords heterocyclic compounds, piperidine derivatives, cyclopen-
tenone, Robinson annulation, ketones, diketones, alicyclic compounds,
bicyclic compounds, alkyne hydration
H
O
4
Since its first report in 1935,1 the synthesis of cyclohex-
enone derivatives from 1,5-diketones via an intramolecular
aldol reaction has been one of the most widely used tools in
organic chemistry and was consequently named Robinson
annulation in honor of its inventor.2 Selected from the myr-
iad examples in the literature, the synthesis of octahy-
droisoquinolone 2 from 1,5-diketone 1 is shown in Scheme
1.3 Compound 2 is the intermediate product for the prepa-
ration of CORT 108297 (3).4 Starting from compound 2, a
sulfonamide moiety was introduced after N-Boc deprotec-
tion, the ethyl ester group was reduced, the resulting
primary alcohol alkylated and a pyrazole annulated to the
Scheme 1 Robinson annulation of heterocyclic 1,5-diketone 1 furnish-
ing compound 2 as an intermediate product for the synthesis of CORT
108297 (3), and the structure of mifepristone (4) (RU 486)
Recently, we reported on the synthesis of hexahydroiso-
indole derivative 6 by Robinson annulation of pyrrolidine
derivative 5 (Scheme 2), which can be regarded as the A-nor
homologue of compound 2 and was therefore included in
structure–activity investigations of derived A-nor homo-
logues of CORT 108297 (3).6 The objective of the study pre-
sented herein is the preparation of cyclopentannulated
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

B
I. Geibel et al.
Feature
Synthesis
piperidine 8a, being the B-nor homologue of compound 2,
by intramolecular aldol reaction of piperidine derivative 7a
possessing a 1,4-diketone moiety. The targeted cyclopen-
tapiperidine derivative 8a is reasonably envisioned as a fur-
ther intermediate product for related studies in a medicinal
chemistry context. There is literature precedent for this
kind of cyclopentannulation,7 although the number of ex-
amples is not as extensive as for the Robinson annulation
reaction to cyclohexenone derivatives. Examples of strongly
basic reactions conditions for this transformation are NaH
in toluene,8 KOtBu in DMSO,9 and KOH in water or etha-
nol.10
O
O
O
two steps
Me
CO2Me
CO2Me
N
N
Boc
Boc
5 (97% ee)
6 (85%)
O
O
Me
O
CO2Me
CO2Me
N
N
Boc
Boc
7a
8a
In addition to piperidine derivatives 7a and 7b, we also
included other cyclic 1,4-diketones in our study, i.e., the ali-
cyclic congeners 9a–d, the indanone derivative 10 and the
benzannulated representatives with a six-membered ring
11a and 11b (Figure 1). All the compounds shown in Figure
1 were racemates and were prepared according to two dif-
ferent pathways, as discussed in further detail below.
First of all, we investigated our standard conditions [po-
lar protic (buffered) with pyrrolidine and AcOH (1 equiv
each) in DMSO] that had already been successfully utilized
Scheme 2 Robinson annulation of heterocyclic 1,5-diketone 5 and the
projected preparation of cyclopentannulated piperidine 8a from 1,4-
diketone 7a
for the Robinson annulation of 1,5-diketone 1 furnishing
compound 2. However, even after tedious variation of the
reaction parameters: stoichiometry, temperature or the sol-
vent, we were only successful in two cases (Scheme 3). For-
tunately, the target reaction of this study proceeded to fur-
nish the piperidine derivative 8a in 62% yield. Changing the
Biographical Sketches
Jens Christoffers (right) was born in 1966
and grew up in northern Germany. He re-
ceived his diploma from Universität Marburg,
Germany in 1992 before moving to Bonn,
where he completed his doctorate in 1994
in the group of Professor K. H. Dötz. After a
postdoctorate with Professor R. G. Bergman
in Berkeley, USA, he joined the group of Pro-
fessor S. Blechert at TU Berlin in 1996,
where he finished his habilitation in 2000.
From 2001 to 2006 he was Associate Profes-
sor at Universität Stuttgart, and since 2006
is a Full Professor at Universität Oldenburg.
His current research interests are in the
fields of heterocyclic chemistry and homo-
geneous catalysis with focus on catalytic ox-
idation reactions utilizing molecular oxygen.
these products.
Christoph Kahrs (center) was born in
1993 in Germany. He received his B.Sc. in
chemistry from Universität Oldenburg in
2014 in the group of Professor Jürgen
Martens in the field of multicomponent re-
actions. He joined the group of Professor
Christoffers in 2016 for his master’s thesis,
which he finished with honors. For his Ph.D.
thesis, he is currently working in the field of
functional coordination polymers based on
sulfonic acids.
Irina Geibel (left) was born in Maikain,
Kazakhstan in 1986. She obtained her B.Sc.
in chemistry from Universität Oldenburg in
2012, where she performed research with
Professor Jürgen Martens in the field of mul-
ticomponent reactions. She received her
M.Sc. with honors in 2014 and is currently
finishing her Ph.D. in the group of Professor
Christoffers. Her research is focused on ceri-
um-catalyzed, oxidative C–C coupling reac-
tions toward 1,4-diketones and δ-lactones
as well as subsequent transformations of
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

C
I. Geibel et al.
Feature
Synthesis
not chemoselectively (Scheme 4 and Table 1). Apart from
the expected products 14b (up to 51% yield) and 14c (13–
15%), the alkoxydecarboxylated compounds 15b (up to 48%)
and 15c (up to 37%) were also obtained. We therefore de-
cided to use NaH in toluene,8 also under strictly anhydrous
conditions. Now we indeed avoided alkoxydecarboxylation,
but observed, for our purpose, a useless, but very remark-
able result, which actually contradicts literature reports:8b
while compounds 14b and 14c were not detectable, the
constitutional isomers 16b, 16c and 17c were obtained (see
Table 1 for yields), where the alkoxycarbonyl moiety
seemed to formally migrate within the carbon skeleton. Ac-
tually, this isomerization could be mechanistically inter-
preted as the result of a sequence of retro-Dieckmann and
Dieckmann reactions. Anyhow, for the cyclopentanone de-
rivative 9a, none of the respective products 14a, 15a, 16a or
17a (with two annulated five-membered rings) could be
isolated. Furthermore, reactions of the benzannulated start-
ing materials 10, 11a and 11b did not result in formation of
the expected products under either of the conditions (a),
(b) or (c).
O
Me
O
Me
O
O
Me
O
Me
O
O
O
X
CO2Me
CO2R
CO2Me
CO2R
N
n
PG
7a (PG = Boc)
7b (PG = Ac)
9a (n = 0, R = Et)
9b (n = 1, R = Et)
9c (n = 2, R = Me)
9d (n = 1, R = tBu)
10
11a (X = CH2, R = Et)
11b (X = NAc, R = Me)
Figure 1 1,4-Diketones submitted to cyclopentannulation experi-
ments
carbamate protecting group to N-acetyl in starting material
7b resulted in unspecified decomposition under similar re-
action conditions for unknown reasons. The other success-
ful case was the cyclization of the indanone 10 furnishing
cyclopentindene derivative 12, also in fair yield. In the for-
mation of products 8a and 12, the methoxycarboxyl group
was retained, which was not always the case in the experi-
ments presented below. The cyclopentene ring of com-
pound 12 could be catalytically hydrogenated with the cor-
responding product 13 being obtained in quantitative yield.
Needless to say, the relative configuration in this case must
be cis, as is always the case for two annulated five-mem-
bered rings. Actually, the formation of compound 12 is a
very interesting issue, since it is the only example of a prod-
uct with two annulated five-membered rings from
throughout this entire study.
O
O
O
Me
O
(a) or (b)
+
CO2R
CO2R
n
n
n
9a–c
14a–c
15a–c
O
O
O
Me
RO2C
O
O
O
Me
(c)
O
RO2C
+
(a)
CO2R
CO2Me
CO2Me
n
n
n
N
N
9a–c
16a–c
17a–c
PG
PG
Scheme 4 Attempts toward the cyclization of alicyclic 1,4-diketones
9a–c. Reagents and conditions: (a) KOtBu (1.2 equiv), DMSO, 50 °C, 20 h;
(b) KOtBu (1.2 equiv), DMSO, 100 °C, 20 h; (c) NaH (4 equiv), toluene,
111 °C, 18 h; for n, R and yields see Table 1.
7a (PG = Boc)
7b (PG = Ac)
8a (62%)
8b (0%)
O
O
Me
O
O
(b)
(c)
CO2Me
CO2Me
12 (42%)
CO2Me
Table 1 Results of the Conversions of the Alicyclic Starting Materials
Shown in Scheme 4
10
13 (quant.)
Scheme 3 Cyclopentannulation and subsequent catalytic hydrogena-
tion. Reagents and conditions: (a) pyrrolidine (1.0 equiv), AcOH (1.0
equiv), DMSO, 80 °C, 18 h; (b) pyrrolidine (1.0 equiv), AcOH (1.0 equiv),
DMSO, 100 °C, 18 h; (c) H2 (2.5 atm), cat. Pd/C, EtOAc, 50 °C, 2 d.
Starting material
Conditionsa
Yield of Yield of Yield of Yield of
14 15 16 17
9a (n = 0, R = Et)
9b (n = 1, R = Et)
9b (n = 1, R = Et)
9c (n = 2, R = Me)
9c (n = 2, R = Me)
9b (n = 1, R = Et)
9c (n = 2, R = Me)
(a), (b) or (c)
0%
0%
0%
0%
We then turned our attention to other Brønsted basic
reaction conditions that had precedent in the literature.
First of all, we investigated the use of KOtBu in DMSO,9
which was performed with exclusion of moisture in order
to prevent ester saponification, followed by decarboxyl-
ation. As a first albeit disappointing result, the conversion
of piperidine derivatives 7a and 7b led to unspecified de-
composition under these reaction conditions. The alicyclic
congeners 9b and 9c gave annulation products, however,
(a)
(b)
(a)
(b)
(c)
(c)
34%
51%
13%
15%
0%
48%
8%
0%
0%
0%
0%
37%
4%
0%
0%
0%
0%
0%
85%
33%
0%
0%
0%
35%
a For conditions (a), (b) and (c), see the caption to Scheme 4.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

D
I. Geibel et al.
Feature
Synthesis
Finally, we attempted to achieve cyclopentannulation
for all the starting materials collected in Figure 1 under
strongly basic, protic conditions10 by using aqueous KOH
solution (15% w/w), although we expected that such condi-
tions would result in saponification and decarboxylation in
almost every case (Scheme 5). Both piperidine derivatives
7a and 7b were converted smoothly at 60 °C to furnish the
two annulation products 18a and 18b in very good yields
(100% and 92%, respectively) (Table 2, entries 1 and 2). At
120 °C, however, no unique products were isolable, pre-
sumably due to cleavage of the N-Boc and N-Ac moieties
and subsequent reactions of the secondary amino function.
In the aliphatic series, the cyclopentenone derivative 9a did
not give any unique product (entry 3). The six- and seven-
membered homologues 9b and 9c gave cyclization prod-
ucts 15b and 15c with very good results at 120 °C (entries 4
and 5). At 60 °C, the yield for the seven-membered ring
product 15c was a little lower (64%) (entry 5). We also in-
vestigated whether a tert-butyl ester would be resistant to-
ward saponification under these conditions. At 60 °C, the
ester moiety was not preserved completely, and the prod-
uct 14d was obtained in only 17% yield (entry 6). At 120 °C,
the tert-butyloxycarbonyl group was completely cleaved
and compound 15b was isolated in 97% yield, which is al-
most equal to that starting with ethyl ester 9b. In the
benzannulated series, the indanone derivative 10 gave no
defined products. The six-membered tetralone 11a and the
tetrahydroquinoline derivative 11b gave very good yields of
products 19a,b at both temperatures (entries 7 and 8). In
the case of starting material 11b, which is an aniline deriva-
tive, the N-acetyl group is cleaved off.
Table 2 Results of the Conversions of the 1,4-Diketones Shown in
Scheme 5
Entry Starting material
Conditions (a)a
Conditions (b)a
Main/By-product (yield) Product (yield)
1
2
3
4
5
6
7
8
7a (PG = Boc)
18a (100%)
18b (92%)
18a (0%)
7b (PG = Ac)
18b (0%)
9a (n = 0, R = Et)
9b (n = 1, R = Et)
9c (n = 2, R = Me)
9d (n = 1, R = tBu)
11a (X = CH2, R = Et)
11b (X = NAc, R = Me)
15a (0%)
15a (0%)
15b (95%)
15b (95%)
15c (91%)
15b (97%)
19a (94%)c
19b (61%)e
15c (64%)
15b (79%)/14d (17%)
19a (97%)b
19b (65%)d
a For conditions (a) and (b) see the caption to Scheme 5. The reaction time
was generally 2 h; for exceptions, see footnotes b–e.
b Time: 6 h.
c Time: 9 h.
d Time: 8 h.
e Time: 5 h.
As mentioned above, the starting materials depicted in
Figure 1 were accessed according to two different routes.
The first method used the cerium-catalyzed aerobic cou-
pling of β-oxoesters 20 and 21 with isopropenyl acetate
furnishing the 1,4-diketones 9 and 10 (Scheme 6). This new
reaction was recently developed by us and can be regarded
as an oxidative Umpolung.11
OAc
O
Me
O
O
+ O2 (air)
Me
CO2R
CO2R
2.5 mol% CeCl3·7H2O
F3CCH2OH, 50 °C, 18 h
O
O
Me
n
n
O
20a (n = 0, R = Et)
20b (n = 1, R = Et)
20c (n = 2, R = Me)
9a (53%)
9b (27%)
9c (28%)
(a) or (b)
CO2Me
N
N
OAc
O
O
Me
O
PG
PG
+ O2 (air)
Me
7a (PG = Boc)
7b (PG = Ac)
18a (PG = Boc)
18b (PG = Ac)
CO2Me
CO2Me
2.5 mol% CeCl3·7H2O
F3CCH2OH, 50 °C, 18 h
O
O
O
Me
O
21
10 (89%)
(a) or (b)
+
Scheme 6 Cerium-catalyzed aerobic coupling of β-oxoesters 20 and
21 with isopropenyl acetate furnishing 1,4-diketones 9 and 10
CO2R
CO2tBu
n
n
9a–d
15a–c
14d
O
Since the above-mentioned one-step method did not
give reliable results in every case, we have also chosen an
alternative two-step protocol, which was less atom eco-
nomic and more cost intensive. The first step was the al-
kylation of the respective β-oxoesters 20d, 22a,b, and 25a,b
with propargyl bromide and K2CO3 in acetone (Scheme 7),
which gave the appropriate α-propargylated compounds
23a,b, 24, and 26a,b in good to excellent yields (63–100%).12
Compound 25b was previously unknown and prepared by
annulation (conjugated addition to methyl acrylate and
subsequent Dieckmann condensation) of N-acetyl anthrani-
O
O
Me
(a) or (b)
CO2R
X
X
11a (X = CH2, R = Et)
11b (X = NAc, R = Me)
19a (X = CH2)
19b (X = NH)
Scheme 5 Cyclization and dealkoxycarbonylation of 1,4-diketones 7, 9
and 11 under strongly basic, protic conditions. Reagents and conditions:
(a) 15% aqueous KOH, 60 °C, 2–9 h; (b) as (a), but 120 °C; for PG, n, R, X
and yields see Table 2.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

E
I. Geibel et al.
Feature
Synthesis
late 27. The second step was the catalytic alkyne hydration,
which is nowadays often reported with very popular gold
catalysts.13 However, in our hands, gold catalysis led to un-
satisfying results. The same is also true for the use of thuli-
um triflate [Tm(OTf)3], as reported recently,14 that did not
yield preparatively useful amounts of the 1,4-diketones in
our cases. Nevertheless, we eventually came across a report
by Xu et al.,15 who recommended PdCl2 as catalyst for the
hydration of alkynylphosphonates. Indeed, using their pro-
cedure, the 1,4-diketones 7a,b, 9d, and 11a could be ob-
tained in yields of 80–96%. Only isoquinoline derivative 11b
gave a poorer result (39% yield).
and being cost intensive, 1,4-diketones 7a,b, 9d, and 11a,b
were prepared in two steps by α-propargylation of oxo-
esters 20d, 22a,b, and 25a,b furnishing the alkynes 23a,b,
24, and 26a,b as intermediate products (yields of 63–100%),
which were subsequently submitted to palladium-cata-
lyzed hydration (yields of 39–96%).
We then turned to the annulation reactions and used a
protocol (pyrrolidine and acetic acid in DMSO) that had
been successfully applied before for the cyclohexenone an-
nulation of the respective 1,5-diketone 5.3 We were able to
cyclize the N-Boc protected compound 7a yielding the cy-
clopentapiperidine 8a (62%) with the ester moiety pre-
served, which is an important result, as this compound
could be a synthetic precursor of the B-nor analogue of
CORT 108297 (3) and therefore was the actual target com-
pound of our study. With a more general view, compound
8a holds three functionalities allowing for further derivati-
zations and defines therefore a new scaffold for lead discov-
ery in medicinal chemistry. Nevertheless, this result seems
to be a little fortunate, because neither the N-acetyl conge-
ner 7b nor the other 1,4-diketones 9a–d and 11a,b gave cy-
clization products under these reaction conditions. An ex-
ception was the preparation of the tricyclic product 12
(42%) from indanone derivative 10, which is the only com-
pound accessed by us via annulation of two five-membered
rings. When using a stronger Brønsted base, albeit under
aprotic (and anhydrous) reaction conditions, as were KOtBu
in DMSO or NaH, the alkoxycarbonyl groups were either to
some extent cleaved and subsequently decarboxylated
(products 15b,c, 37–48%) or were displaced within the car-
bon skeleton (products 16b,c in yields of 85% and 33%, and
compound 17c in 35% yield), most probably due to a se-
quence of retro-Dieckmann and Dieckmann processes. We
finally decided to intentionally accept ester saponification
and decarboxylation and conducted the cyclizations in
aqueous KOH. Indeed, we obtained the corresponding bicy-
clic products 18a,b, 15b,c, and the tricyclic products 19a,b
without alkoxycarbonyl moieties in good to excellent yields.
O
Me
O
O
O
CO2Me
(a)
(b)
CO2Me
CO2Me
N
N
N
PG
PG
PG
22a (PG = Boc)
22b (PG = Ac)
23a (63%)
23b (78%)
7a (96%)
7b (82%)
O
Me
O
O
O
CO2tBu
(a)
(a)
(b)
(b)
CO2tBu
CO2tBu
20d
24 (93%)
9d (80%)
O
O
Me
O
O
CO2R
CO2R
CO2R
X
X
X
25a (X = CH2, R = Et)
25b (X = NAc, R = Me)
26a (89%)
26b (100%)
11a (80%)
11b (39%)
(c) 56% for X = NAc
CO2Me
NHAc
27
Scheme 7 Synthesis of 1,4-diketones in two steps via α-propargyl de-
rivatives. Reagents and conditions: (a) BrCH2C≡CH (2.0 equiv), K2CO3
(1.2 equiv), acetone, 60 °C, 2–6 h; (b) PdCl2 (2 mol%), H2O in 1,4-diox-
ane, 80 °C, 10 min to 8 h; (c) CH2=CHCO2Me (1.1 equiv), KOtBu (1.1
equiv), THF, 23 °C, 3 d. For detailed reaction times of the procedures (a)
and (b), see the experimental section.
Compounds 20d,16 22b,17 and 2718 are known in the literature and
were prepared according to the published procedures. The syntheses
of oxoesters 21,11 25a,11 22a,3 and 1,4-diketones 9a,11 9b,11 9c11 and
1011 were reported by us earlier. All other starting materials were
commercially available. Preparative column chromatography was car-
ried out using Merck SiO2 (35–70 μm, type 60 A) with hexanes, tert-
butyl methyl ether (MTBE), EtOH and MeOH as eluents. TLC was per-
formed on Merck aluminum plates coated with SiO2 F254. Melting
points were recorded using a Gallenkamp apparatus. IR spectra were
recorded on a Bruker Tensor 27 spectrophotometer equipped with a
‘GoldenGate’ diamond ATR unit. 1H and 13C NMR spectra were record-
ed on Bruker Avance DRX 500 and 300 instruments. Multiplicities of
carbon signals were determined with DEPT experiments. HRMS spec-
tra were obtained with a Waters Q-TOF Premier (ESI) spectrometer.
In conclusion, we have prepared cyclic oxoesters with a
1,4-dicarbonyl unit following two different routes, and sub-
sequently submitted them to intramolecular aldol conden-
sation furnishing bicyclic and tricyclic cyclopentenone de-
rivatives. First of all, 1,4-diketones 9a–c, and 10 were pre-
pared in 27–89% yields by cerium-catalyzed aerobic
coupling of oxoesters 20a–c and 21 with isopropenyl ace-
tate, following an oxidative Umpolung strategy reported by
us recently.11 Alternatively, although requiring more work
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

F
I. Geibel et al.
Feature
Synthesis
Pd-Catalyzed Hydration; General Procedure A (GP A)
HRMS (ESI): m/z [M + Li]+ calcd for C12H17LiNO5: 262.1261; found:
262.1257.
PdCl2 (2 mol%) and H2O (50 g/mol) were added to a solution of α-
propargyl-β-oxo ester (1.0 equiv) in 1,4-dioxane (3 L/mol) and the re-
sulting mixture was stirred for 10 min to 8 h at 80 °C. The solvent was
removed in vacuo and the crude product purified by column chroma-
tography to give the respective 1,4-diketone.
tert-Butyl 2-Oxo-1-(2-oxopropyl)cyclohexane-1-carboxylate (9d)
According to GP A, a mixture of α-propargyl-β-oxo ester 24 (900 mg,
3.81 mmol), PdCl2 (14 mg, 76 μmol) and H2O (8 drops, 184 mg) in 1,4-
dioxane (12 mL) was heated at 80 °C for 10 min. The crude mixture
was purified by column chromatography (SiO2, hexanes/MTBE, 1:1,
Rf = 0.39) to yield the title compound 9d (778 mg, 3.06 mmol, 80%) as
a light yellow oil.
1-tert-Butyl 3-Methyl 4-Oxo-3-(2-oxopropyl)piperidine-1,3-dicar-
boxylate (7a)
According to GP A, a mixture of α-propargyl-β-oxo ester 23a (310 mg,
1.05 mmol), PdCl2 (4 mg, 21 μmol) and H2O (3 drops, 66 mg) in 1,4-
dioxane (3 mL) was heated at 80 °C for 30 min. The crude mixture was
purified by column chromatography (SiO2, MTBE, Rf = 0.44) to yield
the title compound 7a (316 mg, 1.01 mmol, 96%) as a colorless oil. The
NMR spectra showed partly broadened and doubled signal sets due to
the carbamate moiety.
IR (ATR): 2976 (w), 2938 (w), 2868 (w), 1710 (vs), 1450 (w), 1424 (w),
1367 (m), 1312 (w), 1270 (w), 1146 (s), 1132 (s), 1079 (w), 949 (w),
845 (m), 735 (m), 703 (w) cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.47 (s, 9 H), 1.64–1.75 (m, 4 H), 2.03
(ddt, J = 13.0 Hz, J = 6.4 Hz, J = 2.9 Hz, 1 H), 2.17 (s, 3 H), 2.32 (dt, J =
10.0 Hz, J = 3.1 Hz, 1 H), 2.41–2.47 (m, 1 H), 2.73–2.78 (m, 1 H), 2.78
(d, J = 17.2 Hz, 1 H), 2.82 (d, J = 17.1 Hz, 1 H).
13C{1H} NMR (125 MHz, CDCl3): δ = 21.98 (CH2), 26.80 (CH2), 27.85 (3
CH3), 30.40 (CH3), 36.79 (CH2), 40.44 (CH2), 48.25 (CH2), 59.98 (C),
82.24 (C), 170.84 (C), 205.40 (C), 207.56 (C).
IR (ATR): 2999 (w), 2958 (w), 2903 (w), 1694 (vs), 1471 (m), 1427
(m), 1365 (m), 1294 (w), 1248 (m), 1230 (m), 1163 (vs), 1098 (w),
1072 (m), 971 (m), 893 (m), 869 (w), 733 (w) cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.37 (s, 9 H), 2.09 (s, 3 H), 2.41 (dt, J =
15.6 Hz, J = 4.0 Hz, 1 H), 2.77 (d, J = 18.0 Hz, 1 H), 2.73–2.85 (m, 1 H),
2.92–3.08 (m, 1 H), 3.19–3.41 (m, 1 H), 3.28 (ddd, J = 13.4 Hz, J = 10.6
Hz, J = 4.4 Hz, 1 H), 3.56–3.66 (m, 3 H), 4.01–4.11 (m, 1 H), 4.21–4.35
(m, 1 H).
13C{1H} NMR (125 MHz, CDCl3): δ = 28.01 (3 CH3), 29.76 (CH3), 39.14
(CH2), 42.28 (1/2 CH2), 43.24 (1/2 CH2), 44.64 (1/2 CH2), 44.74 (1/2
CH2), 49.45 (1/2 CH2), 49.84 (1/2 CH2), 52.54 (CH3), 57.96 (1/2 C),
58.34 (1/2 C), 80.22 (C), 153.73 (1/2 C), 154.07 (1/2 C), 170.38 (C),
204.02 (1/2 C), 204.19 (1/2 C), 204.36 (1/2 C), 204.55 (1/2 C).
HRMS (ESI): m/z [M + Li]+ calcd for C14H22LiO4: 261.1673; found:
261.1680.
Ethyl 2-(2-Oxopropyl)-1-tetralone-2-carboxylate (11a)
According to GP A, a mixture of α-propargyl-β-oxo ester 26a (475 mg,
1.85 mmol), PdCl2 (7 mg, 37 μmol) and H2O (4 drops, 89 mg) in 1,4-
dioxane (5 mL) was heated at 80 °C for 2 h. The crude mixture was
purified by column chromatography (SiO2, hexanes/MTBE, 1:1, Rf =
0.29) to yield the title compound 11a (407 mg, 1.48 mmol, 80%) as a
colorless oil.
1H NMR (500 MHz, CDCl3): δ = 1.13 (t, J = 7.1 Hz, 3 H), 2.22 (s, 3 H),
2.42 (ddd, J = 13.5 Hz, J = 5.1 Hz, J = 4.1 Hz, 1 H), 2.47 (ddd, J = 13.8 Hz,
J = 11.4 Hz, J = 4.8 Hz, 1 H), 2.87 (dt, J = 17.3 Hz, J = 4.4 Hz, 1 H), 2.99
(d, J = 17.4 Hz, 1 H), 3.05 (ddd, J = 16.9 Hz, J = 11.5 Hz, J = 5.5 Hz, 1 H),
3.08 (d, J = 17.4 Hz, 1 H), 4.10–4.19 (m, 2 H), 7.20 (d, J = 7.7 Hz, 1 H),
7.30 (t, J = 7.6 Hz, 1 H), 7.45 (td, J = 7.5 Hz, J = 1.4 Hz, 1 H), 8.01 (dd, J =
7.9 Hz, J = 1.4 Hz, 1 H).
HRMS (ESI): m/z [M + Na]+ calcd for C15H23NNaO6: 336.1418; found:
336.1421.
Methyl 1-Acetyl-4-oxo-3-(2-oxopropyl)piperidine-3-carboxylate
(7b)
According to GP A, a mixture of α-propargyl-β-oxo ester 23b (1.00 g,
4.21 mmol), PdCl2 (15 mg, 84 μmol) and H2O (9 drops, 204 mg) in 1,4-
dioxane (15 mL) was heated at 80 °C for 3 h. The crude mixture was
purified by column chromatography (SiO2, MTBE/MeOH, 16:3, Rf =
0.22) to yield the title compound 7b (880 mg, 3.45 mmol, 82%) as a
colorless oil. The NMR spectra showed doubled signal sets due to ro-
tamers (ratio 3:2).
The data were in accordance with literature values.11
Methyl 1-Acetyl-4-oxo-3-(2-oxopropyl)-1,2,3,4-tetrahydroquino-
line-3-carboxylate (11b)
IR (ATR): 3057 (w), 2984 (w), 2954 (w), 1715 (vs), 1650 (vs), 1432 (s),
1364 (m), 1266 (s), 1227 (m), 1171 (m), 1099 (w), 1046 (w), 1018 (w)
According to GP A, a mixture of α-propargyl-β-oxo ester 26b (500 mg,
1.72 mmol), PdCl2 (6 mg, 34 μmol) and H2O (4 drops, 92 mg) in 1,4-
dioxane (8 mL) was heated at 80 °C for 8 h. The crude mixture was
purified by column chromatography (SiO2, MTBE, Rf = 0.22) to yield
the title compound 11b (203 mg, 0.67 mmol, 39%) as a colorless oil.
NMR spectra showed partly broadened signal sets due to the amide
moiety.
cm–1
.
1H NMR (500 MHz, CDCl3): δ (major rotamer) = 2.01 (s, 3 H), 2.05 (s, 3
H), 2.38 (dt, J = 15.5 Hz, J = 3.8 Hz, 1 H), 2.58 (ddd, J = 15.4 Hz, J = 11.3
Hz, J = 6.8 Hz, 1 H), 2.79 (d, J = 18.0 Hz, 1 H), 2.89 (d, J = 18.0 Hz, 1 H),
2.98–3.16 (m, 1 H), 3.45–3.53 (m, 1 H), 3.57 (s, 3 H), 4.17 (dd, J = 13.9
Hz, J = 2.6 Hz, 1 H), 4.47 (ddt, J = 13.0 Hz, J = 6.4 Hz, J = 3.0 Hz, 1 H); δ
(minor rotamer) = 2.01 (s, 3 H), 2.03 (s, 3 H), 2.46 (dt, J = 15.7 Hz, J =
4.1 Hz, 1 H), 2.51–2.62 (m, 1 H), 2.73 (d, J = 18.2 Hz, 1 H), 2.82 (ddd, J =
17.3 Hz, J = 10.0 Hz, J = 6.0 Hz, 1 H), 2.98–3.16 (m, 2 H), 3.51 (s, 3 H),
3.86 (ddt, J = 13.2 Hz, J = 6.4 Hz, J = 2.9 Hz, 1 H), 4.59 (dd, J = 13.4 Hz,
J = 2.3 Hz, 1 H).
13C{1H} NMR (125 MHz, CDCl3): δ (major rotamer) = 20.54 (CH3),
29.85 (CH3), 38.77 (CH2), 40.37 (CH2), 44.36 (CH2), 51.22 (CH2), 52.76
(CH3), 58.49 (C), 169.26 (C), 169.97 (C), 202.46 (C), 204.53 (C); δ (mi-
nor rotamer) = 20.64 (CH3), 29.53 (CH3), 39.02 (CH2), 44.56 (CH2),
44.70 (CH2), 47.01 (CH2), 52.47 (CH3), 57.62 (C), 169.12 (C), 170.05 (C),
203.23 (C), 204.58 (C).
IR (ATR): 2955 (w), 2923 (w), 2853 (w), 1737 (m), 1720 (m), 1672
(vs), 1601 (m), 1480 (m), 1462 (m), 1379 (m), 1293 (w), 1243 (m),
1213 (m), 1171 (w), 1123 (w), 1083 (w), 961 (w), 765 (m) cm–1
.
1H NMR (500 MHz, CDCl3): δ = 2.14 (s, 3 H), 2.25 (s, 3 H), 3.07 (d, J =
18.4 Hz, 1 H), 3.24 (d, J = 18.4 Hz, 1 H), 3.62 (s, 3 H), 4.19 (d, J = 13.5
Hz, 1 H), 4.65–4.78 (m, 1 H), 7.24 (t, J = 7.9 Hz, 1 H), 7.48–7.56 (m, 2
H), 7.97 (dt, J = 7.9 Hz, J = 1.1 Hz, 1 H).
13C{1H} NMR (125 MHz, CDCl3): δ = 22.71 (CH3), 29.98 (CH3), 44.86
(CH2), 49.66 (CH2), 52.95 (CH3), 56.57 (C), 123.98 (CH), 124.90 (C),
125.41 (CH), 128.17 (CH), 134.14 (CH), 143.26 (C), 169.88 (C), 170.10
(C), 191.17 (C), 204.71 (C).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

G
I. Geibel et al.
Feature
Synthesis
HRMS (ESI): m/z [M + H]+ calcd for C16H18NO5: 304.1179; found:
304.1174.
1H NMR (500 MHz, CDCl3): δ = 2.22 (d, J = 18.7 Hz, 1 H), 2.67 (d, J =
19.1 Hz, 1 H), 2.88–2.94 (m, 2 H), 3.08 (d, J = 16.1 Hz, 1 H), 3.75 (d, J =
16.1 Hz, 1 H), 3.80 (s, 3 H), 4.13 (d, J = 8.9 Hz, 1 H), 7.17–7.19 (m, 1 H),
7.25–7.29 (m, 3 H).
13C{1H} NMR (125 MHz, CDCl3): δ = 41.29 (CH2), 42.71 (CH2), 46.90
(CH2), 50.50 (CH), 52.54 (CH3), 56.18 (C), 124.46 (CH), 125.26 (CH),
127.44 (CH), 127.75 (CH), 140.49 (C), 143.03 (C), 175.80 (C), 215.83
(C).
2-tert-Butyl 7a-Methyl 6-Oxo-2,3,4,6,7,7a-hexahydro-1H-cyclo-
penta[c]pyridine-2,7a-dicarboxylate (8a)
A solution of pyrrolidine (46 mg, 0.64 mmol), glacial AcOH (38 mg,
0.64 mmol) and 1,4-diketone 7a (199 mg, 0.64 mmol) in DMSO (1.5
mL) was heated for 18 h at 80 °C in a tightly closed reaction vial. After
cooling to ambient temperature, the mixture was diluted with brine
(30 mL) and extracted with MTBE (2 × 10 mL). The combined organic
extracts were dried (MgSO4), filtered and the solvent was removed in
vacuo. The residue was purified by column chromatography (SiO2,
MTBE, Rf = 0.43) to yield the title compound 8a (117 mg, 0.40 mmol,
62%) as a yellow oil.
HRMS (ESI): m/z [M + Na]+ calcd for C14H14NaO3: 253.0835; found:
253.0830.
Annulation Using KOtBu in DMSO; General Procedure B (GP B)
Under an anhydrous and inert atmosphere (N2), a solution of KOtBu
(1.2 equiv) and 1,4-diketone 9b or 9c (1 equiv) in anhydrous DMSO (8
L/mol) was stirred for 20 h at the temperature given below. After cool-
ing to ambient temperature, the mixture was acidified with HCl (10%,
ca. 3 L/mol) to pH 4 and extracted with MTBE (3 × 25 L/mol). The
combined organic layers were washed with brine (40 L/mol) and H2O
(40 L/mol), dried (MgSO4), filtered and the solvent was removed in
vacuo. The residue was purified by column chromatography (SiO2,
hexanes/MTBE, 1:2) to yield the indenone-carboxylate 14b or 14c in
the first fraction and the indenone 15b or 15c in the second fraction.
IR (ATR): 2978 (w), 2895 (w), 2863 (w), 1703 (s), 1696 (vs), 1629 (m),
1422 (m), 1365 (m), 1311 (w), 1292 (w), 1274 (w), 1238 (m), 1199
(w), 1165 (s), 1123 (m), 1050 (w), 1036 (w), 956 (w), 898 (w), 847 (w)
cm–1
.
1H NMR (300 MHz, CDCl3): δ = 1.46 (s, 9 H), 2.26 (d, J = 18.8 Hz, 1 H),
2.49–2.91 (m, 5 H), 3.70 (s, 3 H), 4.26–4.59 (m, 1 H), 4.94 (d, J = 13.1
Hz, 1 H), 6.03 (s, 1 H).
13C{1H} NMR (75 MHz, CDCl3): δ = 28.21 (3 CH3), 29.52 (CH2), 43.51
(CH2), 43.75 (CH2), 52.70 (CH3), 53.20 (CH2), 53.87 (C), 80.44 (C),
129.47 (CH), 153.87 (C), 171.88 (C), 177.26 (C), 204.45 (C).
Ethyl 2-Oxo-3,3a,4,5,6,7-hexahydro-2H-indene-3a-carboxylate
(14b)
HRMS (ESI): m/z [M + Li]+ calcd for C15H21LiNO5: 302.1574; found:
KOtBu (37 mg, 0.33 mmol) and 1,4-diketone 9b (62 mg, 0.27 mmol) in
anhydrous DMSO (3 mL) were reacted according to GP B at 100 °C to
furnish compound 14b (29 mg, 0.14 mmol, 51%) in the first fraction
(SiO2, hexanes/MTBE, 1:2, Rf = 0.44) as a colorless oil. Secondly, prod-
uct 15b (3 mg, 22 μmol, 8%) was eluted (Rf = 0.36) as a light yellow oil.
1H NMR (500 MHz, CDCl3): δ = 1.25 (t, J = 7.1 Hz, 3 H), 1.32 (td, J = 13.3
Hz, J = 3.8 Hz, 1 H), 1.40 (qt, J = 13.2 Hz, J = 4.0 Hz, 1 H), 1.54 (qt, J =
13.6 Hz, J = 3.5 Hz, 1 H), 1.74–1.79 (m, 1 H), 1.98–2.04 (m, 1 H), 2.28
(d, J = 18.7 Hz, 1 H), 2.39 (tdd, J = 13.5 Hz, J = 5.7 Hz, J = 1.7 Hz, 1 H),
2.64 (d, J = 18.7 Hz, 1 H), 2.68 (dq, J = 13.4, J = 2.9 Hz, 1 H), 2.79 (ddt,
J = 13.6 Hz, J = 4.1 Hz, J = 1.9 Hz, 1 H), 4.13–4.22 (m, 2 H), 5.96 (d, J =
1.5 Hz, 1 H).
302.1584.
Methyl 2-Oxo-1,2,8,8a-tetrahydrocyclopenta[a]indene-8a-carbox-
ylate (12)
A solution of pyrrolidine (100 mg, 1.40 mmol), glacial AcOH (85 mg,
1.40 mmol) and 1,4-diketone 10 (346 mg, 1.41 mmol) in DMSO (3 mL)
was heated for 18 h at 100 °C in a tightly closed reaction vial. After
cooling to ambient temperature, the mixture was diluted with brine
(10 mL) and extracted with MTBE (2 × 5 mL). The combined organic
extracts were dried (MgSO4), filtered and the solvent was removed in
vacuo. The residue was purified by column chromatography (SiO2,
hexanes/MTBE, 1:1, Rf = 0.31) to yield the title compound 12 (135 mg,
0.59 mmol, 42%) as a red oil.
The data were in accordance with literature values.19
IR (ATR): 2972 (w), 2953 (w), 1730 (s), 1707 (vs), 1626 (s), 1197 (s),
1166 (s), 755 (s), 729 (s) cm–1
.
2,4,5,6,7,7a-Hexahydro-1H-inden-2-one (15b)
1H NMR (300 MHz, CDCl3): δ = 2.64 (d, J = 16.8 Hz, 1 H), 2.92 (d, J =
15.4 Hz, 1 H), 2.98 (d, J = 16.8 Hz, 1 H), 3.61 (s, 3 H), 3.84 (d, J = 15.4
Hz, 1 H), 6.26 (s, 1 H), 7.32–7.34 (m, 1 H), 7.39–7.47 (m, 2 H), 7.59 (d,
J = 7.6 Hz, 1 H).
13C{1H} NMR (125 MHz, CDCl3): δ = 39.59 (CH2), 47.82 (CH2), 53.06
(CH3), 62.15 (C), 121.65 (CH), 124.55 (CH), 125.74 (CH), 127.63 (CH),
132.32 (CH), 133.44 (C), 147.71 (C), 173.23 (C), 180.38 (C), 207.62 (C).
KOtBu (49 mg, 0.44 mmol) and 1,4-diketone 9b (83 mg, 0.37 mmol) in
anhydrous DMSO (3 mL) were reacted according to GP B at 50 °C to
furnish compound 14b (26 mg, 0.13 mmol, 34%) in the first fraction
(SiO2, hexanes/MTBE, 1:2, Rf = 0.44) as a colorless oil. Secondly, prod-
uct 15b (24 mg, 0.18 mmol, 48%) was eluted (Rf = 0.36) as a light yel-
low oil.
1H NMR (300 MHz, CDCl3): δ = 1.12 (qd, J = 12.5 Hz, J = 3.4 Hz, 1 H),
1.35–1.57 (m, 2 H), 1.82–1.94 (m, 1 H), 1.97 (dd, J = 17.7 Hz, J = 6.5 Hz,
1 H), 2.01–2.05 (m, 1 H), 2.15–2.32 (m, 2 H), 2.57 (dd, J = 17.7 Hz, J =
2.0 Hz, 1 H), 2.60–2.68 (m, 1 H), 2.78–2.83 (m, 1 H), 5.83 (s, 1 H).
HRMS (ESI): m/z [M + Li]+ calcd for C14H12LiO3: 235.0941; found:
235.0938.
The data were in accordance with literature values.8a
Methyl 2-Oxo-1,2,3,3a,8,8a-hexahydrocyclopenta[a]indene-8a-
carboxylate (13)
Methyl 2-Oxo-2,3,3a,4,5,6,7,8-octahydroazulene-3a-carboxylate
(14c)
A mixture of Pd/C (10% w/w, 3 mg), enone 12 (25 mg, 0.11 mmol) and
EtOAc (10 mL) was stirred under a H2 atmosphere (2.5 bar) for 48 h at
50 °C. After filtration through SiO2 [MTBE, Rf = 0.36 (hexanes/MTBE,
2:1)], the title compound 13 (25 mg, 0.11 mmol, 100%) was isolated as
a colorless oil.
KOtBu (30 mg, 0.27 mmol) and 1,4-diketone 9c (50 mg, 0.22 mmol) in
anhydrous DMSO (2.7 mL) were reacted according to GP B at 100 °C to
furnish compound 14c (7 mg, 34 μmol, 15%) in the first fraction (SiO2,
hexanes/MTBE, 1:2, Rf = 0.42) as a light yellow oil. Secondly, product
15c (1 mg, 9 μmol, 4%) was eluted (Rf = 0.35) as a colorless oil.
IR (ATR): 2954 (w), 2927 (w), 2859 (w), 1729 (vs), 747 (s) cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

H
I. Geibel et al.
Feature
Synthesis
IR (ATR): 2927 (m), 2856 (w), 1726 (vs), 1689 (vs), 1614 (m), 1449
(m), 1412 (w), 1294 (w), 1246 (m), 1193 (m), 1161 (m), 1013 (w), 931
HRMS (ESI): m/z [M + Na]+ calcd for C12H16NaO3: 231.0992; found:
231.0992.
(w), 864 (w), 842 (w) cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.33–1.39 (m, 1 H), 1.44–1.52 (m, 1 H),
1.54–1.59 (m, 1 H), 1.62–1.72 (m, 2 H), 1.77 (ddd, J = 13.9 Hz, J = 10.1
Hz, J = 1.7 Hz, 1 H), 1.82–1.88 (m, 1 H), 2.29 (d, J = 18.0 Hz, 1 H), 2.31
(ddd, J = 14.1 Hz, J = 8.7 Hz, J = 1.6 Hz, 1 H), 2.54 (dddd, J = 14.5 Hz, J =
9.6 Hz, J = 3.8 Hz, J = 1.2 Hz, 1 H), 2.80 (ddd, J = 10.7 Hz, J = 7.6 Hz, J =
3.8 Hz, 1 H), 2.85 (d, J = 18.1 Hz, 1 H), 3.71 (s, 3 H), 5.98 (t, J = 1.1 Hz, 1
H).
13C{1H} NMR (125 MHz, CDCl3): δ = 24.76 (CH2), 28.99 (CH2), 29.76
(CH2), 31.38 (CH2), 36.29 (CH2), 48.91 (CH2), 52.74 (CH3), 57.42 (C),
132.00 (CH), 174.19 (C), 183.28 (C), 206.62 (C).
Conversion of 1,4-Diketone 9c with NaH in Toluene
Under an anhydrous and inert atmosphere of N2, a solution of 1,4-
diketone 9c (49 mg, 0.22 mmol) in anhydrous toluene (0.3 mL) was
added to a suspension of NaH (35 mg, 60% in mineral oil, 0.87 mmol)
in anhydrous toluene (1.7 mL) and the resulting reaction mixture was
stirred for 18 h at 111 °C. After cooling to 0 °C, the mixture was acidi-
fied with HCl (10%, ca. 0.5 mL) to pH 4 and extracted with MTBE
(3 × 5 mL). The combined organic layers were washed with brine (10
mL) and H2O (10 mL), dried (MgSO4), filtered and the solvent was re-
moved in vacuo. The residue was purified by column chromatography
(SiO2, hexanes/MTBE, 1:2) to yield the azulenone 16c (15 mg, 72
μmol, 33%) in the first fraction (Rf = 0.39) as a colorless oil. Secondly,
the azulenone 17c (16 mg, 77 μmol, 35%) was eluted (Rf = 0.26) as a
colorless oil.
HRMS (ESI): m/z [M + Na]+ calcd for C12H16NaO3: 231.0992; found:
231.0991.
2,3,3a,4,5,6,7,8-Octahydroazulen-2-one (15c)
KOtBu (74 mg, 0.66 mmol) and 1,4-diketone 9c (125 mg, 0.55 mmol)
in anhydrous DMSO (4.7 mL) were reacted according to GP B at 50 °C
to furnish compound 14c (15 mg, 72 μmol, 13%) in the first fraction
(SiO2, hexanes/MTBE, 1:2, Rf = 0.42) as a light yellow oil. Secondly,
product 15c (31 mg, 0.21 mmol, 37%) was eluted (Rf = 0.35) as a color-
less oil.
1H NMR (500 MHz, CDCl3): δ = 1.34–1.54 (m, 3 H), 1.65–1.70 (m, 2 H),
1.71–1.77 (m, 1 H), 1.80–1.86 (m, 1 H), 1.91–1.96 (m, 1 H), 2.00 (dd,
J = 18.4 Hz, J = 2.6 Hz, 1 H), 2.66 (dd, J = 18.4 Hz, J = 6.4 Hz, 1 H), 2.66–
2.77 (m, 2 H), 2.91–2.95 (m, 1 H), 5.85 (q, J = 1.5 Hz, 1 H).
Methyl 2-Oxo-1,2,4,5,6,7,8,8a-octahydroazulene-4-carboxylate
(16c)
IR (ATR): 2926 (m), 2856 (w), 1733 (s), 1701 (vs), 1605 (m), 1437 (m),
1342 (m), 1245 (m), 1193 (w), 1148 (s), 1072 (w), 1023 (w), 996 (w),
924 (w), 812 (w) cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.40–1.48 (m, 1 H), 1.49–1.58 (m, 2 H),
1.67–1.78 (m, 3 H), 1.81–1.87 (m, 1 H), 1.97–2.03 (m, 1 H), 2.66–2.72
(m, 1 H), 2.76–2.82 (m, 1 H), 3.08 (d, J = 3.5 Hz, 1 H), 3.31–3.36 (m, 1
H), 3.77 (s, 3 H), 5.85 (d, J = 1.4 Hz, 1 H).
13C{1H} NMR (125 MHz, CDCl3): δ = 26.65 (CH2), 28.24 (CH2), 30.59
(CH2), 32.85 (CH2), 33.12 (CH2), 48.88 (CH), 52.73 (CH3), 60.78 (CH),
127.86 (CH), 169.82 (C), 187.49 (C), 201.31 (C).
The data were in accordance with literature values.20
Ethyl 2-Oxo-2,4,5,6,7,7a-hexahydro-1H-indene-4-carboxylate
(16b)
HRMS (ESI): m/z [M + Na]+ calcd for C12H16NaO3: 231.0992; found:
231.0992.
Under an anhydrous and inert atmosphere of N2, a solution of 1,4-
diketone 9b (46 mg, 0.20 mmol) in anhydrous toluene (0.3 mL) was
added to a suspension of NaH (33 mg, 60% in mineral oil, 0.81 mmol)
in anhydrous toluene (1.7 mL) and the resulting reaction mixture was
stirred for 18 h at 111 °C. After cooling to 0 °C, the mixture was acidi-
fied with HCl (10%, ca. 0.5 mL) to pH 4 and extracted with MTBE
(3 × 5 mL). The combined organic layers were washed with brine (10
mL) and H2O (10 mL), dried (MgSO4), filtered and the solvent was re-
moved in vacuo. The crude product was purified by column chroma-
tography (SiO2, hexanes/MTBE, 1:1, Rf = 0.36) to yield the indenone
16b (36 mg, 0.17 mmol, 85%) as a colorless oil.
Methyl 2-Oxo-2,3,3a,4,5,6,7,8-octahydroazulene-1-carboxylate
(17c)
IR (ATR): 2925 (m), 2855 (w), 1739 (s), 1707 (vs), 1605 (m), 1436 (m),
1363 (m), 1309 (m), 1230 (m), 1207 (m), 1157 (m), 1111 (w), 1020
(s), 781 (w), 733 (w) cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.33–1.57 (m, 3 H), 1.65–1.93 (m, 4 H),
1.98–2.03 (m, 1 H), 2.10 (dd, J = 18.6 Hz, J = 2.8 Hz, 1 H), 2.76 (dd, J =
18.6 Hz, J = 6.9 Hz, 1 H), 3.00–3.10 (m, 3 H), 3.83 (s, 3 H).
13C{1H} NMR (125 MHz, CDCl3): δ = 26.00 (CH2), 28.87 (CH2), 30.50
(CH2), 33.28 (CH2), 34.58 (CH2), 43.45 (CH), 44.18 (CH2), 51.90 (CH3),
131.04 (C), 164.05 (C), 194.53 (C), 202.84 (C).
IR (ATR): 2979 (w), 2935 (m), 2859 (w), 1732 (s), 1702 (vs), 1621 (s),
1447 (w), 1369 (w), 1336 (w), 1293 (w), 1270 (m), 1252 (m), 1197
(w), 1168 (m), 1144 (s), 1112 (w), 1060 (w), 1025 (m), 941 (w), 857
HRMS (ESI): m/z [M + Na]+ calcd for C12H16NaO3: 231.0992; found:
231.0991.
(w), 840 (m), 786 (w), 677 (w), 650 (w) cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.19 (qd, J = 12.9 Hz, J = 3.6 Hz, 1 H),
1.29 (t, J = 7.2 Hz, 3 H), 1.38 (qt, J = 13.8 Hz, J = 4.2 Hz, 1 H), 1.52 (qt, J =
13.3 Hz, J = 3.4 Hz, 1 H), 1.87 (dtd, J = 13.7 Hz, J = 3.3 Hz, J = 1.7 Hz, 1
H), 2.00–2.05 (m, 1 H), 2.22–2.27 (m, 1 H), 2.31 (td, J = 13.9 Hz, J = 5.8
Hz, 1 H), 2.84 (ddt, J = 14.0 Hz, J = 4.1 Hz, J = 1.9 Hz, 1 H), 3.00–3.04
(m, 2 H), 4.15–4.25 (m, 2 H), 5.80 (s, 1 H).
13C{1H} NMR (125 MHz, CDCl3): δ = 14.34 (CH3), 25.16 (CH2), 26.73
(CH2), 31.03 (CH2), 34.15 (CH2), 46.06 (CH), 59.46 (CH), 61.66 (CH2),
125.12 (CH), 169.37 (C), 184.30 (C), 201.47 (C).
Annulation with Aqueous KOH in Water; General Procedure C (GP
C)
Under an inert atmosphere of N2, aqueous KOH (15% w/w, 2.5 L/mol)
was added dropwise over a period of 15 min to a mixture of the re-
spective 1,4-diketone (1.0 equiv) in H2O (20 L/mol). The mixture was
stirred at 60 °C or 120 °C for 2–9 h, then cooled to ambient tempera-
ture and extracted with CH2Cl2 (3 × 10 L/mol). The combined organic
layers were dried (MgSO4), filtered and the solvent removed in vacuo.
The crude product was purified by column chromatography to give
the cyclopentenone derivatives.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

I
I. Geibel et al.
Feature
Synthesis
tert-Butyl 1,3,4,6,7,7a-Hexahydro-2H-cyclopenta[c]pyridin-6-one-
tert-Butyl 2-Oxo-2,3,4,5,6,7-hexahydroindene-3a-carboxylate
2-carboxylate (18a)
(14d)
According to GP C, 1,4-diketone 7a (55 mg, 0.18 mmol) and KOH (15%
in H2O, 0.5 mL) in H2O (4 mL) were reacted for 2 h at 60 °C to furnish
the title compound 18a (42 mg, 0.18 mmol, 100%) as a yellow oil
without further chromatographic purification. NMR spectra showed
partly broadened signal sets due to rotamers (ratio 1:1).
According to GP C, 1,4-diketone 9d (100 mg, 0.39 mmol) and KOH
(15% in H2O, 1.0 mL) in H2O (8 mL) were reacted for 2 h at 60 °C. The
crude mixture was purified by column chromatography (SiO2, hex-
anes/MTBE, 1:1, Rf = 0.39) to yield the title compound 14d (16 mg, 68
μmol, 17%) in the first fraction as a colorless oil. Secondly, indenone
15b (42 mg, 0.31 mmol, 79%) was eluted (Rf = 0.26) as a colorless liq-
uid.
IR (ATR): 2969 (w), 2932 (w), 2853 (w), 1690 (vs), 1624 (m), 1417
(m), 1365 (m), 1262 (m), 1240 (m), 1161 (s), 1108 (m), 1026 (w), 881
(w) cm–1
.
IR (ATR): 2975 (w), 2943 (w), 2859 (w), 1717 (vs), 1627 (m), 1447 (w),
1369 (w), 1233 (w), 1154 (s), 1135 (m), 990 (w), 848 (w) cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.47 (s, 9 H), 1.94 (dd, J = 18.8 Hz, J =
2.5 Hz, 1 H), 2.31–2.56 (m, 2 H), 2.50 (dd, J = 18.7 Hz, J = 6.6 Hz, 1 H),
2.62–2.86 (m, 3 H), 4.32–4.60 (m, 2 H), 5.94 (t, J = 1.7 Hz, 1 H).
13C{1H} NMR (125 MHz, CDCl3): δ = 28.33 (3 CH3), 30.68 (CH2), 38.48
(CH2), 40.76 (CH), 44.35 (CH2), 50.68 (CH2), 80.37 (C), 128.00 (CH),
154.26 (C), 180.14 (C), 207.45 (C).
1H NMR (500 MHz, CDCl3): δ = 1.22–1.35 (m, 2 H), 1.43 (s, 9 H), 1.54
(qt, J = 13.2 Hz, J = 3.3 Hz, 1 H), 1.70–1.78 (m, 1 H), 2.00 (ddt, J = 10.3
Hz, J = 4.8 Hz, J = 2.3 Hz, 1 H), 2.24 (d, J = 18.7 Hz, 1 H), 2.38 (td, J =
13.4 Hz, J = 5.8 Hz, 1 H), 2.60 (d, J = 18.7 Hz, 1 H), 2.57–2.67 (m, 1 H),
2.73–2.83 (m, 1 H), 5.92 (d, J = 1.6 Hz, 1 H).
13C{1H} NMR (125 MHz, CDCl3): δ = 23.16 (CH2), 27.18 (CH2), 27.81 (3
CH3), 29.82 (CH2), 37.64 (CH2), 48.00 (CH2), 54.61 (C), 81.63 (C),
128.14 (CH), 172.27 (C), 182.19 (C), 206.69 (C).
HRMS (ESI): m/z [M + Li]+ calcd for C13H19LiNO3: 244.1519; found:
244.1520.
HRMS (ESI): m/z [M + Li]+ calcd for C14H20LiO3: 243.1567; found:
243.1561.
2-Acetyl-1,2,3,4,7,7a-hexahydro-6H-cyclopenta[c]pyridin-6-one
(18b)
According to GP C, 1,4-diketone 7b (108 mg, 0.42 mmol) and KOH
(15% in H2O, 1.1 mL) were reacted for 2 h at 60 °C. The crude mixture
was purified by column chromatography (SiO2, MTBE/MeOH, 4:1, Rf =
0.27) to yield the title compound 18b (70 mg, 0.39 mmol, 92%) as a
yellow solid (mp 132 °C). This compound has been reported in the lit-
erature previously, but was not sufficiently characterized.21 NMR
spectra showed doubled signal sets due to rotamers (ratio 1:1).
2,4,5,6,7,7a-Hexahydro-1H-inden-2-one (15b) from Oxoester 9d
According to GP C, the 1,4-diketone 9d (235 mg, 0.92 mmol) and KOH
(15% in H2O, 3 mL) were reacted for 2 h at 120 °C. The crude material
was purified by column chromatography (SiO2, hexanes/MTBE, 1:1,
Rf = 0.27) to yield the title compound 15b (121 mg, 0.89 mmol, 97%)
as a colorless liquid; for characterization see above.
IR (ATR): 2917 (w), 2876 (w), 1702 (s), 1673 (m), 1640 (s), 1620 (vs),
1426 (s), 1363 (w), 1264 (m), 1230 (m), 1137 (w), 1016 (m), 878 (w),
3,3a,4,5-Tetrahydro-2H-cyclopenta[a]naphthalen-2-one (19a)
841 (w), 685 (w) cm–1
.
According to GP C, 1,4-diketone 11a (100 mg, 0.36 mmol) and KOH
(15% in H2O, 1.0 mL) were reacted for 6 h at 60 °C to yield the title
compound 19a (64 mg, 0.35 mmol, 97%) as a colorless solid (mp
74 °C) without further chromatographic purification.
1H NMR (500 MHz, CDCl3): δ = 1.63–1.71 (m, 1 H), 2.20 (dd, J = 18.3
Hz, J = 3.5 Hz, 1 H), 2.29 (dtd, J = 12.1 Hz, J = 4.8 Hz, J = 2.1 Hz, 1 H),
2.79 (dd, J = 18.3 Hz, J = 6.5 Hz, 1 H), 2.99 (ddd, J = 17.2 Hz, J = 5.2 Hz,
J = 2.2 Hz, 1 H), 3.02–3.09 (m, 2 H), 6.39 (d, J = 2.0 Hz, 1 H), 7.23–7.28
(m, 2 H), 7.36 (td, J = 7.5 Hz, J = 1.4 Hz, 1 H), 7.66 (dd, J = 7.8 Hz, J = 1.3
Hz, 1 H).
1H NMR (500 MHz, CDCl3): δ = 1.97 (dd, J = 18.7 Hz, J = 2.4 Hz, 2 H),
2.14 (s, 3 H), 2.15 (s, 3 H), 2.19 (t, J = 12.1 Hz, 1 H), 2.41–2.55 (m, 5 H),
2.75–2.84 (m, 5 H), 3.09 (td, J = 13.1 Hz, J = 3.1 Hz, 1 H), 4.06 (ddt, J =
13.5 Hz, J = 6.2 Hz, J = 2.0 Hz, 1 H), 4.14 (ddd, J = 12.0 Hz, J = 4.7 Hz, J =
2.0 Hz, 1 H), 4.92 (ddt, J = 12.2 Hz, J = 5.6 Hz, J = 2.0 Hz, 1 H), 5.00 (ddd,
J = 12.5 Hz, J = 6.3 Hz, J = 2.2 Hz, 1 H), 5.95 (t, J = 1.7 Hz, 1 H), 5.96 (t,
J = 1.7 Hz, 1 H).
13C{1H} NMR (125 MHz, CDCl3): δ = 21.39 (2 CH3), 30.32 (C), 31.07 (C),
38.28 (CH2), 38.53 (CH2), 40.47 (CH), 41.24 (CH), 41.80 (CH2), 46.35
(CH2), 48.02 (CH2), 52.67 (CH2), 128.32 (CH), 128.39 (CH), 168.93 (2
C), 178.47 (C), 179.08 (C), 206.57 (C), 207.09 (C).
The data were in accordance with literature values.22
HRMS (ESI): m/z [M + Li]+ calcd for C10H13LiNO2: 186.1101; found:
3,3a,4,5-Tetrahydrocyclopenta[c]quinolin-2-one (19b)
186.1113.
According to GP C, 1,4-diketone 11b (96 mg, 0.32 mmol) and KOH
(15% in H2O, 1.0 mL) were reacted for 8 h at 60 °C. The crude mixture
was purified by column chromatography (SiO2, MTBE, Rf = 0.22) to
yield the title compound 19b (39 mg, 0.21 mmol, 65%) as a light yel-
low oil.
1H NMR (500 MHz, CDCl3): δ = 2.03–2.08 (m, 1 H), 2.71–2.77 (m, 1 H),
3.08–3.16 (m, 2 H), 3.58–3.67 (m, 1 H), 4.56 (br s, 1 H), 6.28 (d, J = 1.7
Hz, 1 H), 6.64 (dd, J = 8.3 Hz, J = 1.1 Hz, 1 H), 6.73 (ddd, J = 8.0 Hz, J =
7.1 Hz, J = 1.1 Hz, 1 H), 7.20 (ddd, J = 8.4 Hz, J = 7.1 Hz, J = 1.5 Hz, 1 H),
7.49 (dd, J = 7.9 Hz, J = 1.5 Hz, 1 H).
2,4,5,6,7,7a-Hexahydro-1H-inden-2-one (15b) from Oxoester 9b
According to GP C, the 1,4-diketone 9b (100 mg, 0.44 mmol) and KOH
(15% in H2O, 1.1 mL) were reacted for 2 h at 60 °C to yield the title
compound 15b (57 mg, 0.42 mmol, 95%) as a colorless liquid without
further chromatographic purification; for characterization see above.
4,5,6,7,8,8a-Hexahydro-1H-azulen-2-one (15c)
According to GP C, the 1,4-diketone 9c (100 mg, 0.44 mmol) and KOH
(15% in H2O, 1.1 mL) were reacted for 2 h at 120 °C. The crude mixture
was purified by column chromatography (SiO2, hexanes/MTBE, 1:2,
Rf = 0.36) to yield the title compound 15c (42 mg, 0.28 mmol, 64%) as
a colorless liquid; for characterization see above.
The data were in accordance with literature values.23
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

J
I. Geibel et al.
Feature
Synthesis
Alkylation of Oxoesters; General Procedure D (GP D)
rotamer) = 21.20 (CH3), 21.42 (CH2), 39.57 (CH2), 44.85 (CH2), 47.12
(CH2), 53.06 (CH3), 59.41 (C), 71.78 (CH), 78.61 (C), 169.37 (C), 169.53
(C), 202.11 (C).
HRMS (ESI): m/z [M + Li]+ calcd for C12H15LiNO4: 244.1156; found:
A solution of propargyl bromide (80% w/w in toluene, 2.0 equiv) and
K2CO3 (1.2 equiv) were added to a mixture of the respective β-oxo-
ester (1.0 equiv) in acetone (3 L/mol). The mixture was heated to re-
flux for 2–6 h, then cooled to ambient temperature, diluted with H2O
(10 L/mol) and extracted with MTBE (3 × 10 L/mol). The combined or-
ganic layers were dried (MgSO4), filtered and the solvent was re-
moved in vacuo. The crude product was purified by column chroma-
tography to give the α-propargyl-β-oxoester derivatives.
244.1164.
tert-Butyl 2-Oxo-1-propargylcyclohexane-1-carboxylate (24)
According to GP D, β-oxoester 20d (1.50 g, 7.57 mmol), K2CO3 (1.26 g,
9.08 mmol) and propargyl bromide (2.25 g, 80% w/w in toluene, 15.1
mmol) in acetone (25 mL) were heated to reflux for 4 h. The crude
material was purified by column chromatography (SiO2, hexanes/MTBE,
1:1, Rf = 0.57) to yield the title compound 24 (1.67 g, 7.05 mmol, 93%)
as a light yellow oil.
1-(tert-Butyl) 3-Methyl 4-Oxo-3-propargylpiperidine-1,3-dicar-
boxylate (23a)
According to GP D, β-oxoester 22a (600 mg, 2.33 mmol), K2CO3 (387
mg, 2.80 mmol) and propargyl bromide (694 mg, 80% w/w in toluene,
4.66 mmol) in acetone (6 mL) were heated to reflux for 4 h. The crude
material was purified by column chromatography (SiO2, hexanes/
MTBE, 1:1, Rf = 0.41) to yield the title compound 23a (435 mg, 1.47
mmol, 63%) as a light yellow oil. NMR spectra showed partly broad-
ened signal sets due to the carbamate moiety.
IR (ATR): 3283 (w), 2945 (w), 2868 (w), 1713 (vs), 1453 (w), 1369 (m),
1217 (w), 1151 (s), 1091 (w), 845 (w), 650 (w) cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.45 (s, 9 H), 1.51–1.67 (m, 2 H), 1.74–
1.81 (m, 2 H), 2.00 (t, J = 2.7 Hz, 1 H), 2.01–2.07 (m, 1 H), 2.43–2.46
(m, 2 H), 2.50 (dd, J = 17.0 Hz, J = 2.7 Hz, 1 H), 2.61 (dq, J = 13.7 Hz, J =
3.2 Hz, 1 H), 2.70 (dd, J = 16.9 Hz, J = 2.7 Hz, 1 H).
13C{1H} NMR (125 MHz, CDCl3): δ = 22.34 (CH2), 24.76 (CH2), 27.37
(CH2), 27.81 (3 CH3), 35.42 (CH2), 40.81 (CH2), 60.42 (C), 71.11 (CH),
79.72 (C), 82.38 (C), 169.33 (C), 206.18 (C).
IR (ATR): 3284 (w), 2977 (w), 2936 (w), 1720 (m), 1693 (vs), 1469 (w),
1421 (m), 1366 (m), 1312 (w), 1249 (m), 1236 (m), 1162 (s), 1131 (s),
971 (m), 860 (w), 769 (w) cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.42 (s, 9 H), 2.00 (t, J = 2.7 Hz, 1 H),
2.42 (dt, J = 15.1 Hz, J = 4.3 Hz, 1 H), 2.61 (dd, J = 16.8 Hz, J = 2.7 Hz, 1
H), 2.62–2.77 (m, 2 H), 3.23 (ddd, J = 13.9 Hz, J = 10.7 Hz, J = 4.3 Hz, 1
H), 3.31–3.47 (m, 1 H), 3.67 (s, 3 H), 4.10 (dt, J = 12.3 Hz, J = 5.1 Hz, 1
H), 4.47–4.65 (m, 1 H).
HRMS (ESI): m/z [M + Li]+ calcd for C14H20LiO3: 243.1567; found:
243.1580.
Ethyl 2-Propargyl-1-tetralone-2-carboxylate (26a)
13C{1H} NMR (125 MHz, CDCl3): δ = 21.35 (CH2), 28.07 (3 CH3), 39.44
(CH2), 42.57 (CH2), 49.51 (CH2), 52.76 (CH3), 59.66 (C), 71.65 (CH),
78.65 (C), 80.41 (C), 153.99 (C), 169.38 (C), 202.74 (C).
HRMS (ESI): m/z [M + Na]+ calcd for C15H21NNaO5: 318.1312; found:
318.1312.
According to GP D, β-oxoester 25a (2.00 g, 9.16 mmol), K2CO3 (1.52 g,
11.0 mmol) and propargyl bromide (2.72 g, 80% w/w in toluene, 18.3
mmol) in acetone (25 mL) were heated to reflux for 6 h. The crude
material was purified by column chromatography (SiO2, hexanes/MTBE,
10:1, Rf = 0.20) to yield the title compound 26a (2.09 g, 8.15 mmol,
89%) as a colorless oil.
IR (ATR): 3277 (w), 2981 (w), 2935 (w), 1730 (s), 1685 (vs), 1601 (m),
1455 (m), 1423 (m), 1389 (w), 1366 (m), 1355 (m), 1321 (m), 1293
(m), 1274 (m), 1236 (s), 1211 (s), 1121 (m), 1076 (m), 1018 (m), 965
(w), 939 (m), 919 (w), 897 (m), 861 (w), 808 (w), 788 (m), 745 (m),
Methyl 1-Acetyl-4-Oxo-3-propargylpiperidine-3-carboxylate
(23b)
According to GP D, β-oxoester 22b (1.40 g, 7.03 mmol), K2CO3 (1.17 g,
8.44 mmol) and propargyl bromide (2.09 g, 80% w/w in toluene, 14.1
mmol) in acetone (20 mL) were heated to reflux for 2 h. The crude
material was purified by column chromatography (SiO2, MTBE/EtOH,
8:1, Rf = 0.32) to yield the title compound 23b (1.30 g, 5.48 mmol,
78%) as a colorless oil. NMR spectra showed doubled signal sets due to
rotamers (ratio 3:1).
646 (m) cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.15 (t, J = 7.1 Hz, 3 H), 2.00 (t, J = 2.7
Hz, 1 H), 2.44 (ddd, J = 13.9 Hz, J = 10.9 Hz, J = 4.9 Hz, 1 H), 2.63 (dt, J =
13.8 Hz, J = 4.7 Hz, 1 H), 2.88 (d, J = 2.6 Hz, 2 H), 2.95 (dt, J = 17.4 Hz,
J = 4.7 Hz, 1 H), 3.14 (ddd, J = 17.4 Hz, J = 10.9 Hz, J = 4.8 Hz, 1 H), 4.14
(q, J = 7.1 Hz, 2 H), 7.22 (d, J = 7.7 Hz, 1 H), 7.30 (t, J = 7.6 Hz, 1 H), 7.47
(td, J = 7.5 Hz, J = 1.5 Hz, 1 H), 8.04 (dd, J = 7.9 Hz, J = 1.5 Hz, 1 H).
13C{1H} NMR (125 MHz, CDCl3): δ = 13.90 (CH3), 24.21 (CH2), 25.73
(CH2), 30.49 (CH2), 56.55 (C), 61.63 (CH2), 71.17 (CH), 79.58 (C),
126.72 (CH), 127.99 (CH), 128.69 (CH), 131.61 (C), 133.62 (CH),
143.16 (C), 170.50 (C), 193.70 (C).
IR (ATR): 3283 (w), 2954 (w), 2875 (w), 1719 (vs), 1645 (vs), 1425 (s),
1367 (w), 1263 (m), 1212 (m), 1183 (w), 1033 (m), 1016 (m), 957 (w),
848 (w) cm–1
.
1H NMR (500 MHz, CDCl3): δ (major rotamer) = 2.10 (t, J = 2.7 Hz, 1
H), 2.29 (s, 3 H), 2.49 (dt, J = 14.8 Hz, J = 3.9 Hz, 1 H), 2.56 (ddd, J = 14.7
Hz, J = 11.3 Hz, J = 6.5 Hz, 1 H), 2.62 (dd, J = 17.3 Hz, J = 2.8 Hz, 1 H),
2.78 (dd, J = 17.3 Hz, J = 2.8 Hz, 1 H), 3.00 (ddd, J = 13.4 Hz, J = 11.4 Hz,
J = 4.2 Hz, 1 H), 3.38 (d, J = 13.9 Hz, 1 H), 3.73 (s, 3 H), 4.58 (dd, J = 13.9
Hz, J = 2.7 Hz, 1 H), 4.71 (ddt, J = 13.0 Hz, J = 6.4 Hz, J = 3.1 Hz, 1 H); δ
(minor rotamer) = 2.03 (t, J = 2.7 Hz, 1 H), 2.15 (s, 3 H), 2.46–2.68 (m,
2 H), 2.80 (dd, J = 17.2 Hz, J = 2.6 Hz, 1 H), 2.81–2.89 (m, 1 H), 3.33 (d,
J = 13.8 Hz, 1 H), 3.50–3.58 (m, 1 H), 3.70 (s, 3 H), 3.98 (dddd, J = 13.3
Hz, J = 6.6 Hz, J = 4.3 Hz, J = 2.7 Hz, 1 H), 4.97 (dd, J = 13.7 Hz, J = 2.2
Hz, 1 H).
HRMS (ESI): m/z [M + H]+ calcd for C16H17O3: 257.1172; found:
257.1180.
Methyl 1-Acetyl-4-oxo-3-propargyl-1,2,3,4-tetrahydroquinoline-
3-carboxylate (26b)
According to GP D, β-oxoester 25b (502 mg, 2.03 mmol), K2CO3 (337
mg, 2.44 mmol) and propargyl bromide (604 mg, 80% w/w in toluene,
4.06 mmol) in acetone (6 mL) were heated to reflux for 6 h. The crude
material was purified by column chromatography (SiO2, hexanes/
MTBE, 1:2, Rf = 0.19) to yield the title compound 26b (590 mg, 2.03
mmol, 100%) as a yellow oil.
13C{1H} NMR (125 MHz, CDCl3): δ (major rotamer) = 21.08 (CH3),
21.63 (CH2), 39.75 (CH2), 41.21 (CH2), 51.58 (CH2), 53.23 (CH3), 59.75
(C), 72.60 (CH), 77.79 (C), 168.98 (C), 170.06 (C), 201.55 (C); δ (minor
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

K
I. Geibel et al.
Feature
Synthesis
IR (ATR): 3276 (w), 2958 (w), 1739 (m), 1670 (vs), 1602 (m), 1578
(w), 1481 (m), 1379 (m), 1317 (m), 1239 (s), 1212 (vs), 1084 (w), 971
(2) Reviews: (a) Gawley, R. E. Synthesis 1976, 777. (b) Jung, M. E.
Tetrahedron 1976, 32, 3. (c) Varner, M. A.; Grossman, R. B.
Tetrahedron 1999, 55, 13867.
(w), 766 (m), 737 (w), 665 (w) cm–1
.
(3) Christoffers, J.; Scharl, H. Eur. J. Org. Chem. 2002, 1505.
(4) Clark, R. D.; Ray, N. C.; Williams, K.; Blaney, P.; Ward, S.;
Crackett, P. H.; Hurley, C.; Dyke, H. J.; Clark, D. E.; Lockey, P.;
Devos, R.; Wong, M.; Porres, S. S.; Bright, C. P.; Jenkins, R. E.;
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1H NMR (500 MHz, CDCl3): δ = 2.01 (t, J = 2.7 Hz, 1 H), 2.37 (s, 3 H),
2.88 (dd, J = 17.1 Hz, J = 2.7 Hz, 1 H), 2.98 (dd, J = 17.3 Hz, J = 2.7 Hz, 1
H), 3.68 (s, 3 H), 4.12 (d, J = 13.6 Hz, 1 H), 4.85–4.94 (m, 1 H), 7.27 (d,
J = 8.0 Hz, 1 H), 7.52–7.68 (m, 2 H), 8.06 (dt, J = 7.8 Hz, J = 1.1 Hz, 1 H).
13C{1H} NMR (125 MHz, CDCl3): δ = 21.85 (CH2), 23.04 (CH3), 50.33
(CH2), 53.21 (CH3), 57.43 (C), 72.12 (CH), 78.31 (C), 124.06 (CH),
124.60 (C), 125.41 (CH), 128.46 (CH), 134.62 (CH), 143.60 (C), 169.32
(C), 170.26 (C), 190.06 (C).
HRMS (ESI): m/z [M + Na]+ calcd for C16H15NNaO4: 308.0893; found:
308.0899.
Methyl 1-Acetyl-4-oxo-1,2,3,4-tetrahydroquinoline-3-carboxylate
(25b)
Under an anhydrous and inert atmosphere (N2), methyl acrylate (1.47
g, 17.1 mmol) and KOtBu (1.91 g, 17.1 mmol) were added to a cooled
(ice/water bath) solution of methyl 2-acetamidobenzoate (27) (3.00 g,
15.5 mmol) in anhydrous THF (33 mL). The reaction mixture was
stirred for 3 d at 23 °C and then evaporated. The crude product was
purified by column chromatography (SiO2, hexanes/MTBE, 1:1, Rf =
0.18) to yield the oxoester 25b (2.15 g, 8.68 mmol, 56%) as a yellow
solid (mp 126 °C). This product has been reported in the literature
previously,24 but not fully characterized. The product was isolated as a
mixture of keto and enol tautomers (ratio 1:5 by 1H NMR).
IR (ATR): 3353 (m), 3074 (w), 2959 (w), 1708 (m), 1667 (vs), 1583
(m), 1495 (s), 1440 (m), 1379 (m), 1365 (m), 1314 (m), 1260 (m),
1218 (w), 1179 (w), 1087 (w), 950 (w) cm–1
.
1H NMR (500 MHz, CDCl3): δ (keto tautomer) = 2.35 (s, 3 H), 3.70 (dd,
J = 7.1 Hz, J = 4.3 Hz, 1 H), 3.75 (s, 3 H), 4.37–4.41 (m, 1 H), 4.55 (dd,
J = 13.5 Hz, J = 7.2 Hz, 1 H), 7.26–7.29 (m, 1 H), 7.40–7.44 (m, 1 H),
7.57 (ddd, J = 8.9 Hz, J = 7.2 Hz, J = 1.7 Hz, 1 H), 8.05 (dt, J = 7.9 Hz, J =
1.0 Hz, 1 H); δ (enol tautomer) = 2.22 (s, 3 H), 3.84 (s, 3 H), 4.65 (s, 2
H), 7.26–7.29 (m, 2 H), 7.42 (td, J = 7.8 Hz, J = 1.6 Hz, 1 H), 7.81 (dd, J =
7.8 Hz, J = 1.5 Hz, 1 H), 11.97 (br s, 1 H).
13C{1H} NMR (125 MHz, CDCl3): δ (keto tautomer) = 22.86 (CH3),
46.31 (CH2), 52.60 (CH3), 53.94 (CH), 123.97 (CH), 124.44 (C), 125.37
(CH), 128.12 (CH), 134.46 (CH), 143.61 (C), 167.93 (C), 169.62 (C),
188.56 (C); δ (enol tautomer) = 22.22 (CH3), 39.69 (CH2), 51.73 (CH3),
97.12 (C), 123.72 (CH), 124.61 (C), 124.67 (CH), 125.34 (CH), 130.70
(CH), 139.53 (C), 162.71 (C), 169.20 (C), 170.22 (C).
(14) Chang, M.-Y.; Cheng, Y.-C. Synlett 2016, 27, 1931.
(15) Li, X.; Hu, G.; Luo, P.; Tang, G.; Gao, Y.; Xu, P.; Zhao, Y. Adv. Synth.
Catal. 2012, 354, 2427.
(16) Palomo, C.; Oiarbide, M.; Garcia, J. M.; Bañuelos, P.; Odriozola, J.
M.; Razkin, J.; Linden, A. Org. Lett. 2008, 10, 2637.
(17) Grigg, R.; Sakee, U.; Sridharan, V.; Sukirthalingam, S.;
Thangavelauthum, R. Tetrahedron 2006, 62, 9523.
(18) Englert, L.; Silber, K.; Steuber, H.; Brass, S.; Over, B.; Gerber, H.-
D.; Heine, A.; Diederich, W. E.; Klebe, G. ChemMedChem 2010, 5,
930.
(19) Beth, A.; Pelletier, J.; Russo, R.; Soucy, M.; Burnell, R. H. Can. J.
Chem. 1975, 53, 1504.
HRMS (EI): m/z [M]+ calcd for C13H13NO4: 247.0839; found: 247.0843.
Acknowledgment
MTBE was obtained as a generous gift from Evonik Industries, Marl,
Germany.
(20) Shook, C. A.; Romberger, M. L.; Jung, S.-H.; Xiao, M.; Sherbine, J.
P.; Zhang, B.; Lin, F.-T.; Cohen, T. J. Am. Chem. Soc. 1993, 115,
10754.
(21) Brown, S. W.; Pauson, P. L. J. Chem. Soc., Perkin Trans. 1 1990,
1205.
Supporting Information
(22) Bannett, F.; Fenton, G.; Knight, D. W. Tetrahedron 1994, 50,
5147.
(23) Pérez-Serrano, L.; Blanco-Urgoiti, J.; Casarrubios, L.; Domínguez,
G.; Pérez-Castells, J. J. Org. Chem. 2000, 65, 3513.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1590812.
S
u
p
p
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p
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(24) McHugh, M.; Proctor, G. R. J. Chem. Res., Miniprint 1984, 2230.
References
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K