Lithium perchlorate-, acetic anhydride-, and triphenylphosphine-assisted multicomponent syntheses of 4-unsubstituted 2,5-dioxooctahydroquinoline-3- carboxylates and 3-carbonitriles

Article abstract of DOI:10.1016/j.tet.2013.08.081

Lithium perchlorate and acetic anhydride were the key additives for the multi-component reaction between 3-aminocyclohex-2-enones, formaldehyde, and malonates yielding adducts that were annulated under acidic conditions to afford bicyclic 2,5-dioxooctahydroquinoline-3-carboxylates. When methyl cyanoacetate was subjected to the same reaction conditions in the presence of a catalytic amount of triphenylphosphine, the bicyclic 2,5-dioxooctahydroquinoline-3- carbonitriles were obtained in a one-flask reaction.

Full text of DOI:10.1016/j.tet.2013.08.081

Tetrahedron 69 (2013) 9406e9416
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Lithium perchlorate-, acetic anhydride-, and triphenylphosphine-
assisted multicomponent syntheses of 4-unsubstituted 2,5-
dioxooctahydroquinoline-3-carboxylates and 3-carbonitriles
,
,
Xingxian Gu a b, Gunda I. Georg b
*
a Department of Medicinal Chemistry, University of Kansas, Lawrence, KS 66045, United States
b Department of Medicinal Chemistry and Institute for Therapeutics Discovery and Development, University of Minnesota, 717 Delaware Street, SE,
Minneapolis, MN 55414, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 July 2013
Received in revised form 29 August 2013
Accepted 30 August 2013
Available online 5 September 2013
Lithium perchlorate and acetic anhydride were the key additives for the multi-component reaction
between 3-aminocyclohex-2-enones, formaldehyde, and malonates yielding adducts that were annu-
lated under acidic conditions to afford bicyclic 2,5-dioxooctahydroquinoline-3-carboxylates. When
methyl cyanoacetate was subjected to the same reaction conditions in the presence of a catalytic amount
of triphenylphosphine, the bicyclic 2,5-dioxooctahydroquinoline-3-carbonitriles were obtained in a one-
flask reaction.
Keywords:
Multicomponent reaction
Catalysis
Ó 2013 Elsevier Ltd. All rights reserved.
Lithium perchlorate
Acetic anhydride
Triphenylphosphine
2,5-Dioxooctahydroquinolines
1. Introduction
O
NO2
CO2Me
1,4-Dihydropyridines, 1,4-dihydropyridine-2-pyridones, pyri-
dines, and piperidines are closely related structural motifs found in
many natural products and bioactive molecules. 1,4-
Dihydropyridines are considered to be privileged structures, be-
cause they bind to multiple ion channels and receptors.1 For ex-
ample, the 4-aryl-1,4-dihydropyridine moiety is a component of
the cardiovascular drug nifedipine (1, Fig. 1), which is a calcium
channel antagonist.2,3 The annulated 1,4-dihydropyridine analogue
2 (Fig. 1) initiates cardiac differentiation in mouse embryonic stem
CO2Et
Me
MeO2C
Me
Pr
N
H
N
H
Me
nifedipine (
1
)
TGF
O
β
inhibitor
2
N
CN
O
CO2Me
O
Me
N
H
N
H
cells by inhibiting TGFb signalingda mechanism unrelated to cal-
cium channel blockade.4 These analogues represent a new class of
agents for potential use in cardiac regenerative medicine.5 The
structurally related 1,4-dihydropyridine-2-pyridone scaffold is also
of medicinal interest. The 2-pyridone moiety is a component of
clinically used phosphodiesterase-3 (PDE3) inhibitors, such as
milrinone (3, Fig. 1) and related derivatives,6,7 including the
annulated PDE3 inhibitor 4 (Fig. 1).8 2-Pyridones are also found as
structural elements in a variety of other bioactive compounds
milrinone (
3
)
PDE-3 inhibitor
O
4
Cl
H
CO2Me
5
3
7
R1
R1
N
O
N
Me
O
R2
H
target scaffold
5
LY191704
Fig. 1. Representative structures of cardiovascular drugs, 1,4-dihydropyridine nifedi-
pine (1), a calcium channel blocker, TGFb inhibitor 2, milrinone (3), annulated 2-
* Corresponding author. Tel.: þ1 612 626 6320; fax: þ1 612 626 6318; e-mail
pyridone phosphodiesterase-3 inhibitor 4, human type I steroid 5-
hibitor LY191704, and target scaffold 5.
a-reductase in-
addresses: georg@umn.edu, georg239@umn.edu (G.I. Georg).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.08.081

X. Gu, G.I. Georg / Tetrahedron 69 (2013) 9406e9416
9407
including natural products.7,9 Octahydro-2-pyridones, such as
LY191704 and the related tetrahydro analogues were found to be
aldehydes can be employed, but the reaction products lack the 3-
carboxylic acid moiety (Scheme 1, Eq. 3), which is lost by de-
carboxylation.17 In related chemistry (Scheme 1, Eq. 4), hydrazinyl
enamines of 1,3-cyclohexanediones, and the arylidenemalonates
are preformed and then reacted in the presence of butyl lithium to
form the Michael addition products that are subsequently cyclized
to yield 4-aryl-2,5-dioxooctahydroquinoline-3-carboxylates.19
specific inhibitors of human type I steroid 5-a
-reductase.10e12 De-
spite the fact that these structural types have displayed interesting
bioactivities, 3,4-dihydropyridinones and their annulated ana-
logues, 2,5-dioxooctahydroquinoline-3-carboxylates
5
(target
scaffold 5, Fig. 1) have not been examined extensively yet in terms
of synthesis, biological activity, and structureeactivity
relationships.
2. Results and discussion
It is well known that 1,3-diketones, including cyclic ketones,13
react via enamine formation (Scheme 1, Eq. 1) to produce
substituted 1,4-dihydropyridines (Hantzsch reaction). Similar to
the Hantzsch-type reaction that is used to synthesize annulated
1,4-dihydropyridines (Scheme 1, Eq. 1), formal [3þ3] cycloaddition
reactions were employed to construct dihydro-2-pyridones in-
cluding annulated core structures.9,14e17 In these multi-component
reactions 1,3-cyclohexanediones, malonates or Meldrum’s acid,
aldehydes, and amines or ammonia are reacted in one flask, as is
depicted in Scheme 1, Eq. 2. In the example shown in Eq. 2, ZnO
serves as an efficient catalyst to effect the reaction with aromatic
aldehydes in excellent yields, but apparently does not work with
formaldehyde or aliphatic aldehydes.18 When Meldrum’s acid is
used in the multicomponent reaction, formaldehyde and aliphatic
In our efforts to prepare structurally diverse and novel nitrogen-
containing heterocyclic compounds with privileged structures
for biological screening, we targeted the synthesis of bicyclic
1,4-dihydropyridine-2-pyridones
5
(Fig. 1) that do not
contain a substituent at C4 but an ester moiety at C3 (2,5-
dioxooctahydroquinoline-3-carboxylates). While aromatic alde-
hydes have been employed in the multicomponent reaction shown
in Eq. 2 in Scheme 1, the reaction apparently did not take place
when formaldehyde was used.18 The availability of a method that
provides the target compounds 5 without a substituent at C4 is of
importance to expand the scope of this chemistry. Once an aryl or
aliphatic group is present at C4 it will require multiple steps for
removal if unsubstituted analogues are desired for biological
investigations.
We started our investigations by carrying out a one-flask re-
action similar to the one shown in Scheme 1, Eq. 3, by following
a reported procedure17 using 1,3-cyclohexanedione, formaldehyde,
dimethyl malonate, and benzylamine, but failed to obtain the de-
sired bicyclic reaction product. We then decided to explore the
possibility of synthesizing the target molecule in a step-wise
manner in order to simplify the reaction system. 3-(Benzylamino)
cyclohex-2-enone (6a), easily prepared by condensation of 1,3-
cyclohexanedione and benzylamine,20 paraformaldehyde, and di-
methyl malonate, were envisaged to form an adduct, followed by
a subsequent cyclization to yield the target molecule. Yet, when
a mixture of the enaminone, formaldehyde, and dimethyl malonate
were heated in a reaction vessel, only little of adduct 7a formed and
instead bis-addition of the enaminone to formaldehyde took place
and 8a was isolated as the major product in 74% (Scheme 2, Eq. 1).
Clearly, this side reaction needed to be suppressed in order to allow
the desired multi-component reaction to become the major re-
action pathway and yield the desired adduct 7a. Since LiClO4 has
been introduced as a useful reagent to facilitate Mannich-type
reactions,21e25 we tested this Lewis acid as an additive in the re-
action (Scheme 2, Eq. 2). The reaction was heated to 90 ꢀC in ace-
tonitrile in the presence of 1 equiv of LiClO4, and the desired adduct
7a was isolated as the major product in 77%, along with the bis-
addition side product 8 in 13% as the minor product.
R2
O
O
R4CHO
(eq 1)
R2
CO2R3
R4
NH4OAc
CO2R3
+
O
R1
R1
R1
EtOH, I2
N
H
O
R1
O
(eq 2)
CO2Et
NH4OAc
ZnO, H2O
+
+ ArCHO
Me
Me
EtO
O
O
heat
O
Ar
CO2Et
+
Me
Me
N
O
R3
(eq 3)
O
O
R2CHO
NH2R3 or
NH4OAc
O
+
Me
Me
R1
R1
O
O
O
heat or MW
O
R2
+
+
Me2CO
CO2
R1
R1
N
O
R3
O
O
O
dimethyl
malonate
(HCHO)n
MeCN, Δ
R1 = H, Me, R2 = aryl, alkyl, R3 = H, alkyl,
O
CO2Me
CO2Me
(eq 4)
O
+
NH
NH HN
n-BuLi,
TMEDA
-78 °C
MeO2C
CO2Me
Bn
Bn
+
Bn
R1
R1
NMe2
dimethyl
malonate
(HCHO)n
MeCN
N
H
NH
Bn
(eq 1)
(eq 2)
Ar
7a, 12%
8, 74%
6a
O
Ar
O
Ar
CO2Me
LiClO4
CO2Me
O
toluene
heat
90 °C
8, 13%
R1
R1
7a, 77%
CO2Me
R1
R1
NH
NMe2
N
NMe2
Scheme 2. Multi-component reactions of 3-(benzylamino)cyclohex-2-enone (6a) with
and without LiClO4 as additive.
R1 = H, Me
Optimization of the reaction conditions (Table 1) showed that an
equimolar amount of LiClO4 was crucial to obtain good yields (Table
1, entries 1e3) and that excess LiClO4 was unnecessary (entries 4
and 5). In an attempt to annulate the adduct in the same flask,
Scheme 1. Multicomponent literature methods for the synthesis of 5-
oxohexahydroquinoline-3-carboxylates (Eq. 1), 2,5-dioxooctahydroquinoline-3-
carboxylates (Eqs.
2
and 3) and
a
step-wise reaction to form 2,5-
dioxooctahydroquinoline-3-carboxylates (Eq. 4).

9408
X. Gu, G.I. Georg / Tetrahedron 69 (2013) 9406e9416
Table 1
was employed in the reaction. Methyl acetoacetate, methyl cya-
Optimization of the LiClO4-assisted formation of 7a
noacetate, and triethyl phosphonoacetate were tested as surrogates
of malonates, but no product was detected under the standard
conditions. We propose that methyl acetoacetate forms an in-
termediate similar to 9a through Knoevenagel reaction,26 however
such an intermediate would be a more reactive Michael acceptor
than 9a, due to the higher electrophilicity provided by the ketone
carbonyl versus the ester carbonyl. Thus, this intermediate would
get consumed rapidly via self-polymerization,26 without reacting
with 6a. We have provided the 1H NMR of 9a (see Supplementary
data), showing its rapid self-polymerization. The Michael accep-
tor intermediate derived from methyl acetoacetate can be expected
to polymerize even faster.26,27
O
O
dimethyl malonate (1.5 equiv)
CO2Me
CO2Me
(HCHO)n (2 equiv)
LiClO4, Ac2O, MeCN, Δ
NH
Bn
NH
Bn
7a
6a
Entry
Temp (ꢀC)
LiClO4 (equiv)
Ac2O (equiv)
Yield (%)
1
2
3
4
5
6
7
8
9
90
90
90
90
90
60
60
60
60
0
0.9
1.0
1.9
10.0
1.0
0
0
0
0
12
63
77
75
62
93a
57
0b
0
Similar to what has been proposed in the literature17 and is
shown in Scheme 1, Eq. 4,19 we assume that product 7a formed via
a conjugate addition of the enaminone to an intermediate gener-
ated from an in situ Knoevenagel reaction between dimethyl
malonate and formaldehyde, followed by an imineeenamine tau-
tomerism (Scheme 3). To investigate the proposed pathway, di-
methyl methylenemalonate (9a) was prepared following
a literature procedure,28 and the conjugate addition by the enam-
inone successfully yielded 7a in 90% without the assistance of
LiClO4 and acetic anhydride. Thus, LiClO4 and acetic anhydride fa-
cilitate the formation of intermediate 9a and thereby, favoring the
Michael addition of the enamine 6a to intermediate 9a over the
formation of the bis-addition product 8, although the detailed
mechanism is not clear.
1.0
1.0
1.0
1.0
LiþTFAꢁ 1.0
Ti(OiPr)4 1.0
MgBr2$OEt2
0b
a
Used as the standard condition.
b
Bis-addition product observed, none of the desired product was observed.
acetic anhydride was added as an additive. Whereas no annulated
product was detected, the yield for the adduct formation of 7a
improved to 93% (Table 1, entry 6). When acetic anhydride was
added, the reaction could be completed at a lower temperature
(60 ꢀC instead of 90 ꢀC) in a comparable amount of time (0.5e3.0 h).
Several other mild Lewis acids (Table 1, entries 7e9) were also
tested, but the results were not satisfactory.
In order to explore the scope of the reaction we subjected a va-
riety of N-substituted 3-aminocyclohex-2-enones and malonates to
the reaction under the optimized conditions (Table 2). Most of the
reactions yielded the corresponding adducts in moderate to ex-
cellent yields (66%e97%). Attempts to replace formaldehyde with
benzaldehyde were not successful. No product formation was
detected when a sterically hindered malonate tert-butyl ester
(Table 2, entry 16) or dimethyl methylmalonate (Table 2, entry 17)
O
O
MeO
OMe
O
9a
MeCN, 60 °C
NH
Bn
6a
O
H
O
OH
CO2Me
CO2Me
Table 2
OMe
CO2Me
Scope of the LiClO4-assisted multi-component reaction
N
Bn
N
Bn
O
O
O
LiClO4 (1 equiv)
CO2R4
CO2R3
(HCHO)n (2 equiv)
R1
R1
R1
R1
O
O
CO2Me
CO2Me
NH
R2
NH
R2
n
n
R3O
Ac2O (1 equiv), MeCN, 60 °C
OR4
(1.5 equiv)
7
6
NH
Bn
Entry Compound
n
R1 R2
R3
R4
Yield
(%)
7a 90%
1
2
3
3
5
6
7
8
7b
7c
7d
7e
7f
7g
7h
7i
1
1
1
1
1
1
1
1
1
1
1
1
1
0
0
1
1
1
1
1
H
H
H
H
H
H
H
H
Ph
Ph
Bn
Me
Bn
Me
Bn
Me
Bn
Me
Bn
Bn
Bn
Me
Bn
Me
Bn
Me
Bn
Me
Bn
Me
Me
Me
Et
90
97
73
90
66
80
72
86
83
87
95
88
88
96
94
np
npa
np
np
np
Scheme 3. Reaction of enaminone 6a with Knoevenagel intermediate 9a.
Bn
nBu
nBu
No product formation was detected when benzaldehyde was
used in the LiClO4-assisted reaction (Table 2, entry 20). Based on the
proposed mechanism, the difficulty in the corresponding conjugate
addition to the sterically more demanding intermediate and/or
a difference in electronic properties could be the cause of the lack of
reactivity. To confirm that hypothesis, dimethyl benzylidenemalo-
nate (9b)29 was prepared and subjected to the reaction with the
enaminone. Indeed, the enaminone did not add to dimethyl 2-
benzylidenemalonate (9b) in the presence of LiClO4 or without it.
The observed rate enhancement after the addition of acetic
anhydride most likely facilitates the LiClO4-catalyzed Knoevenagel
reaction by in situ formation of the more reactive geminal form-
aldehyde diacetate,30 similar to what has been described for the
iodine-catalyzed Knoevenagel reaction in the presence of acetic
anhydride (Scheme 4).31
Morpholine Me
Morpholine Bn
9
7j
7k
7l
Me Ph
Me Ph
Me Bn
Me Bn
Me nBu
H
H
H
H
H
H
H
Me
Bn
Me
Bn
Me
Me
Me
tBu
10
11
12
13
14
15
16
17
18
19
20
7m
7n
7o
7p
7q
7r
7s
7t
Ph
Bn
Bn
Bn
Bn
Bn
Bn
Dimethyl methylmalonate
Methyl acetoacetate
Triethyl phosphonoacetate
Benzaldehyde, dimethyl
malonate
7u
a
np¼no product.

X. Gu, G.I. Georg / Tetrahedron 69 (2013) 9406e9416
9409
Table 4
+ LiClO4
HCHO + Ac2O
Synthesis of dioxooctahydroquinoline-3-carbonitriles 10
Li
O
O
O
CO2Me
CO2Me
CN
O
CN
OAc
H
OAc
(HCHO)n (2 equiv)
LiClO4 (1 equiv)
+
R1
R1
R1
R1
H
H
O
H
Me
N
NH CO2
PPh3 (0.5 equiv)
MeCN, 60 °C
R2
R2
O
O
(1.5 equiv)
6
10
O
Entry
Compound
R1
R2
Yield (%)
O
1
2
3
4
5
10a
10b
10c
10d
10e
H
H
H
Me
Me
Bn
Ph
Bu
Pr
85
65
73
75
67
MeO
OMe
9a
MeO(CH2)2e
Scheme 4. Proposed mechanism for the LiClO4-catalyzed Knoevenagel reaction in the
presence of acetic anhydride.
triphenylphosphine but without LiClO4. We did not obtain any of
the desired product and only bis-addition product 8 was found. We
therefore concluded that LiClO4 is responsible for the formation of
the presumed methyl 2-cyanoacrylate intermediate, rather than
triphenylphosphine.
Intermediates 7 were next treated with trifluoroacetic acid at
90 ꢀC in dichloroethane or toluene in a sealed reaction vessel to
yield the desired 2,5-dioxooctahydroquinoline-3-carboxylate es-
ters 5 in mostly moderate yields as shown in Table 3.32e34 The
cyclization of dimethyl malonate adducts was carried out in di-
chloroethane, while toluene was a better choice of solvent for the
dibenzyl malonate adducts, with an approximately 10% improve-
ment in yields on average. Adducts containing a 1-morpholino
group (7h and 7i, Table 2) decomposed under the acidic condi-
tions, furnishing none of the annulated products.
Triphenylphosphine is
a strong nucleophile that adds to
electron-deficient double and triple bonds.36e39 Scheme 5 shows
a possible mechanism for the formation of compounds 10, which is
similar to the mechanism reported by Steward et al. for the
triphenylphosphine catalyzed conjugate addition of alcohols
and water to enones.40 Triphenylphosphine adds to methyl 2-
cyanoacrylate and forms phosphonium enolate 11, which ab-
stracts a proton from 6a forming ion pair 12, which then adds to an
equivalent of methyl 2-cyanoacrylate. The new ion pair 13 abstracts
a proton from another molecule of 6a to form intermediate 14 that
cyclizes to yield product 10a. Deprotonated 6a and regenerated 11
re-form ion pair 12. (Steward et al. were able to rule out a direct
Table 3
Synthesis of dioxooctahydroquinoline esters 5
O
O
CO2R3
CO2R3
CO2R3
O
TFA
proton abstraction by triphenylphosphine.40
)
DCE or PhMe
R1
R1
R1
The cyclization reaction is most likely catalyzed by triphenyl-
phosphine as well since it has been reported that triphenylphos-
phine can be a catalyst for transesterifications,41 although an
influence of steric and/or electronic effects of the nitrile group on
the cyclization cannot be ruled out. We propose that triphenyl-
phosphine adds to the ester 14 and forms acylphosphonium in-
termediate 15 that would cyclize to form compound 10a and
regenerate PPh3.
Formaldehyde was the only viable aldehyde in this reaction.
Malonates were also subjected to such reaction conditions in order
to obtain 5 in one step, but no cyclized product was detected after
12 h. Instead the bis-addition product 8 was the major product, and
only a small amount of the conjugated addition adduct 7a was
detected.
The syntheses of structurally related monocyclic 4-aryl-2-oxo-
tetrahydropyridine-3-carbonitriles from 4H-pyrans has recently
been reported.42,43 The 4H-pyrans were prepared from aromatic
aldehydes, malononitrile, and ethyl acetoacetate in the presence of
ZnO as the catalyst.43 Another recent publication describes a three-
component reaction that employed aromatic aldehydes (and one
aliphatic aldehyde) with either malononitrile or 2-cyanoacetamide
in the presence of PEGeSO3H or vitamin B1, respectively, to
90 °C, 18-24 h
NH
N
n
n
R1
R2
R2
5
7
Entry
Compound
n
R1
R2
R3a
Yield (%)
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
5g
5h
5i
1
1
1
1
1
1
1
1
1
1
1
0
0
H
H
H
H
H
H
Me
Me
Me
Me
Me
H
Bn
Bn
Ph
Ph
nBu
nBu
Bn
Bn
Ph
Ph
nBu
Bn
Ph
Me
Bn
Me
Bn
Me
Bn
Me
Bn
Me
Bn
Me
Me
Me
79
70
84
49
57
60
67
64
64
72
62
62
49
9
10
11
12
13
5j
5k
5l
5m
H
a
Reaction performed in dichloroethane when R3¼Me, in toluene when R3¼Bn.
We next subjected methyl cyanoacetate (instead of a malonate
ester) to the same reaction conditions but no reaction product was
obtained. However, when a catalytic amount of triphenylphosphine
was added to the reaction mixture, the annulated products 10aee
(Table 4) were formed directly.
The triphenylphosphine catalyst presumably plays multiple
roles in this reaction. It is well known that triphenylphosphine
catalyzes the Knoevenagel condensation between aldehydes and
provide
bicyclic
4-substituted-2,5-dioxooctahydroquinolone-
3-carbonitriles.44 Thus, our technique complements existing
methods for the synthesis of these types of scaffolds in that we are
employing formaldehyde rather than aromatic or aliphatic alde-
hydes in the multi-component reaction and thereby providing
a method for the synthesis of 4-unsubstituted analogues.
The compounds were submitted to the NIH Molecular Libraries
Program and screened in several assays that are reported in
PubChem.45
cyanoacetates to form
a-cyanoacrylonitriles, but not with malo-
nates.35 To probe whether triphenylphosphine catalyzed this re-
action in our case, we carried out the reaction in the presence of

9410
X. Gu, G.I. Georg / Tetrahedron 69 (2013) 9406e9416
O
O
O
O
O
NH
Bn
NC
NC
NC
OMe
6a
OMe
OMe
N
Bn
Ph3P
Ph3P
12
PPh3
11
O
O
NC
OMe
CN
O
+ PPh3
N
Bn
O
10a
NH
Bn
6a
O
O
O
O
O
CN
H
H
NC
Ph3P
PPh3
CN
CO2Me
OMe
OMe
PPh3
CN
O
N
Bn
N
N
Bn
Bn
15
14
13
Scheme 5. Proposed mechanism for the triphenylphosphine catalyzed synthesis of 10a.
3. Conclusion
(10 mL, w35 mL/mmol) was stirred and pre-heated in a sealed
screw-cap vial until the reaction mixture turned into a clear solu-
tion after approximately 5 min. To the reaction medium was then
added paraformaldehyde (2.0 equiv). The reaction was then sealed,
stirred at 60 ꢀC, and monitored by TLC. In general, the reaction
reached completion within 0.5e3 h, and was quenched sub-
sequently with H2O (20 mL, w70 mL/mmol). The aqueous phase
was extracted with EtOAc (3ꢂ10 mL, w35 mL/mmol), and then, the
organic layers were combined, and washed with brine, and dried
over MgSO4. The organic solvent was then removed under reduced
pressure and the resulting residue was purified by flash column
chromatography on silica gel, using 50% acetone/hexanes as the
eluent.
In summary, a LiClO4-assisted multi-component reaction of 3-
aminocyclohex-2-enones 6 with malonates or cyanoacetates, and
formaldehyde in the presence of acetic anhydride is described,
providing access to 4-unsubstituted 2,5-dioxooctahydroquinoline-
3-carboxylates and 3-carbonitriles.
4. Experimental section
4.1. General
Proton nuclear magnetic resonance spectra were recorded at
400 MHz and carbon nuclear magnetic resonance spectra were
recorded at 100 MHz. All chemical shifts were recorded as parts per
million (ppm), and all samples were dissolved in CDCl3 using the
residual solvent peak as internal standard. Mass spectra were ob-
tained from a ZAB HS mass spectrometer equipped with an 11/250
data system. Fast-atom bombardment mass spectrometry (FAB-
MS) experiments were performed with a Xenon gun operated at
8 KeV energy and 0.8 mA emission at the Institute for Therapeutic
Discovery and Development at University of Minnesota. Fast-atom
bombardment high resolution mass spectra (FAB-HRMS) were
recorded at 1:10,000 resolution using linear voltage scans under
data system control and collected in a multi-channel analyzer
mode (MCA). A Recording Infrared Spectrophotometer or a FT-IR
was used to record infrared spectra. Melting points are un-
corrected. Solvents and reagents that are commercially available
were used without further purification. Acetonitrile, di-
chloroethane, and toluene were distilled freshly from calcium hy-
dride under argon. Silica gel (230e400 mesh) was used for flash
column chromatography. All compounds were concentrated using
a standard rotary evaporator and high-vacuum techniques.
4.2.1. Dimethyl 2-((2-(benzylamino)-6-oxocyclohex-1-enyl)methyl)
malonate (7a). The N-benzyl-enaminone (50 mg, 0.25 mmol),
LiClO4 (27 mg, 0.25 mmol), paraformaldehyde (16 mg, 0.50 mmol),
dimethyl malonate (0.042 mL, 0.37 mmol), and acetic anhydride
(0.024 mL, 0.25 mmol) were subjected to the standard reaction
conditions, and yielded a viscous colorless oil (80 mg, 0.23 mmol,
93%). 1H NMR (CDCl3, 400 MHz, ppm):
d 7.36e7.34 (m, 2H),
7.30e7.26 (m, 3H), 6.35 (m, 1H), 4.43 (d, J¼6.1 Hz, 2H), 3.80 (t,
J¼7.2 Hz, 1H), 3.69 (s, 6H), 2.83 (d, J¼7.2 Hz, 2H), 2.39 (t, J¼6.2 Hz,
2H), 2.26 (t, J¼6.2 Hz, 2H), 1.84 (m, 2H); 13C NMR (CDCl3, 100 MHz,
ppm): d 194.9,171.1,162.8,138.4,129.0,127.8,127.0,105.8, 52.7, 50.6,
47.2, 36.3, 25.8, 23.6, 21.3; ESI-HRMS: calcd m/e for [MþNaþ]
C19H23NNaO5: 368.1474, found 368.1484; IR (neat, NaCl, cmꢁ1):
2951, 1733,1575, 1436, 1409, 1357, 1299, 1246, 1202, 1158, 1118,1031.
4.2.2. Dimethyl 2-((6-oxo-2-(phenylamino)cyclohex-1-enyl)methyl)
malonate (7b). The N-phenyl-enaminone (47 mg, 0.25 mmol),
LiClO4 (27 mg, 0.25 mmol), paraformaldehyde (16 mg, 0.50 mmol),
dimethyl malonate (0.042 mL, 0.37 mmol), and acetic anhydride
(0.024 mL, 0.25 mmol) were subjected to the standard reaction
conditions and yielded a viscous colorless oil (74 mg, 0.22 mmol,
4.2. General method for LiClO4-assisted reaction of enami-
nones with malonates and formaldehyde to form adducts 7
(Table 2)
90%). 1H NMR (CDCl3, 400 MHz, ppm):
d 8.03 (s, 1H), 7.33e7.35 (m,
2H), 7.16 (m, 1H), 7.06e7.09 (m, 2H), 3.82 (t, J¼7.2 Hz, 1H), 3.74 (s,
6H), 2.91 (d, J¼7.2 Hz, 2H), 2.50 (t, J¼6.0 Hz, 2H), 2.37 (t, J¼6.0 Hz,
2H), 1.86 (m, 2H); 13C NMR (CDCl3, 100 MHz, ppm):
d 195.9, 171.3,
A suspension of the enaminone, LiClO4 (1.0 equiv), the malonate
diester (1.5 equiv), and acetic anhydride (1.0 equiv) in acetonitrile
160.6, 139.3, 129.3, 125.0, 124.1, 109.0, 52.9, 50.9, 36.9, 27.4, 23.8,

X. Gu, G.I. Georg / Tetrahedron 69 (2013) 9406e9416
9411
22.2; ESI-HRMS: calcd m/e for [MþHþ] C18H22NO5: 332.1498, found
332.1505; IR (neat, NaCl, cmꢁ1): 2593, 1733, 1567, 1499, 1435, 1398,
1306, 1245, 1204, 1080, 1038.
21.3, 20.1, 13.9; ESI-HRMS: calcd m/e for [MþHþ] C16H26NO5:
312.1811, found 312.1801; IR (neat, NaCl, cmꢁ1): 2954, 1733, 1570,
1436, 1417, 1368, 1301, 1243, 1203, 1155, 1100.
4.2.3. Dibenzyl 2-((6-oxo-2-(phenylamino)cyclohex-1-enyl)methyl)
malonate (7c). The N-phenyl-enaminone (47 mg, 0.25 mmol),
LiClO4 (27 mg, 0.25 mmol), paraformaldehyde (16 mg,
0.50 mmol), dibenzyl malonate (0.070 mL, 0.37 mmol), and
acetic anhydride (0.024 mL, 0.25 mmol) were subjected to the
standard reaction conditions, and yielded a viscous light yellow
oil (120 mg, 0.24 mmol, 97%). 1H NMR (CDCl3, 400 MHz, ppm):
4.2.7. Dibenzyl
2-((2-(butylamino)-6-oxocyclohex-1-enyl)methyl)
malonate (7g). The N-butyl-enaminone (42 mg, 0.25 mmol), LiClO4
(27 mg, 0.25 mmol), paraformaldehyde (16 mg, 0.50 mmol),
dibenzyl malonate (0.070 mL, 0.37 mmol), and acetic anhydride
(0.024 mL, 0.25 mmol) were subjected to the standard reaction
conditions, and yielded a viscous colorless oil (92 mg, 0.20 mmol,
80%). 1H NMR (CDCl3, 400 MHz, ppm):
d 7.32e7.26 (m, 10H), 5.69 (t,
d
7.89 (s, 1H), 7.35e7.29 (m, 12H), 7.15 (m, 1H), 7.01 (m, 2H), 5.17
J¼4.8 Hz,1H), 5.13 (q-like, J¼12.4 Hz, 4H), 3.92 (t, J¼7.4 Hz,1H), 3.04
(m, 2H), 2.81 (d, J¼7.3 Hz, 2H), 2.28 (t, J¼6.2 Hz, 2H), 2.22 (t,
J¼6.1 Hz, 2H), 1.81 (m, 2H), 1.50 (m, 2H), 1.37 (m, 2H), 0.94 (t,
(q-like, J¼12.4 Hz, 4H), 3.95 (t, J¼7.4 Hz, 1H), 2.95 (d, J¼7.4 Hz,
2H), 2.39 (t, J¼6.0 Hz, 2H), 2.32 (t, J¼6.0 Hz, 2H), 1.76 (m, 2H);
13C NMR (CDCl3, 100 MHz, ppm):
d
196.0, 170.6, 160.8, 139.2,
J¼7.3 Hz, 3H); 13C NMR (CDCl3,100 MHz, ppm):
d 194.4,170.6,162.8,
135.7, 129.3, 128.7, 128.4, 128.2, 125.1, 124.2, 108.6, 67.4, 51.1, 36.8,
27.3, 23.7, 22.0; ESI-HRMS: calcd m/e for [MþHþ] C30H30NO5:
484.2124, found 484.2118; IR (neat, NaCl, cmꢁ1): 2948, 1736,
1578, 1498, 1454, 1431, 1396, 1304, 1233, 1199, 1153, 1080, 1030,
1003.
135.8, 128.6, 128.3, 128.1, 104.7, 67.1, 50.7, 43.1, 36.3, 32.3, 25.8, 23.4,
21.2, 20.1, 13.79; ESI-HRMS: calcd m/e for [MþHþ] C28H34NO5:
464.2437, found 464.2444; IR (neat, NaCl, cmꢁ1): 2955, 1731, 1575,
1438, 1413, 1377, 1198, 1152.
4.2.8. Dimethyl
2-((2-(morpholinoamino)-6-oxocyclohex-1-enyl)
4.2.4. 1-Benzyl 3-methyl 2-((2-(benzylamino)-6-oxocyclohex-1-en-
1-yl)methyl)malonate (7d). The N-benzyl-enaminone (50 mg,
0.25 mmol), LiClO4 (27 mg, 0.25 mmol), paraformaldehyde (16 mg,
0.50 mmol), benzyl methyl malonate (0.070 mL, 0.37 mmol), and
acetic anhydride (0.024 mL, 0.25 mmol) were subjected to the
standard reaction conditions, and yielded a viscous light yellow oil
(77 mg, 0.18 mmol, 73%). 1H NMR (CDCl3, 400 MHz, ppm):
methyl)malonate (7h). The N-morpholino-enaminone (49 mg,
0.25 mmol), LiClO4 (27 mg, 0.25 mmol), paraformaldehyde
(16 mg, 0.50 mmol), dimethyl malonate (0.042 mL, 0.37 mmol),
and acetic anhydride (0.024 mL, 0.25 mmol) were subjected to
the standard reaction conditions, and yielded a viscous light
yellow oil (58 mg, 0.17 mmol, 72%). 1H NMR (CDCl3, 400 MHz,
ppm):
d
6.78 (s, 1H), 3.77 (t, J¼7.2 Hz, 1H), 3.76 (br, 4H), 3.71 (s,
d
7.37e7.24 (m, 10H), 6.24 (t, J¼6.2 Hz, 1H), 5.17 (q-like, J¼12.4 Hz,
6H), 2.76 (br, 4H), 2.74 (d, J¼7.2 Hz, 2H), 2.64 (t, J¼6.2 Hz, 2H),
2H), 4.36 (d, J¼6.1 Hz, 2H), 3.89 (t, J¼7.6 Hz, 1H), 3.67 (s, 3H), 2.84
2.27 (t, J¼6.2 Hz, 2H), 1.86 (m, 2H); 13C NMR (CDCl3, 100 MHz,
(m, 2H), 2.33 (m, 2H), 2.24 (m, 2H), 1.81 (m, 2H); 13C NMR (CDCl3,
ppm): d 195.6, 171.1, 162.6, 103.6, 66.7, 56.9, 52.7, 50.6, 36.7, 25.2,
100 MHz, ppm):
d
194.9, 170.9, 170.7, 162.7, 138.4, 129.0, 128.6,
23.2, 21.4; ESI-HRMS: calcd m/e for [MþHþ] C16H25N2O6:
341.1713, found 341.1699; IR (neat, NaCl, cmꢁ1): 2953, 2857, 1733,
1583, 1438, 1403, 1303, 1267, 1243, 1201, 1157, 1111, 1074, 1042,
1028.
128.4, 128.2, 127.0, 105.8, 67.2, 54.2, 52.7, 50.71, 47.2, 36.4, 25.8,
23.6, 21.3; ESI-HRMS: calcd m/e for [MþHþ] C25H28NO5: 422.1967,
found 422.1973; IR (neat, NaCl, cmꢁ1): 2949, 1732, 1575, 1497,
1455, 1436, 1409, 1378, 1356, 1297, 1242, 1202, 1154, 1119, 1079,
1029.
4.2.9. Dibenzyl
2-((2-(morpholinoamino)-6-oxocyclohex-1-enyl)
methyl)malonate (7i). The N-morpholino-enaminone (49 mg,
0.25 mmol), LiClO4 (27 mg, 0.25 mmol), paraformaldehyde
(16 mg, 0.50 mmol), dibenzyl malonate (0.070 mL, 0.37 mmol),
and acetic anhydride (0.024 mL, 0.25 mmol) were subjected to
the standard reaction conditions, and yielded a viscous light
yellow oil (106 mg, 0.22 mmol, 86%). 1H NMR (CDCl3, 400 MHz,
4.2.5. Dibenzyl 2-((2-(benzylamino)-6-oxocyclohex-1-enyl)methyl)
malonate (7e). The N-benzyl-enaminone (50 mg, 0.25 mmol),
LiClO4 (27 mg, 0.25 mmol), paraformaldehyde (16 mg, 0.50 mmol),
dibenzyl malonate (0.070 mL, 0.37 mmol), and acetic anhydride
(0.024 mL, 0.25 mmol) were subjected to the standard reaction
conditions, and yielded a viscous light yellow oil (112 mg,
ppm):
d
7.33e7.25 (m, 10H), 6.64 (s, 1H), 5.14 (q-like, J¼12.5 Hz,
0.23 mmol, 90%). 1H NMR (CDCl3, 400 MHz, ppm):
d
7.36e7.22 (m,
4H), 3.94 (t, J¼7.4 Hz, 1H), 3.90e3.40 (br, 4H), 2.78 (d, J¼7.3 Hz,
15H), 6.20 (t, J¼6.1 Hz, 1H), 5.12 (q-like, J¼12.4 Hz, 4H), 4.30 (d,
J¼6.1 Hz, 2H), 3.95 (t, J¼7.3 Hz, 1H), 2.87 (d, J¼7.3 Hz, 2H), 2.28 (t,
J¼6.2 Hz, 2H), 2.22 (t, J¼6.3 Hz, 2H), 1.77 (m, 2H); 13C NMR (CDCl3,
100 MHz, ppm): 194.9, 170.4, 162.7, 138.3, 135.7, 129.0, 128.6, 128.3,
128.1, 127.7, 127.0, 105.6, 67.2, 50.7, 47.1, 36.3, 25.7, 23.5, 21.1; ESI-
HRMS: calcd m/e for [MþHþ] C31H32NO5: 498.2280, found
498.2275; IR (neat, NaCl, cmꢁ1): 2945, 1731, 1577, 1497, 1456, 1434,
1372, 1356, 1295, 1200, 1149, 1028.
2H), 2.58 (s, 4H), 2.54 (t, J¼6.2 Hz, 2H), 2.25 (t, J¼6.2 Hz, 2H), 1.82
(m, 2H); 13C NMR (CDCl3, 100 MHz, ppm):
d 195.5, 170.4, 162.6,
135.8, 128.6, 128.3, 127.9, 103.5, 67.2, 66.6, 56.7, 50.8, 36.7, 25.2,
23.1, 21.3; ESI-HRMS: calcd m/e for [MþHþ] C28H33N2O6:
493.2339, found 493.2342; IR (neat, NaCl, cmꢁ1): 2917, 2850,
1732, 1584, 1497, 1455, 1402, 1385, 1266, 1233, 1200, 1152, 1112,
1076.
4.2.10. Dimethyl 2-((4,4-dimethyl-6-oxo-2-(phenylamino)cyclohex-
1-enyl)methyl)-malonate (7j). The N-phenyl-enaminone (54 mg,
0.25 mmol), LiClO4 (27 mg, 0.25 mmol), paraformaldehyde (16 mg,
0.50 mmol), dimethyl malonate (0.042 mL, 0.37 mmol), and acetic
anhydride (0.024 mL, 0.25 mmol) were subjected to the standard
reaction conditions, and yielded a viscous colorless oil (75 mg,
4.2.6. Dimethyl 2-((2-(butylamino)-6-oxocyclohex-1-enyl)methyl)
malonate (7f). The N-butyl-enaminone (42 mg, 0.25 mmol), LiClO4
(27 mg, 0.25 mmol), paraformaldehyde (16 mg, 0.50 mmol), di-
methyl malonate (0.042 mL, 0.37 mmol), and acetic anhydride
(0.024 mL, 0.25 mmol) were subjected to the standard reaction
conditions, and yielded a viscous colorless oil (52 mg, 0.17 mmol,
0.21 mmol, 83%). 1H NMR (CDCl3, 400 MHz, ppm):
d 7.94 (s, 1H),
66%). 1H NMR (CDCl3, 400 MHz, ppm):
d
5.88 (s, 1H), 3.75 (t,
7.35 (m, 2H), 7.16 (m, 1H), 7.06 (m, 2H), 3.86 (t, J¼7.4 Hz,1H), 3.75 (s,
J¼6.2 Hz, 1H), 3.69 (s, 6H), 3.18 (m, 2H), 2.76 (d, J¼7.1 Hz, 2H), 2.41
(t, J¼6.2 Hz, 2H), 2.26 (t, J¼6.3 Hz, 2H), 1.87 (m, 2H), 1.57 (m, 2H),
1.40 (m, 2H), 0.95 (t, J¼7.3 Hz, 3H); 13C NMR (CDCl3,100 MHz, ppm):
6H), 2.93 (d, J¼7.4 Hz, 2H), 2.36 (s, 2H), 2.23 (s, 2H), 0.97 (s, 6H); 13C
NMR (CDCl3, 100 MHz, ppm):
d 195.5, 171.3, 158.4, 139.3, 129.4,
124.9, 123.9, 108.0, 52.9, 50.7, 50.5, 40.8, 32.8, 28.1, 23.8; ESI-HRMS:
d
194.4, 171.2, 163.0, 104.9, 52.7, 50.6, 43.2, 36.3, 32.4, 25.8, 23.4,
calcd m/e for [MþHþ] C20H26NO5: 360.1811, found 360.1801; IR

9412
X. Gu, G.I. Georg / Tetrahedron 69 (2013) 9406e9416
(neat, NaCl, cmꢁ1): 2954, 1735, 1579, 1498, 1436, 1395, 1321, 1270,
1243, 1150.
0.25 mmol), LiClO4 (27 mg, 0.25 mmol), paraformaldehyde (16 mg,
0.50 mmol), dimethyl malonate (0.042 mL, 0.37 mmol), and acetic
anhydride (0.024 mL, 0.25 mmol) were subjected to the standard
reaction conditions, and yielded a viscous colorless oil (76 mg,
4.2.11. Dibenzyl 2-((4,4-dimethyl-6-oxo-2-(phenylamino)cyclohex-1-
enyl)methyl)-malonate (7k). The N-phenyl-enaminone (54 mg,
0.25 mmol), LiClO4 (27 mg, 0.25 mmol), paraformaldehyde (16 mg,
0.50 mmol), dibenzyl malonate (0.070 mL, 0.37 mmol), and acetic
anhydride (0.024 mL, 0.25 mmol) were subjected to the standard
reaction conditions, and yielded a viscous light yellow oil (111 mg,
0.24 mmol, 96%). 1H NMR (CDCl3, 400 MHz, ppm):
d 8.20 (s, 1H),
7.34 (t, J¼7.7 Hz, 2H), 7.14 (m, 3H), 3.75 (s, 6H), 3.72 (t, J¼7.2 Hz, 1H),
2.78 (d, J¼7.0 Hz, 2H), 2.70 (s, 2H), 2.37 (s, 2H); 13C NMR (CDCl3,
100 MHz, ppm): d 202.9,171.5,170.8,139.3, 129.5,124.9,122.3, 111.6,
52.9, 50.3, 33.2, 26.3, 21.7; ESI-HRMS: calcd m/e for [MþHþ]
C17H20NO5: 318.1341, found 318.1344; IR (neat, NaCl, cmꢁ1): 2953,
1734, 1667, 1581, 1499, 1435, 1410, 1340, 1293, 1240, 1158, 1079,
1063.
0.22 mmol, 87%). 1H NMR (CDCl3, 400 MHz, ppm):
d 7.90 (s, 1H), 7.34
(m, 2H), 7.29 (m, 10H), 7.16 (m, 1H), 7.00 (m, 2H), 5.16 (dt, J¼3.2,
14.0 Hz, 4H), 3.99 (t, J¼7.5 Hz,1H), 2.95 (d, J¼7.5 Hz, 2H), 2.27 (s, 2H),
2.18 (s, 2H), 0.91 (s, 6H); 13C NMR (CDCl3, 100 MHz, ppm):
d 195.5,
170.5,158.4, 139.3, 135.5,129.3, 128.7, 128.4, 128.2, 124.9,124.0,107.9,
67.4, 51.0, 50.5, 40.7, 32.7, 28.1, 23.7; ESI-HRMS: calcd m/e for [MþHþ]
C32H34NO5: 512.2437, found 512.2431; IR (neat, NaCl, cmꢁ1): 2956,
1733, 1579, 1498, 1455, 1395, 1384, 1321, 1271, 1227, 1147, 1071.
4.2.16. Dimethyl
2-((2-(benzylamino)-5-oxocyclopent-1-enyl)
methyl)malonate (7p). The N-benzyl-enaminone (47 mg,
0.25 mmol), LiClO4 (27 mg, 0.25 mmol), paraformaldehyde (16 mg,
0.50 mmol), dimethyl malonate (0.042 mL, 0.37 mmol), and acetic
anhydride (0.024 mL, 0.25 mmol) were subjected to the standard
reaction conditions, and yielded a viscous colorless oil (78 mg,
4.2.12. Dimethyl 2-((2-(benzylamino)-4,4-dimethyl-6-oxocyclohex-
1-enyl)methyl)-malonate (7l). The N-benzyl-enaminone (57 mg,
0.25 mmol), LiClO4 (27 mg, 0.25 mmol), paraformaldehyde (16 mg,
0.50 mmol), dimethyl malonate (0.042 mL, 0.37 mmol), and acetic
anhydride (0.024 mL, 0.25 mmol) were subjected to the standard
reaction conditions, and yielded a viscous colorless oil (81 mg,
0.24 mmol, 94%). 1H NMR (CDCl3, 400 MHz, ppm):
d 7.36 (m, 2H),
7.29 (m, 3H), 6.43 (s, 1H), 4.47 (d, J¼6.4 Hz, 2H), 3.71 (t, J¼6.9 Hz,
1H), 3.69 (s, 6H), 2.69 (d, J¼7.2 Hz, 2H), 2.54 (s, 2H), 2.33 (s, 2H); 13C
NMR (CDCl3, 100 MHz, ppm):
d 202.3, 174.1, 170.6, 138.0, 129.0,
127.9, 127.0, 108.6, 52.8, 50.3, 47.3, 32.9, 24.9, 21.8; ESI-HRMS: calcd
m/e for [MþHþ] C18H22NO5: 332.1498, found 332.1492; IR (neat,
NaCl, cmꢁ1): 2952, 1733, 1669, 1594, 1578, 1496, 1436, 1353, 1279,
1238, 1156, 1118, 1077, 1056, 1030.
0.24 mmol, 95%). 1H NMR (CDCl3, 400 MHz, ppm):
d 7.37 (m, 2H),
7.29 (m, 3H), 6.20 (m, 1H), 4.43 (d, J¼6.2 Hz, 2H), 3.82 (t, J¼7.4 Hz,
1H), 3.69 (s, 6H), 2.84 (d, J¼7.3 Hz, 2H), 2.24 (s, 2H), 2.16 (s, 2H), 0.96
(s, 6H); 13C NMR (CDCl3, 100 MHz, ppm):
d 194.4, 171.1, 161.0, 138.5,
129.0, 127.8, 126.9, 104.5, 52.7, 50.5, 50.0, 47.1, 39.3, 31.8, 28.5, 23.4;
ESI-HRMS: ESI-HRMS: calcd m/e for [MþHþ] C21H28NO5: 374.1967,
found 374.1964; IR (neat, NaCl, cmꢁ1): 2953, 1732, 1576, 1436, 1407,
1357, 1325, 1271, 1245, 1150, 1118, 1036.
4.2.17. 2,20-Methylenebis(3-(benzylamino)cyclohex-2-enone)
(8). The N-benzyl enaminone (50 mg, 0.25 mmol) was dissolved in
acetonitrile (10 mL), and paraformaldehyde (16 mg, 0.50 mmol),
and dimethyl malonate (0.042 mL, 0.37 mmol) were added se-
quentially. The reaction was stirred at 60 ꢀC for 2 h, the solvent was
then removed under reduced pressure, and the crude material was
purified by flash column chromatography on silica gel, using 50%
acetone/hexanes (v/v) as the eluent. After purification, a light yel-
low oil was obtained (38 mg, 74%). 1H NMR (CDCl3, 400 MHz, ppm):
4.2.13. Dibenzyl 2-((2-(benzylamino)-4,4-dimethyl-6-oxocyclohex-1-
enyl)methyl)malonate (7m). The N-benzyl-enaminone (57 mg,
0.25 mmol), LiClO4 (27 mg, 0.25 mmol), paraformaldehyde (16 mg,
0.50 mmol), dibenzyl malonate (0.070 mL, 0.37 mmol), and acetic
anhydride (0.024 mL, 0.25 mmol) were subjected to the standard
reaction conditions, and yielded a viscous light yellow oil (115 mg,
d
9.51 (s, 2H), 7.33e7.20 (m,10H), 4.48 (d, J¼6.4 Hz, 4H), 3.77 (s, 2H),
2.36 (br, 4H), 2.27 (br, 4H), 1.82 (m, 4H); 13C NMR (CDCl3, 100 MHz,
0.22 mmol, 88%). 1H NMR (CDCl3, 400 MHz, ppm):
d
7.37e7.23 (m,
ppm): d 194.9, 166.9, 139.1, 128.8, 127.3, 126.7, 108.9, 63.8, 46.8, 35.7,
15H), 6.10 (t, J¼6.5 Hz, 1H), 5.11 (q-like, J¼12.4 Hz, 4H), 4.32 (d,
J¼6.3 Hz, 2H), 3.95 (t, J¼7.4 Hz, 1H), 2.87 (d, J¼7.4 Hz, 2H), 2.13 (s,
2H), 2.10 (s, 2H), 0.92 (s, 6H); 13C NMR (CDCl3, 100 MHz, ppm):
25.6, 21.5; ESI-HRMS: calcd m/e for [MþHþ] C27H31N2O2: 415.2386,
found 415.2390; IR (neat, NaCl, cmꢁ1): 3262, 3171, 3030, 2946,1734,
1610, 1560, 1478, 1433, 1355, 1317, 1201, 1127, 1106, 1051, 1011.
d
194.4, 170.4, 160.9, 138.5, 135.6, 129.0, 128.6, 128.3, 128.2, 127.7,
126.9, 104.3, 67.2, 50.8, 49.9, 47.0, 39.2, 31.8, 28.5, 23.3; ESI-HRMS:
calcd m/e for [MþHþ] C33H36NO5: 526.2593, found 526.2586; IR
(neat, NaCl, cmꢁ1): 2955, 1731, 1577, 1497, 1455, 1407, 1356, 1324,
1271, 1233, 1147, 1028.
4.2.18. Dimethyl 2-methylenemalonate (9a). Dimethyl malonate
(11.5 mL, 100.0 mmol) was dissolved in acetic acid (45 mL),
Cu(OAc)2 (2.0 g, 11.2 mmol) was added, and the reaction mixture
was heated at 100 ꢀC (external bath temperature) for 4 h. After
cooling to ambient temperature, the salts were filtered off, and the
acetic acid was removed using bulb-to-bulb distillation (bp
50e60 ꢀC, 100 mmHg). Further bulb-to-bulb distillation (bp
120e130 ꢀC, 20 mmHg) gave a colorless oil (3.7 g, 25.7 mmol, 26%).
The product tended to polymerize rapidly and was therefore, taken
to the reaction with the enaminone immediately after isolation. 1H
4.2.14. Dimethyl 2-((2-(butylamino)-4,4-dimethyl-6-oxocyclohex-1-
enyl)methyl)malonate (7n). The N-butyl-enaminone (49 mg,
0.25 mmol), LiClO4 (27 mg, 0.25 mmol), paraformaldehyde (16 mg,
0.50 mmol), dimethyl malonate (0.042 mL, 0.37 mmol), and acetic
anhydride (0.024 mL, 0.25 mmol) were subjected to the standard
reaction conditions, and yielded a viscous colorless oil (75 mg,
NMR (CDCl3, 400 MHz, ppm):
(CDCl3, 100 MHz, ppm):
d
6.56 (s, 2H), 3.83 (s, 6H); 13C NMR
d 167.1, 135.2, 134.5, 52.7; ESI-HRMS: calcd
0.22 mmol, 88%). 1H NMR (CDCl3, 400 MHz, ppm):
d
5.73 (s, 1H),
3.77 (t, J¼7.3 Hz, 1H), 3.69 (s, 6H), 3.18 (m, 2H), 2.77 (d, J¼7.3 Hz,
m/e for [MþHþ] C6H9O4: 145.0501, found 145.0500.
2H), 2.25 (s, 2H), 2.16 (s, 2H), 1.57 (m, 2H), 1.40 (m, 2H), 1.02 (s, 6H),
0.96 (t, 7.3 Hz, 3H); 13C NMR (CDCl3, 100 MHz, ppm):
d
193.8, 171.1,
4.2.19. Dimethyl 2-benzylidenemalonate (9b). To a solution of
161.1, 103.5, 52.6, 50.5, 49.9, 43.2, 39.5, 32.7, 31.8, 28.6, 23.3, 20.1,
13.9; ESI-HRMS: calcd m/e for [MþHþ] C18H30NO5: 340.2124, found
340.2126; IR (neat, NaCl, cmꢁ1): 2953, 1733, 1576, 1436, 1407, 1357,
1325, 1271, 1245, 1150, 1118, 1036.
benzaldehyde (6.6 mL, 60 mmol) in DMSO (20 mL), proline
(690.0 mg, 6.0 mmol) was added. The mixture was stirred for 5 min
before the addition of dimethyl malonate (13.7 mL, 120 mmol).
After stirring at ambient temperature for 24 h, the reaction was
diluted with EtOAc (60 mL) and washed with water (60 mLꢂ2). The
combined organic layer was dried over Na2SO4, and the solvent was
removed under reduced pressure. The residue was purified by flash
4.2.15. Dimethyl
2-((5-oxo-2-(phenylamino)cyclopent-1-enyl)
methyl)malonate (7o). The N-phenyl-enaminone (43 mg,

X. Gu, G.I. Georg / Tetrahedron 69 (2013) 9406e9416
9413
column chromatography on silica gel using 50% acetone/hexanes
(v/v) as the eluent to furnish a viscous oil (12.8 g, 98%): 1H NMR
1497, 1454, 1437, 1392, 1365, 1326, 1299, 1280, 1259, 1195, 1167,
1128.
(CDCl3, 400 MHz, ppm):
d
7.78 (s, 1H), 7.42e7.40 (m, 5H), 3.86 (s,
167.3, 164.6,
3H), 3.85 (s, 3H); 13C NMR (CDCl3, 100 MHz, ppm):
d
4.3.2. Benzyl 1-benzyl-2,5-dioxo-1,2,3,4,5,6,7,8-octahydroquinoline-
3-carboxylate (5b). The adduct (108 mg, 0.22 mmol) was dissolved
in toluene (7 mL), TFA (0.50 mL, 6.5 mmol) was added, and the
reaction mixture was then treated under the standard conditions to
yield a light yellow oil (60 mg, 0.15 mmol, 70%). 1H NMR (CDCl3,
143.1,132.9,130.8,129.5,129.0,125.6, 52.87, 52.86; ESI-HRMS: calcd
m/e for [MþHþ] C12H13O4: 221.0814, found 221.0805.
Four reactions were set up in parallel, utilizing the enami-
none(3-(benzylamino)cyclohex-2-enone) to react with dimethyl 2-
methylenemalonate 9a and dimethyl 2-benzylidenemalonate 9b
synthesized above, respectively:
400 MHz, ppm):
d 7.37e7.24 (m, 8H), 7.16 (m, 2H), 5.20 (q-like,
J¼12.2 Hz, 2H), 5.00 (q-like, J¼16.5 Hz, 2H), 3.68 (t, J¼7.0 Hz, 1H),
3.15 (dd, J¼7.5, 16.8 Hz, 1H), 2.80 (dd, J¼6.6, 16.8 Hz, 1H), 2.41 (m,
2H), 2.26 (m, 2H), 1.84 (m, 2H); 13C NMR (CDCl3, 100 MHz, ppm):
a) A solution of enaminone (50.2 mg, 0.25 mmol), LiClO4 (30 mg,
0.25 mmol), and dimethyl 2-methylenemalonate (54 mg,
d
195.6, 168.9, 167.1, 154.7, 136.6, 135.4, 129.0, 128.6, 128.4, 128.3,
ꢀ
0.38 mmol) was heated in a sealed screw-cap vial at 60 C;
127.5, 126.1, 115.0, 67.3, 47.5, 45.6, 35.9, 26.3, 21.6, 20.8; ESI-HRMS:
calcd m/e for [MþHþ] C24H24NO4: 390.1705, found 390.1700; IR
(neat, NaCl, cmꢁ1): 2953, 1738, 1691, 1652, 1622, 1497, 1455, 1428,
1390, 1364, 1297, 1258, 1194, 1164, 1126.
b) A solution of enaminone (50.2 mg, 0.25 mmol) and dimethyl 2-
methylenemalonate (54 mg, 0.38 mmol) was heated in a sealed
ꢀ
screw-cap vial at 60 C;
c) A solution of enaminone (50.2 mg, 0.25 mmol), LiClO4 (30 mg,
0.25 mmol), and dimethyl 2-benzylidenemalonate (83 mg,
4.3.3. Methyl 2,5-dioxo-1-phenyl-1,2,3,4,5,6,7,8-octahydroquinoline-
3-carboxylate (5c). The adduct (57 mg, 0.17 mmol) was dissolved in
dichloroethane (5 mL), TFA (0.40 mL, 5.2 mmol) was added, and the
reaction mixture was treated under the standard conditions to
yield a white solid (43 mg, 0.14 mmol, 84%, mp: 120e121 ꢀC). 1H
ꢀ
0.38 mmol) was heated in a sealed screw-cap vial at 60 C;
d) A solution of enaminone (50.2 mg, 0.25 mmol) and dimethyl 2-
benzylidenemalonate (83 mꢀg, 0.38 mmol) was heated in
a sealed screw-cap vial at 60 C.
NMR (CDCl3, 400 MHz, ppm): d 7.48e7.40 (m, 3H), 7.17 (s, 2H), 3.76
The reactions were monitored by TLC for product formation.
After the starting material was completely consumed, the reaction
medium was then allowed to cool to ambient temperature and was
subsequently washed with H2O (20 mL). The aqueous phase was
extracted with EtOAc (3ꢂ10 mL). The organic layers were com-
bined, washed with brine, and dried with MgSO4. The organic
solvent was then removed under reduced pressure, and the residue
was purified by flash column chromatography on silica gel. Re-
actions a and b gave the desired adduct in a yield of 90%, while only
starting material was recovered for reactions c and d.
(s, 3H), 3.68 (t, J¼7.6 Hz, 1H), 3.18 (dd, J¼8.4, 17.0 Hz, 1H), 2.90 (dd,
J¼8.6, 17.0 Hz, 1H), 2.39 (t, J¼6.0 Hz, 2H), 2.09 (t, J¼6.0 Hz, 2H), 1.93
(m, 2H); 13C NMR (CDCl3, 100 MHz, ppm):
d 196.0, 169.6, 167.1,
154.8, 137.0, 129.7, 129.0, 128.8, 113.9, 52.8, 47.5, 36.3, 28.0, 21.9,
21.1; ESI-HRMS: calcd m/e for [MþHþ] C17H18NO4: 300.1236, found
300.1228; IR (neat, NaCl, cmꢁ1): 2953, 1742, 1702, 1652, 1625, 1594,
1493, 1380, 1271, 1244, 1154.
4.3.4. Benzyl 2,5-dioxo-1-phenyl-1,2,3,4,5,6,7,8-octahydroquinoline-
3-carboxylate (5d). The adduct (117 mg, 0.24 mmol) was dissolved
in toluene (7 mL), TFA (0.55 mL, 7.2 mmol) was added, and the
reaction mixture was treated under the standard conditions to
yield a light yellow solid (44 mg, 0.12 mmol, 49%, mp: 117e118 ꢀC).
4.3. General method for the synthesis of 2,5-dioxo-
1,2,3,4,5,6,7,8-octahydroquinoline-3-carboxylates 5 (Table 3)
1H NMR (CDCl3, 400 MHz, ppm):
d 7.43 (m, 3H), 7.35 (m, 5H), 7.09
(m, 2H), 5.20 (q-like, J¼12.1 Hz, 2H), 3.73 (t, J¼6.5 Hz, 1H), 3.30 (dd,
The adduct 7 was dissolved in the corresponding solvent
(30 mL/mmol) in a screw-cap vial. Dichloroethane was selected as
the solvent for the adducts derived from dimethyl malonate, and
toluene was used for those derived from dibenzyl malonate. To the
solution was slowly added trifluoroacetic acid (30 equiv). The vial
was sealed and stirred at 90 ꢀC for 0.5e3 h. The reaction medium
was cooled to ambient temperature and washed with saturated
NaHCO3 solution (20 mL). The aqueous phase was extracted with
CH2Cl2 or EtOAc (3ꢂ10 mL). The organic layers were combined,
washed with brine, and dried over MgSO4. The organic solvent was
then removed under reduced pressure, and the residue was puri-
fied by flash column chromatography on silica gel, using 20% EtOAc/
hexanes (v/v) as the eluent.
J¼6.5, 17.0 Hz, 1H), 2.85 (dd, J¼6.6, 16.9 Hz, 1H), 2.33 (m, 2H), 1.99
(m, 2H), 1.81 (m, 2H); 13C NMR (CDCl3, 100 MHz, ppm):
d 195.8,
168.8, 167.0, 154.8, 136.9, 135.3, 129.6, 128.9, 128.6, 128.5, 128.4,
113.8, 67.4, 47.6, 36.1, 27.9, 21.7, 21.2; ESI-HRMS: calcd m/e for
[MþHþ] C23H22NO4: 376.1549, found 376.1546; IR (neat, NaCl,
cmꢁ1): 2951, 1740, 1704, 1652, 1624, 1595, 1491, 1455, 1379, 1350,
1311, 1271, 1244, 1197, 1155.
4.3.5. Methyl 1-butyl-2,5-dioxo-1,2,3,4,5,6,7,8-octahydroquinoline-
3-carboxylate (5e). The adduct (42 mg, 0.14 mmol) was dissolved in
dichloroethane (4 mL), TFA (0.31 mL, 3.8 mmol) was added, and
then, the reaction mixture was treated under the standard condi-
tions to yield a viscous yellow oil (24 mg, 0.077 mmol, 57%). 1H NMR
(CDCl3, 400 MHz, ppm):
d
3.74 (s, 3H), 3.69 (m, 2H), 3.48 (dd, J¼6.8,
4.3.1. Methyl 1-benzyl-2,5-dioxo-1,2,3,4,5,6,7,8-octahydroquinoline-
3-carboxylate (5a). The adduct (80 mg, 0.23 mmol) was dissolved
in dichloroethane (7 mL); then TFA (0.54 mL, 7.0 mmol) was
added, and the reaction was treated under the standard condi-
tions to yield a light yellow oil (58 mg, 0.18 mmol, 79%). 1H NMR
9.3 Hz, 1H), 2.94 (dd, J¼9.3, 17.0 Hz, 1H), 2.79 (dd, J¼6.8, 16.6 Hz,
1H), 2.60 (m, 2H), 2.40 (t, J¼6.2 Hz, 2H), 2.07 (m, 2H), 1.54 (m, 2H),
1.35 (m, 2H), 0.94 (t, J¼7.3 Hz, 2H); 13C NMR (CDCl3,100 MHz, ppm):
d
195.7, 169.6, 166.8, 154.3, 114.7, 52.6, 47.3, 42.6, 36.0, 31.2, 26.2,
21.8, 20.6, 20.1, 13.8; ESI-HRMS: calcd m/e for [MþHþ] C15H22NO4:
280.1549, found 280.1544; IR (neat, NaCl, cmꢁ1): 2957, 1744, 1690,
1652, 1618, 1435, 1393, 1279, 1245, 1201, 1121.
(CDCl3, 400 MHz, ppm):
d 7.27 (m, 2H), 7.20 (m, 1H), 7.11 (m, 2H),
4.96 (q-like, J¼16.4 Hz, 2H), 3.70 (s, 3H), 3.57 (t, J¼8.3 Hz, 1H),
3.00 (dd, J¼8.4, 16.9 Hz, 1H), 2.78 (dd, J¼8.5, 16.9 Hz, 1H), 2.42 (t,
J¼6.3 Hz, 2H), 2.28 (t, J¼6.2 Hz, 2H), 1.88 (m, 2H); 13C NMR
4.3.6. Benzyl 1-butyl-2,5-dioxo-1,2,3,4,5,6,7,8-octahydroquinoline-3-
carboxylate (5f). The adduct (96 mg, 0.21 mmol) was dissolved in
toluene (6 mL), TFA (0.48 mL, 6.2 mmol) was added, and then, the
reaction mixture was treated under the standard conditions to
yield a viscous colorless oil (44 mg, 0.13 mmol, 60%). 1H NMR
(CDCl3, 100 MHz, ppm):
d 195.8, 169.6, 167.2, 154.7, 136.7, 129.0,
127.7, 126.2, 115.0, 52.8, 47.4, 45.7, 36.0, 26.5, 21.8, 20.8; ESI-
HRMS: calcd m/e for [MþHþ] C18H20NO4: 314.1392, found
314.1385; IR (neat, NaCl, cmꢁ1): 2953, 1743, 1692, 1654, 1622,

9414
X. Gu, G.I. Georg / Tetrahedron 69 (2013) 9406e9416
(CDCl3, 400 MHz, ppm):
d
7.36e7.29 (m, 5H), 5.16 (q-like, J¼12.2 Hz,
ppm): d 195.7, 168.8, 167.2, 152.9, 136.9, 135.2, 129.62, 129.61, 128.9,
2H), 3.68 (m, 2H), 3.52 (dd, J¼6.6, 8.0 Hz, 1H), 3.04 (dd, J¼8.0,
16.7 Hz, 1H), 2.73 (dd, J¼6.4, 17.2 Hz, 1H), 2.51 (m, 2H), 2.34 (m, 2H),
1.96 (m, 2H), 1.50 (m, 2H), 1.34 (m, 2H), 0.93 (t, J¼7.2 Hz, 3H); 13C
128.7, 128.52, 128.47, 112.8, 67.5, 49.8, 47.6, 41.4, 33.0, 28.6, 27.6,
20.9; ESI-HRMS: calcd m/e for [MþHþ] C25H26NO4: 404.1862, found
404.1864; IR (neat, NaCl, cmꢁ1): 2958, 1740, 1705, 1654, 1628, 1596,
1492, 1455, 1379, 1351, 1317, 1292, 1240, 1262, 1173, 1143.
NMR (CDCl3, 100 MHz, ppm):
d 195.6, 168.9, 166.7, 154.5, 135.4,
128.6, 128.4, 128.3, 114.7, 67.2, 47.5, 42.6, 35.9, 31.2, 26.1, 21.7, 20.8,
20.1, 13.7; ESI-HRMS: calcd m/e for [MþHþ] C21H26NO4: 356.1862,
found 356.1861; IR (neat, NaCl, cmꢁ1): 2958, 1741, 1691, 1652, 1618,
1498, 1456, 1394, 1278, 1245, 1197, 1172, 1121.
4.3.11. Methyl 1-butyl-7,7-dimethyl-2,5-dioxo-1,2,3,4,5,6,7,8-
octahydroquinoline-3-carboxylate (5k). The adduct (75 mg,
0.22 mmol) was dissolved in dichloroethane (7 mL), TFA (0.51 mL,
6.6 mmol) was added, and then, the reaction mixture was treated
under the standard conditions to yield a viscous light yellow oil
4.3.7. Methyl 1-benzyl-7,7-dimethyl-2,5-dioxo-1,2,3,4,5,6,7,8-
octahydroquinoline-3-carboxylate (5g). The adduct (52 mg,
0.14 mmol) was dissolved in dichloroethane (5 mL), TFA (0.32 mL,
4.2 mmol) was added, and then, the reaction mixture was treated
under the standard conditions to yield a viscous colorless oil
(42 mg, 0.14 mmol, 62%). 1H NMR (CDCl3, 400 MHz, ppm):
d 3.71 (s,
3H), 3.68 (m, 2H), 3.48 (dd, J¼6.6, 8.0 Hz, 1H), 3.00 (dd, J¼8.1,
16.7 Hz, 1H), 2.72 (dd, J¼6.6, 16.8 Hz, 1H), 2.42 (s, 2H), 2.27 (s, 2H),
1.53 (m, 2H), 1.35 (m, 2H), 1.10 (s, 3H), 1.07 (s, 3H), 0.94 (t, J¼7.3 Hz,
(32 mg, 0.093 mmol, 67%). 1H NMR (CDCl3, 400 MHz, ppm):
d
7.34
3H); 13C NMR (CDCl3, 100 MHz, ppm):
d 195.6, 169.7, 167.1, 152.6,
(m, 2H), 7.26 (m, 1H), 7.17 (m, 2H), 5.09 (q-like, J¼16.4 Hz, 2H), 3.75
(s, 3H), 3.64 (t, J¼6.9 Hz, 1H), 3.14 (dd, J¼7.2, 16.8 Hz, 1H), 2.80 (dd,
J¼6.6, 16.8 Hz, 1H), 2.34 (s, 2H), 2.22 (s, 2H), 0.95 (s, 3H), 0.92 (s,
113.8, 52.7, 49.8, 47.4, 42.5, 40.1, 33.2, 31.4, 29.0, 27.9, 20.5, 20.2,
13.9; ESI-HRMS: calcd m/e for [MþHþ] C17H26NO4: 308.1862, found
308.1868; IR (neat, NaCl, cmꢁ1): 2958, 2872, 1745, 1692, 1653, 1623,
1439, 1391, 1310, 1279, 1248, 1206, 1173, 1118, 1032, 1009.
3H); 13C NMR (CDCl3, 100 MHz, ppm):
d 195.7, 169.6, 167.4, 152.9,
136.8, 129.1, 127.7, 126.1, 114.1, 52.8, 49.8, 47.5, 45.6, 40.1, 33.2, 28.9,
27.5, 20.6; ESI-HRMS: calcd m/e for [MþHþ] C20H24NO4: 342.1705,
found 342.1698; IR (neat, NaCl, cmꢁ1): 2956, 1741, 1693, 1653, 1625,
1497, 1454, 1439, 1386, 1303, 1280, 1252, 1204, 1168.
4.3.12. Methyl 1-benzyl-2,5-dioxo-2,3,4,5,6,7-hexahydro-1H-cyclo-
penta[b]pyridine-3-carboxylate (5l). The adduct (51 mg, 0.15 mmol)
was dissolved in dichloroethane (5 mL), TFA (0.36 mL, 4.6 mmol)
was added, and then, the reaction mixture was treated under the
standard conditions to yield a white solid (29 mg, 0.095 mmol, 62%,
4.3.8. Benzyl 1-benzyl-7,7-dimethyl-2,5-dioxo-1,2,3,4,5,6,7,8-
octahydroquinoline-3-carboxylate (5h). The adduct (117 mg,
0.22 mmol) was dissolved in toluene (7 mL), TFA (0.46 mL,
6.7 mmol) was added, and then, the reaction mixture was treated
under the standard conditions to yield a viscous colorless oil
(60 mg, 0.14 mmol, 64%). 1H NMR (CDCl3, 400 MHz, ppm):
mp: 134e135 ꢀC). 1H NMR (CDCl3, 400 MHz, ppm):
d 7.37e7.29 (m,
3H), 7.24 (m, 2H), 4.96 (q-like, J¼15.8 Hz, 2H), 3.77 (s, 3H), 3.72 (t,
J¼7.6 Hz, 1H), 2.96 (dd, J¼7.3, 17.3 Hz, 1H), 2.75 (dd, J¼7.9, 17.0 Hz,
1H), 2.65 (m, 2H), 2.46 (m, 2H); 13C NMR (CDCl3, 100 MHz, ppm):
d
201.5, 169.6, 168.4, 167.4, 136.3, 129.1, 128.0, 126.9, 116.9, 53.0, 47.5,
d
7.35e7.25 (m, 8H), 7.16 (m, 2H), 5.18 (q-like, J¼12.2 Hz, 2H), 5.00
46.5, 34.3, 25.4, 19.8; ESI-HRMS: calcd m/e for [MþHþ] C17H18NO4:
300.1236, found 300.1230; IR (neat, NaCl, cmꢁ1): 2953, 2928, 1742,
1687, 1640, 1496, 1437, 1412, 1363, 1322, 1281, 1253, 1213, 1167, 1137,
1123, 1027, 1083.
(q-like, J¼16.6 Hz, 2H), 3.69 (t, J¼6.8 Hz,1H), 3.19 (dd, J¼7.0,16.8 Hz,
1H), 2.79 (dd, J¼4.7, 16.8 Hz, 1H), 2.27 (q-like, J¼10.2 Hz, 2H), 2.15
(q-like, J¼16.3 Hz, 2H), 0.90 (s, 3H), 0.84 (s, 3H); 13C NMR (CDCl3,
100 MHz, ppm): d 195.6,169.0,167.3,153.0,136.7,135.4,129.0,128.7,
128.5, 128.4, 127.6, 126.0, 114.0, 67.4, 49.7, 47.6, 45.5, 40.0, 33.0, 28.6,
27.7, 20.7; ESI-HRMS: calcd m/e for [MþHþ] C26H28NO4: 418.2018,
found 418.2021; IR (neat, NaCl, cmꢁ1): 2959, 1739, 1694, 1653, 1625,
1497, 1455, 1386, 1369, 1303, 1252, 1213, 1169, 1124.
4.3.13. Methyl 2,5-dioxo-1-phenyl-2,3,4,5,6,7-hexahydro-1H-cyclo-
penta[b]pyridine-3-carboxylate (5m). The adduct (76 mg,
0.24 mmol) was dissolved in dichloroethane (7 mL), TFA (0.55 mL,
7.2 mmol) was added, and then, the reaction mixture was treated
under the standard conditions to yield a white solid (34 mg,
0.12 mmol, 49%, mp: 100e101 ꢀC). 1H NMR (CDCl3, 400 MHz,
4.3.9. Methyl 7,7-dimethyl-2,5-dioxo-1-phenyl-1,2,3,4,5,6,7,8-
octahydroquinoline-3-carboxylate (5i). The adduct (54 mg,
0.21 mmol) was dissolved in toluene (6 mL), TFA (0.48 mL,
6.2 mmol) was added, and then, the reaction mixture was treated
under the standard conditions to yield a white solid (44 mg,
0.12 mmol, 64%, mp: 123e124 ꢀC). 1H NMR (CDCl3, 400 MHz, ppm):
ppm):
d
7.50e7.44 (m, 3H), 7.24 (m, 2H), 3.79 (t, J¼6.4 Hz, 1H), 3.78
(s, 3H), 3.06 (dd, J¼6.3, 17.1 Hz, 1H), 2.83 (dd, J¼7.8, 17.1 Hz, 1H),
2.45 (m, 2H), 2.33 (m, 2H); 13C NMR (CDCl3, 100 MHz, ppm):
d
201.9, 169.7, 168.6, 167.3, 136.1, 129.8, 129.4, 128.3, 116.1, 53.1, 47.6,
34.3, 26.0, 20.1; ESI-HRMS: calcd m/e for [MþHþ] C16H16NO4:
286.1079, found 286.1074; IR (neat, NaCl, cmꢁ1): 2954, 2929, 1743,
1690, 1641, 1595, 1564, 1492, 1439, 1395, 1352, 1317, 1293, 1257,
1140, 1024, 1000.
d
7.50e7.42 (m, 3H), 7.21e7.10 (m, 2H), 3.75 (s, 3H), 3.69 (t, J¼5.8 Hz,
1H), 3.25 (dd, J¼6.6, 16.9 Hz, 1H), 2.86 (dd, J¼6.6, 16.9 Hz, 1H), 2.26
(s, 2H), 1.95 (q-like, J¼17.6 Hz, 2H), 0.97 (s, 3H), 0.95 (s, 3H); 13C
NMR (CDCl3, 100 MHz, ppm):
d 195.8, 169.5, 167.2, 153.0, 136.9,
129.7, 128.9, 128.5, 113.0, 52.7, 49.9, 47.5, 41.5, 33.2, 28.8, 27.4, 20.8;
ESI-HRMS: calcd m/e for [MþHþ] C19H22NO4: 328.1549, found
328.1540; IR (neat, NaCl, cmꢁ1): 2956, 1740, 1704, 1654, 1628, 1596,
1492, 1437, 1380, 1317, 1292, 1263, 1239, 1144.
4.4. General procedure for the preparation of 2,5-dioxo-
1,2,3,4,5,6,7,8-octahydroquinoline-3-carbonitriles 10 (Table 4)
The enaminone 6 was dissolved in acetonitrile (100 mL/mmol)
and stirred at ambient temperature. To the solution, LiClO4
(1 equiv) was added, followed by the addition of PPh3 (0.5 equiv),
methyl cyanoacetate (1.5 equiv), and paraformaldehyde (1.0 equiv)
in sequence. The reaction was heated to 60 ꢀC in a sealed vessel for
14 h (monitored by TLC). The reaction was quenched with saturated
NaHCO3 solution, upon consumption of starting material. The
mixture was then extracted with CH2Cl2 (10 mLꢂ2), and the or-
ganic layers were combined, dried over MgSO4, and concentrated in
vacuo. The crude product was purified by flash column chroma-
tography on silica gel, using 25% EtOAc/hexanes (v/v) as the eluent.
4.3.10. Benzyl 7,7-dimethyl-2,5-dioxo-1-phenyl-1,2,3,4,5,6,7,8-
octahydroquinoline-3-carboxylate (5j). The adduct (111 mg,
0.22 mmol) was dissolved in toluene (7 mL), TFA (0.50 mL,
6.5 mmol) was added, and then, the reaction mixture was treated
under the standard conditions to yield a white solid (63 mg,
0.16 mmol, 72%, mp: 126e127 ꢀC). 1H NMR (CDCl3, 400 MHz, ppm):
d
7.43 (m, 3H), 7.34 (m, 5H), 7.07 (m, 2H), 5.18 (q-like, J¼12.2 Hz,
2H), 3.73 (t, J¼6.3 Hz, 1H), 3.33 (dd, J¼5.8, 16.9 Hz, 1H), 2.84 (dd,
J¼6.3, 16.9 Hz, 1H), 2.19 (q-like, J¼16.4 Hz, 2H), 1.88 (q-like,
J¼17.0 Hz, 2H), 0.94 (s, 3H), 0.86 (s, 3H); 13C NMR (CDCl3, 100 MHz,

X. Gu, G.I. Georg / Tetrahedron 69 (2013) 9406e9416
9415
4.4.1. 1-Benzyl-2,5-dioxo-1,2,3,4,5,6,7,8-octahydroquinoline-3-
carbonitrile (10a). The N-benzyl enaminone (50 mg, 0.25 mmol),
LiClO4 (27 mg, 0.25 mmol), paraformaldehyde (8 mg, 0.25 mmol),
methyl cyanoacetate (0.033 mL, 0.37 mmol), and triphenylphos-
phine (33 mg, 0.13 mmol) in acetonitrile (25 mL) were subjected to
the standard conditions and yielded a colorless oil (60 mg,
yielded a white solid (47 mg, 0.17 mmol, 67%, mp: 77e79 ꢀC). 1H
NMR (CDCl3, 400 MHz, ppm):
1H), 3.52 (m, 2H), 3.28 (s, 3H), 3.08 (dd, J¼6.2, 16.3 Hz, 1H), 2.80 (m,
1H), 2.61 (d, J¼17.2 Hz,1H), 2.49 (d, J¼17.2 Hz,1H), 2.28 (d, J¼3.0 Hz,
2H), 1.10 (s, 3H), 1.08 (s, 3H); 13C NMR (CDCl3, 100 MHz, ppm):
d
3.91 (m, 2H), 3.63 (dd, J¼6.2,11.1 Hz,
d
195.4, 163.1, 153.6, 115.7, 112.6, 70.3, 59.1, 49.5, 43.3, 40.2, 34.4,
0.21 mmol, 85%). 1H NMR (CDCl3, 400 MHz, ppm):
d
7.37e7.27 (m,
33.0, 28.4, 28.3, 21.5; ESI-HRMS: calcd m/e for [MþHþ] C15H21N2O3:
277.1552, found 277.1558; IR (neat, NaCl, cmꢁ1): 2957, 2889, 2252,
1770, 1715, 1655, 1627, 1249, 1207.
3H), 7.13 (m, 2H), 5.12 (d, J¼16.3 Hz, 1H), 4.91 (d, 16.3 Hz, 1H), 3.75
(dd, J¼6.3, 11.3 Hz, 1H), 3.17 (ddd, J¼1.4, 4.8, 15.3 Hz, 1H), 2.87 (m,
1H), 2.53 (m, 2H), 2.38 (t, J¼6.2 Hz, 2H), 1.99 (m, 2H); 13C NMR
(CDCl3, 100 MHz, ppm):
d 195.1, 163.0, 154.6, 135.8, 129.2, 127.9,
Notes
126.1, 115.6, 114.6, 46.0, 35.7, 34.4, 26.3, 21.8, 21.5; ESI-HRMS: calcd
m/e for [MþHþ] C17H17N2O2: 281.1290, found 281.1281; IR (neat,
NaCl, cmꢁ1): 2959, 2890, 2256, 1756, 1700, 1655, 1627, 1497.
The authors declare no competing financial interest.
Acknowledgements
4.4.2. 2,5-Dioxo-1-phenyl-1,2,3,4,5,6,7,8-octahydroquinoline-3-
carbonitrile (10b). The N-phenyl enaminone (47 mg, 0.25 mmol),
LiClO4 (27 mg, 0.25 mmol), paraformaldehyde (8 mg, 0.25 mmol),
methyl cyanoacetate (0.033 mL, 0.37 mmol), and triphenylphos-
phine (33 mg, 0.13 mmol) in acetonitrile (25 mL) were subjected to
the standard conditions and yielded a yellow solid (43 mg,
0.16 mmol, 65%, mp: 158e160 ꢀC). 1H NMR (CDCl3, 400 MHz, ppm):
We gratefully acknowledge financial support from the NIH
(Grant No. P41 GM076302 and P41 GM081267) and the University
of Minnesota through the Vince and McKnight Endowed Chairs (to
G.I.G).
Supplementary data
d
7.57e7.46 (m, 3H), 7.15 (m, 2H), 3.83 (dd, J¼6.4, 11.1 Hz, 1H), 3.24
(dd, J¼6.3,15.2 Hz,1H), 2.97 (m,1H), 2.42 (dt, J¼1.9, 6.4 Hz, 2H), 2.13
(m, 2H), 1.96 (m, 2H); 13C NMR (CDCl3, 100 MHz, ppm):
195.3,
1H NMR and 13C NMR spectra for all new compounds are
available. Supplementary data related to this article can be found at
http://dx.doi.org/10.1016/j.tet.2013.08.081.
d
162.7, 154.8, 136.1, 129.9, 129.4, 128.5, 115.5, 113.6, 36.0, 34.7, 27.9,
22.1, 21.6; ESI-HRMS: calcd m/e for [MþHþ] C16H15N2O2: 267.1134,
found 267.1134; IR (neat, NaCl, cmꢁ1): 2940, 2260, 1765, 1710, 1655,
1627, 1500.
References and notes
1. Triggle, D. J. Cell. Mol. Neurobiol. 2003, 23, 293e303.
2. Rose, U. Arch. Pharmacol. 1990, 323, 281e286.
4.4.3. 1-Butyl-2,5-dioxo-1,2,3,4,5,6,7,8-octahydroquinoline-3-
carbonitrile (10c). The N-butyl enaminone (42 mg, 0.25 mmol),
LiClO4 (27 mg, 0.25 mmol), paraformaldehyde (8 mg, 0.25 mmol),
methyl cyanoacetate (0.033 mL, 0.37 mmol), and triphenylphos-
phine (33 mg, 0.13 mmol) in acetonitrile (25 mL) were subjected to
the standard conditions and yielded a colorless oil (44 mg,
3. Takahashi, D.; Oyunzul, L.; Onoue, S.; Ito, Y.; Uchida, S.; Simsek, R.; Gunduz, M.
G.; Safak, C.; Yamada, S. Biol. Pharm. Bull. 2008, 31, 473e479.
4. Willems, E.; Cabral-Teixeira, J.; Schade, D.; Cai, W.; Reeves, P.; Bushway, P. J.;
Lanier, M.; Walsh, C.; Kirchhausen, T.; Izpisua, B. J. C.; Cashman, J.; Mercola, M.
Cell Stem Cell 2012, 11, 242e252.
5. Schade, D.; Lanier, M.; Willems, E.; Okolotowicz, K.; Bushway, P. J.; Wahlquist,
C.; Gilley, C.; Mercola, M.; Cashman, J. R. J. Med. Chem. 2012, 55, 9946e9957.
6. Movsesian, M. A.; Kukreja, R. C. Phosphodiesterase Inhibition in Heart Failure In
Phosphodiesterases as Drug Targets; Francis, S. H., Conti, M., Houslay, M. D., Eds.;
Springer: Berlin, Germany, 2011; pp 237e250.
7. Gorobets, N. Y.; Yousefi, B. H.; Belaj, F.; Kappe, C. O. Tetrahedron 2004, 60,
8633e8644.
8. Fossa, P.; Menozzi, G.; Dorigo, P.; Floreani, M.; Mosti, L. Bioorg. Med. Chem. 2003,
11, 4749e4759.
9. Noguez, M. O.; Marcelino, V.; Rodriguez, H.; Martin, O.; Martinez, J. O.; Arroy, G.
A.; Perez, F. J.; Suarez, M.; Miranda, R. Int. J. Mol. Sci. 2011, 12, 2641e2649.
10. Hirsch, K. S.; Jones, C. D. Preparation of Hexahydrobenzo[f]quinolinones as 5-
a-
0.18 mmol, 73%). 1H NMR (CDCl3, 400 MHz, ppm):
d 3.77 (m, 1H),
3.63 (m, 2H), 3.11 (dd, J¼6.3, 16.5 Hz, 1H), 2.74 (m, 1H), 2.61 (m, 2H),
2.43 (t, J¼7.1 Hz, 2H), 2.11 (m, 2H), 1.53 (m, 2H), 1.34 (m, 2H), 0.94 (t,
J¼7.3 Hz, 3H); 13C NMR (CDCl3,100 MHz, ppm):
d 195.0,162.5,154.4,
115.7, 114.3, 43.1, 35.8, 34.4, 31.2, 26.2, 21.8, 21.7, 20.0, 13.7; ESI-
HRMS: calcd m/e for [MþHþ] C14H19N2O2: 247.1447, found
247.1449; IR (neat, NaCl, cmꢁ1): 2964, 2897, 2256, 1756, 1700, 1655,
1627.
Reductase Inhibitors. 1992-307636, 531026, 19920820, 1993.
11. Jones, C. D.; Audia, J. E.; Lawhorn, D. E.; McQuaid, L. A.; Neubauer, B. L.; Pike, A.
J.; Pennington, P. A.; Stamm, N. B.; Toomey, R. E.; Hirsch, K. S. J. Med. Chem. 1993,
36, 421e423.
12. Astleford, B. A.; Audia, J. E.; Deeter, J.; Heath, P. C.; Janisse, S. K.; Kress, T. J.;
Wepsiec, J. P.; Weigel, L. O. J. Org. Chem. 1996, 61, 4450e4454.
13. Ko, S.; Sastry, M. N. V.; Lin, C.; Yao, C. Tetrahedron Lett. 2005, 46, 5771e5774.
14. Sun, J.; Xia, E.-Y.; Wu, Q.; Yan, C.-G. ACS Comb. Sci. 2011, 13, 421e426.
15. Fan, X. S.; Li, Y. Z.; Zhang, X. Y.; Qu, G. R.; Wang, J. J.; Hu, X. Y. Heteroat. Chem.
2006, 17, 382e388.
4.4.4. 7,7-Dimethyl-2,5-dioxo-1-propyl-1,2,3,4,5,6,7,8-
octahydroquinoline-3-carbonitrile (10d). The N-propyl enaminone
(45 mg, 0.25 mmol), LiClO4 (27 mg, 0.25 mmol), paraformaldehyde
(8 mg, 0.25 mmol), methyl cyanoacetate (0.033 mL, 0.37 mmol),
and triphenylphosphine (33 mg, 0.13 mmol) in acetonitrile (25 mL)
were subjected to the standard conditions and yielded a white solid
(49 mg, 0.19 mmol, 75%, mp: 136e137 ꢀC). 1H NMR (CDCl3,
16. Tu, S.; Zhu, X.; Zhang, J.; Xu, J.; Zhang, Y.; Wang, Q.; Jia, R.; Jiang, B.; Zhang, J.;
Yao, C. Bioorg. Med. Chem. Lett. 2006, 16, 2925e2928.
400 MHz, ppm):
d
3.71 (m, 1H), 3.62 (m, 2H), 3.03 (dd, J¼6.3,
ꢀ
ꢀ
17. Suarez, M.; Ochoa, E.; Verdecia, Y.; Pita, B.; Moran, L.; Martín, N.; Quinteiro, M.;
Seoane, C.; Soto, J.; Novoa, H.; Blaton, N.; Peters, O. M. Tetrahedron 1999, 55,
875e884.
16.6 Hz, 1H), 2.81 (m, 1H), 2.43 (m, 2H), 2.29 (d, J¼16.9 Hz, 2H), 1.53
(m, 2H), 1.08 (s, 3H), 1.06 (s, 3H), 0.88 (t, J¼7.4 Hz, 3H); 13C NMR
(CDCl3, 100 MHz, ppm): d 194.0, 161.7, 151.5, 114.8, 112.2, 48.5, 43.6,
18. Azzam, S. H. S.; Siddekha, A.; Pasha, M. A. Tetrahedron Lett. 2012, 53,
6306e6309.
19. Enders, D.; Demir, A. S.; Puff, H.; Franken, S. Tetrahedron Lett. 1987, 28,
3795e3798.
20. Wang, G.; Miao, C. Green Chem. 2006, 8, 1080e1085.
21. Saidi, M. R.; Azizi, N.; Zali-Boinee, H. Tetrahedron 2001, 57, 6829e6832.
22. Azizi, N.; Saidi, M. R. Tetrahedron 2003, 59, 5329e5332.
23. Saidi, M. R.; Azizi, N.; Naimi-Jamal, M. R. Tetrahedron Lett. 2001, 42, 8111e8113.
24. Saidi, M. R.; Azizi, N. Tetrahedron: Asymmetry 2002, 13, 2523e2527.
25. Aryanasab, F.; Saidi, M. R. Synth. Commun. 2008, 38, 4036e4044.
26. Hoye, T. R.; Caruso, A. J.; Magee, A. S. J. Org. Chem. 1982, 47, 4152e4156.
27. Nenajdenko, V. G.; Statsuk, A. V.; Balenkova, E. S. Tetrahedron 2000, 56,
6549e6556.
38.9, 33.4, 32.1, 27.5, 27.3, 21.5, 20.5, 10.0; ESI-HRMS: calcd m/e for
[MþHþ] C15H21N2O2: 261.1603, found 261.1612; IR (neat, NaCl,
cmꢁ1): 2962, 2903, 2252, 1754, 1702, 1652, 1628.
4.4.5. 1-(2-Methoxyethyl)-7,7-dimethyl-2,5-dioxo-1,2,3,4,5,6,7,8-
octahydroquinoline-3-carbonitrile
(10e). The
N-methoxyethyl
enaminone (49 mg, 0.25 mmol), LiClO4 (27 mg, 0.25 mmol), para-
formaldehyde (8 mg, 0.25 mmol), methyl cyanoacetate (0.033 mL,
0.37 mmol), and triphenylphosphine (33 mg, 0.13 mmol) in ace-
tonitrile (25 mL) were subjected to the standard conditions and
28. Cannon, J. G. J. Am. Pharm. Assoc. 1956, 45, 430.

9416
X. Gu, G.I. Georg / Tetrahedron 69 (2013) 9406e9416
29. Smith, A. B.; Liu, Z. Org. Lett. 2008, 10, 4363e4365.
38. Methot, J. L.; Roush, W. R. Adv. Synth. Catal. 2004, 346, 1035e1050.
39. Liu, H.; Zhang, Q.; Wang, L.; Tong, X. Chem. Commun. 2010, 312e314.
40. Stewart, I. C.; Bergman, R. G.; Toste, F. D. J. Am. Chem. Soc. 2003, 125,
8696e8697.
41. Yadav, J. S.; Reddy, B. V. S.; Krishna, A. D.; Reddy, C. S.; Narsaiah, A. V. J. Mol.
Catal. A: Chem. 2007, 261, 93e97.
42. Dyachenko, V. D.; Chernega, A. N. Russ. J. Gen. Chem. 2005, 75, 952e960.
43. Bhattacharyya, P.; Pradhan, K.; Paul, S.; Das, A. R. Tetrahedron Lett. 2012, 53,
4687e4691.
44. Pradhan, K.; Bhattacharyya, P.; Paul, S.; Das, A. R. Tetrahedron Lett. 2012, 53,
5840e5844.
30. Deka, N.; Kalita, D. J.; Borah, R.; Sarma, J. C. J. Org. Chem. 1997, 62, 1563e1564.
31. Li, Z.-X.; Liu, X.-P.; Qiu, Z.; Xu, D.; Yu, X.-J. J. Chem. Res. 2011, 35, 35e36.
32. Hourcade, S.; Ferdenzi, A.; Retailleau, P.; Mons, S.; Marazano, C. Eur. J. Org.
Chem. 2005, 2005, 1302e1310.
33. Gray, D.; Gallagher, T. Angew. Chem., Int. Ed. 2006, 45, 2419e2423.
34. Barnett, C. J.; Wilson, T. M.; Evans, D. A.; Somers, T. C. Tetrahedron Lett. 1997, 38,
735e738.
35. Yadav, J. S.; Reddy, B. V. S.; Basak, A. K.; Visali, B.; Narsaiah, A. V.; Nagaiah, K. Eur.
J. Org. Chem. 2004, 546e551.
36. Lu, X.; Zhang, C.; Xu, Z. Acc. Chem. Res. 2001, 34, 535e544.
37. Nair, V.; Menon, R. S.; Sreekanth, A. R.; Abhilash, N.; Biju, A. T. Acc. Chem. Res.
2006, 39, 520e530.
45. http://pubchem.ncbi.nlm.nih.gov.