Further Insight into the Castagnoli-Cushman-type Synthesis of 1,4,6-Trisubstituted 1,6-Dihydropyridin-2-(3 H)-ones from 3-Arylglutaconic Acid Anhydrides

Article abstract of DOI:10.1021/acs.joc.0c00836

The earlier reported three-component Castagnoli-Cushman-type synthesis of 1,4,6-trisubstituted 1,6-dihydropyridin-2-(3H)-ones from 3-arylglutaconic acids, primary amines, and aromatic aldehydes has been further investigated. It was shown to proceed via 3-arylglutaconic anhydrides, which, in turn, were found to give superior results in the two-component reactions with imines. The initial formation of the Castagnoli-Cushman carboxylic acids was shown to be the case, and their decarboxylation was found to follow a complex, forked pathway, which was confirmed by deuterium incorporation experiments.

Full text of DOI:10.1021/acs.joc.0c00836

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Note
Further Insight into the Castagnoli-Cushman-type
Synthesis of 1,4,6-Trisubstituted 1,6-Dihydropyridin-2-
3H)-ones from 3-Arylglutaconic Acid Anhydrides
(
Andrei Firsov, Olga Bakulina, Dmitry V. Dar'in, Natalia Guranova, and Mikhail Krasavin
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 27 Apr 2020
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Further Insight into the Castagnoli–Cushman-type Synthesis of 1,4,6-
Trisubstituted 1,6-Dihydropyridin-2-(3H)-ones from 3-Arylglutaconic Acid
Anhydrides
1
1
1
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Andrei Firsov, Olga Bakulina, Dmitry Dar’in, Natalia Guranova, and Mikhail Krasavin*
Saint Petersburg State University, Saint Petersburg 199034, Russian Federation
ABSTRACT: The earlier reported three-component Castagnoli–Cushman-type synthesis of
1
,4,6-trisubstituted 1,6-dihydropyridin-2-(3H)-ones from 3-arylglutaconic acids, primary amines
and aromatic aldehydes has been further investigated. It was shown to proceed via 3-
arylglutaconic anhydrides which, in turn, were found to give superior results in the two-
component reactions with imines. The initial formation of the Castagnoli–Cushman carboxylic
acids was shown to be the case and their decarboxylation was found to follow a complex,
‘forked’ pathway, which was confirmed by deuterium incorporation experiments.
R2
N
O
O
O
R2
R1
R1
R2
R1
N
O
N
+
CO2
toluene
10 oC, 16 h
Ar
Ar
O
Ar
1
CO2H
Initial
19 examples
45-91%
Castagnoli-Cushman
adduct
The reaction between imines 1 and -C-H dicarboxylic acid anhydrides 2 offers a remarkably
facile and often diastereoselective entry into polysubstituted lactams 3 bearing a carboxylic acid
1
functionality. The reaction was discovered over 45 years ago by Castagnoli and Cushman and
2
has been recently dubbed the Castagnoli–Cusman reaction (or the CCR). The ability of the
3
cyclic anhydride to ‘enolize’ has a direct bearing on the rate of the CCR. This ability, in turn,
4
5
can be increased by introducing electron-withdrawing substituents or heteroatoms at the -
position of the cyclic anhydride. Alternatively, resonance stabilization of the anhydride’s enol
6
form can provide a strong driving force for the enolization and the resulting CCR. Recently, we
investigated a new type of highly reactive cyclic anhydrides for the CCR, namely, those of 3-
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arylglutaconic acids 5. Anhydrides 4 are highly enolizable due to its being a ‘vinylogous
malonate’ in which the enol form 4′ is effectively stabilized by conjugation to the other carbonyl
group (the nearby aryl group, likely providing additional stabilization). A rather convenient
variant of the CCR involves the preparation of a cyclic anhydride from the respective
0
1
2
3
4
5
6
7
8
9
0
1
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7
8
9
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9
0
1
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3
4
5
6
7
8
9
0
8
dicarboxylic acid in situ either under the influence of various dehydrating agents or via
9
azeotropic removal of water. In the reaction of 3-arylglutaconic acids 5 with primary amines
and aromatic aldehydes under the azeotropic reflux with toluene (proceeding, presumably, via
the formation of the requisite imine in situ and cyclodehydration 54), the sole product of the
reaction was 4,6-diaryl-1,6-dihydropyridin-2(3H)-one 6 and not anticipated carboxylic acid 7, i.
e. decarboxylation with concomitant double bond migration took place (Figure 1). In our initial
report on this new reaction, a tentative mechanism for the formation of 6 was proposed which
postulated the initial involvement of 3-arylglutaconic anhydride 5 and subsequent
1
0
decarboxylation of 7 due to steric crowding. Both postulates needed to be tested and probed
experimentally and thus we undertook a more in-depth investigation of the reaction course in
order to verify the said mechanistic hypothesis. Herein, we report the results of our latest
findings in this regard.
O

O
2
H
O
R
O
R1
(a)
N
R2
1N
COOH
R2
1
3
O
O
O
O
(b)

Ar
O
Ar
OH
4'
4
O
R
Ar1
R
toluene, reflux
NH2
N
CO2H
X
+
Ar2 Dean-Stark trap
16 h
(c)
Ar1
Ar2
O
CO2H
O
N
R
Ar2
Ar1
CO2H
7
5
6
Figure 1. (a) The Castagnoli–Cushman reaction; (b) resonance stabilization of the enol form 4′
of 3-arylglutaconic anhydride 4; (c) unusual formation of 4,6-diaryl-1,6-dihydropyridin-2(3H)-
one 6 in the three-component reaction of 5 with aldehydes and amines.
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Establishing that the formation of 3-arylglutaconic anhydrides 4 indeed took place under the
reaction conditions shown in Figure 1c was rather straightforward as 3-phenylglutaconic acid 5a
gave nearly quantitative yield of respective anhydride 4a on refluxing in toluene with azeotropic
removal of water over 24 h. Moreover, addition of imine 1a to the toluene solution of 4a and
continued heating at reflux over 16 h delivered the same 1,6-dihydropyridin-2(3H)-one 6a as
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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3
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3
4
4
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4
4
4
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5
5
5
6
0
1
2
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5
6
7
8
9
0
1
2
3
4
5
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7
8
9
0
1
2
3
4
5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
0
was obtained previously in the three component reaction of 5a with the same aldehyde and
amine components as form 1a, albeit with nearly two-fold improvement of the yield: from 50%10
to 91% (Scheme 1).
Bu-n
O
N
O
CO2H
toluene, reflux
1a
O
MeO
N
CO2H
5a
Dean-Stark trap
toluene, reflux
16 h
Ph
O
Ph
Ph
24 h
4a, quant.
6a
, 91%
OMe
Scheme 1. Preparation of 3-phenylglutaconic anhydride (4a) and its reaction with imine 1a.
Encouraged by this remarkable improvement of the yield we reasoned that, while the three-
component synthesis of 1,6-dihydropyridin-2(3H)-ones 6 (Figure 1c) carries an obvious
convenience from the standpoint of array synthesis, greater yield (and possibly broader scope)
might be achieved in two-component reactions such as 4a6a. The latter approach of course
would require that anhydrides 4 and imines 1 be prepared in two separate (albeit distinctly
straightforward) chemical operations. To investigate the yield and scope advantages of the two-
component reactions of 4 with 1, several 3-arylglutaconic anhydrides 4a-j were prepared from
7
respective 3-arylglutaconic acids 5a-j as depicted in Scheme 2. Only with three acids (5a-c) full
conversion was achieved on simple reflux in toluene (Method A), leading to nearly quantitative
yields. For the rest of acids (5d-j) the reaction stalled and the full conversion was not achieved
even after 72 h, likely due to limited solubility of these acids in toluene. However, we found it
possible to achieve full conversion of these starting materials and excellent yields of the
respective anhydrides 4d-j by performing cyclodehydration of the former in ethyl acetate at
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5
5
5
5
5
6
ambient temperature using trifluoroacetic anhydride (TFAA) as the dehydrating agent (Method
B).
O
CO H
2
O
Method A or B
CO H
2
Ar
O
Ar
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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5
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8
9
0
1
2
3
4
5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
5a-j
4a-j
4
4
4
4
4
a, Ar = Ph, quant.a
4f, Ar = 4-CF OC H , 91%
b
3
6 4
a
b
b, Ar = 4-MeOC H , 90%
4g, Ar = 3-O NC H , 81%
2 6 4
6
4
a
b
c, Ar = 4-ClC H , 94%
4h, Ar = 3-AcC H , 97%
6 4
6
4
b
b
d, Ar = 2-ClC H , 91%
4i, Ar = 2-MeOC H , 90%
6 4
6
4
b
b
e, Ar = 3,4-(OCH CH O)C H , 93%
4j, Ar = 4-AdC H , 86%
6 4
2
2
6
3
a
Scheme 2. Preparation of 3-arylglutaconic anhydrides 4a-j (Ad = 1-adamantyl): Method A:
b
toluene, reflux, Dean-Stark trap, 24 h; Method B: EtOAc, TFAA, r. t., 2 days.
With the diverse selection of 3-arylglutaconic anhydrides 4a-j at hand, we proceeded to
investigate possible advantages of the two-component reaction 4+16 with respect to the
1
0
product yield and substrate scope, compared to the three-component reaction of 5. The results
of these studies are presented in Scheme 3.
Even a brief examination of these results reveals a number of advantages of the two-component
(
4+16) reaction format in comparison to the earlier investigated three-component reaction
(56). Besides the marked improvement of the product yield (from 50% to 91% for 6a, from
7% to 77% for 6n), the reaction for the first time tolerated the use of imines derived from
3
aliphatic aldehydes (6b, 6f-g, 6q), including ‘enolizable’ ones (i. e. -C-H), as well as from
electron-deficient heterocyclic aldehydes (6r). In addition, cyclic imines (6c-d) as well 3-
arylglutaconic inputs (acids or respective anhydrides) containing electron-withdrawing
substituents in the aromatic portion (6o-p) were investigated in these two-component reactions
for the first time and proved successful. Notably, attempts to run the reactions with respective
diacids (5g-h) in the three-component format failed. Notably, it was subsequently discovered
that in some cases (6f-g, 6p), moderate yields of the reaction could be significantly improved by
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changing the solvent to DMSO. However, this approach carries the inconvenience of removing
DMSO as a solvent during the product isolation.
R1
O
R2
O
N
R1
R2
1
O
N
toluene
10 oC, 16 h
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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8
9
0
1
2
3
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7
8
9
0
Ar
O
Ar
1
6a-s
4
O
O
O
N
O
O
N
N
Ph
N
N
6
a, 91%a
OMe
6b
80%b
6c
, 76%c
6d
, 73%c
O
,
6e, 71%
O
O
O
O
PMP
PMP
N
N
N
N
N
PMP
Ad
S
6f, 61%b,d
g, 45%b,d
Ad
Ad
6j, 48%
6
6h, 63%
6i, 55%
O
OMe
O
O
O
N
N
N
N
O
, 77%f
6n
6l, 75%e
OMe
F3CO
6m, 55%
OBn MeO
6
k, 85%
F3CO
O
OMe
O
O
N
O
O
O
N
O
Ph
N
N
OMe
Cl
N
N
OMe Cl
o, 70%g
6p, 55%g,d
6q, 53%b
6r, 49%h
6
6s, 43%
NO2
O
a
10
b
cf. yield in the three-component format: 50% ; successful reactions with aliphatic aldehyde-derived imines
1
0
c
(
including -C-H) which did not work in the three-component format ; the first examples of this reaction with
d
cyclic imines; the yield of the reaction run in DMSO, respective yields obtained in toluene: 6f – 38%, 6g – 29%, 6p
–
e
f
10 g
55%; the yield of the reaction run on 3.3 mmol scale: 72%; cf. yield in the three-component format: 37% ; 3-
1
0
arylglutaconic acids with electron-withdrawing substituents are not tolerated in the three-component reactions ;
h
10
electron-deficient aldehydes (such as pyridine-3-carboxaldehyde) did not work in the three-component reactions.
Scheme 3. Two-component reaction of 3-arylglutaconic anhydrides 4 with imines 1.
Having confirmed the intermediacy of 3-arylglutaconic anhydrides 4 en route to 1,6-
dihydropyridin-2(3H)-ones 6, we focused on investigating the course of the reaction in order to
confirm that the formation of the initial Castagnoli–Cushman carboxylic acids 7 does indeed
take place and that it is their decarboxylation that ultimately leads to the isolated products 6. In
order to be able to follow the reaction course at ambient temperature (so as to detect CCR
adducts 7), we tried replacing toluene (in which 3-arylglutaconic anhydrides are poorly soluble)
with other polar solvents (chlorobenzene, THF, chloroform, acetone, acetonitrile and DMSO)
amongst which DMSO was found most suitable for further experiments.
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4
4
4
4
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5
5
5
5
5
5
5
6
The reaction of anhydride 4a and imine 1e (which had given 71% yield of compound 6e when
1
conducted at 110 °C in toluene, Scheme 3) was followed by H NMR in DMSO-d at room
6
temperature. We were pleasantly surprised to observe a full conversion to the CCR carboxylic
acid 7e, albeit with no diastereoselectivity, in only 3 min, thus making this reaction one of the
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
fastest examples of the CCR known. This result unequivocally confirmed the intermediacy of
CCR adducts 7 en route to 6. However, attempted isolation of cis/trans-7e failed as this mixture
of diastereomers continued to gradually transform itself at room temperature into a mixture of
compound 8e (presumably originating from one of the diastereomers of 7e via double bond
migration) and the other diastereomer of 7e which remained unchanged (trans stereochemistry
was assigned to it based on the differences in vicinal coupling constants, in analogy with many
other CCR adducts where this difference allows distinguishing the cis or trans isomers
reliably3,8a). Full conversion to the mixture of trans-7e and 8e (the sole components of the
reaction mixture that point) was achieved in 16 h at room temperature whereupon it remained
unchanged (Scheme S1). This mixture was isolated in 64% (relative to 4a) and fully
characterized by 1D and 2D NMR spectroscopy as well as HRMS. Unfortunately, all attempts to
separate this mixture by HPLC or to convert it to ester or amide derivatives, as well as to oxidize
it with DDQ, failed as they only resulted in decomposition. In contrast, raising the temperature
above 40 °C already led to a noticeable accumulation of end-point 1,6-dihydropyridin-2(3H)-one
6
e. Full conversion and quantitative NMR yield of 6e were obtained from the trans-7e/8e
mixture in only 1 h at 110 °C (Scheme 4).
?
Et
O
O
N
O
O
O
Et
110 o
Tol-p 1h
p-Tol
16 h
r. t.
Et
Et
C
Et
N
O
N
N
N
+
DMSO-d6
r. t., 3 min
Ph
Tol-p
Ph
O
Ph
Tol-p Ph
CO H
Ph
Tol-p
CO H
e, quant.a
4a
2
CO H
2
2
8e
, quant.a
6e
7
trans-7e
a
NMR yield.
dr 1:1
1
Scheme 4. Following the course of the reaction between 4a and 1e by H NMR.
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The observed transformations could be rationalized by the presumed ability of compound trans-
7
e to undergo decarboxylation into 6e directly, while 8e (essentially, a cinnamic acid) would
need to be tautomerized into 7e (cis or trans) first, before losing a CO molecule. In order to
2
trace the course of these transformations and possibly gain evidence for the above preliminary
mechanistic interpretation, we heated the mixture of trans-7e and 8e, generated and isolated as
described above, at 110 °C in DMSO-d in the presence of 10 equiv. of D O. Within 1h, the
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
6
2
decarboxylation was complete and a 1:1 mixture of mono- and tris-deuterated compounds 9 and
0 formed in quantitative NMR yield (Scheme 5 and Scheme S2).
1
O
O
DMSO-d6
O
O
D
Et
Et
D O (10 equiv.)
Et
2
D
Et
N
N
N
+
N
D
+
110 oC, 1 h
Ph
Tol-p
Ph
Tol-p Ph
Tol-p
Ph
Tol-p
CO2H
CO H
D
2
trans-7e
8e
9, dr 1:1
10
Scheme 5. Decarboxylation of the trans-7e/8e mixture in the presence of D O.
2
Mechanistically, the formation of 9 and 10 can be rationalized as follows and, therefore, it
confirms the above hypothesis regarding the course of decarboxylation of the trans-7e/8e
mixture. Notably, it is also consistent with the preliminary mechanistic picture proposed in the
previous report on the preparation of 1,6-dihydropyridin-2(3H)-ones 6.10 Monodeuterated
compound 9 (obtained as a 1:1 mixture of diastereomers) most likely arises from direct
decarboxylation of trans-7e whereby the intermediate enolate 11 is re-protonated by D O in non-
2
diastereoselective fashion. Compound 8e, being essentially a vinylogous variant of malonic acid
monoamide, contains a highly acidic methylene group which is likely to undergo deuterium
exchange to give bis-deuterated compound 12. Subsequently (and much in line of our initial
hypothesis), this compound had to undergo an allylic proton transposition in order to be set for
decarboxylation. This process resulted in the formation of 13 which, upon decarboxylation and
re-protonation of intermediate enolate 14, delivered the observed tris-deuterated compound 10
1
(Scheme 6). All structural assignments are consistent with the H NMR and HRMS data.
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O
O
O
Et
- H
Et
D
Et
N
N
D2O
N
Ph
Tol-p - CO2
Ph
D
Tol-p
Ph
Tol-p
CO2H
trans-7e
11
9, dr 1:1
Et
O
O
O
Et
D
Et
1,3-D
D2O
N
N
N
D
Ph
HO2C
Tol-p
Ph
Tol-p
Ph
Tol-p
D
CO2H
CO2H
0
1
2
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7
8
9
0
1
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9
0
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9
0
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8
9
0
1
2
3
4
5
6
7
8
9
0
13
8e
12
O
O
D
D
D2O
Et
D
Et
N
N
D
-
H
-
CO2
Ph
Tol-p
Ph
Tol-p
D
14
10
Scheme 6. Mechanistic rationale for the formation of compounds 9 and 10.
We further tested this mechanistic interpretation by exposing the mixture of trans-7e and 8e to
D O (10 equiv.) in DMSO-d at ambient temperature. To our delight, as prognosticated in the
2
6
above mechanistic reasoning, 8e underwent a complete deuterium exchange over 2 days to give
bis-deuterated compounds 12 while trans-7e remained intact. Ultimately, when the temperature
was raised to 110 °C, the mixture of trans-7e and 12 rapidly (over 1 h) and quantitatively
converted to a mixture of 9 and 10, thus confirming the correctness of the mechanistic picture
outlined above, which involves a ‘forked’ decarboxylation pathway, ultimately leading to 1,6-
dihydropyridin-2(3H)-ones 6 (Scheme 7 and Schemes S3,S4).
O
O
DMSO-d6
O
O
O
D
O
Et
110 o
Tol-p 1 h
C
D
Et
Et
D O (10 equiv.)
Et
2
Et
N
N
N
N
D
Et
+
+
D
N
N
D
+
Ph
Tol-p Ph
Tol-p
r. t., 2 days
Ph
Tol-p
Ph
Ph
Tol-p
Ph
Tol-p
9, dr 1:1
CO2H
CO H
CO2H
CO2H
2
D
trans-7e
8e
trans-7e
12
10
Scheme 7. Successive incorporation of deuterium en route to 9 and 10.
In summary, we have investigated the earlier discovered three-component synthesis of 4,6-
disubstituted 1,6-dihydropyridin-2-(3H)-ones via a Castagnoli–Cushman-type reaction of 3-
arylglutaconic acids with amines and aldehydes, accompanied by decarboxylation. Firstly, the
reaction was shown to involve cyclodehydration of the diacids to the respective cyclic
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anhydrides. The latter, when prepared and isolated, were shown to give superior results in a two-
component reaction with imines, compared to the earlier reported three-component reaction, both
in terms of the yield and reagent scope. Further investigation of the reaction path leading to 1,6-
dihydropyridin-2-(3H)-ones, particularly with respect to the alleged decarboxylation of the initial
1
1
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Castagnoli–Cushman carboxylic acid adduct, revealed that both diastereomers of the latter are
rapidly formed in the reaction mixture. However, each diastereomer then follows a different
1
decarboxylation pathway, which was confirmed by H NMR monitoring of the deuterium
incorporation in the final product as the result of decarboxylation in the presence of D O. These
2
findings validate the reaction of 3-arylglutaconic anhydrides with imines as a convenient and
high-yielding method to prepare rare11 4,6-disubstituted 1,6-dihydropyridin-2-(3H)-ones and
reveal intriguing mechanistic details underlying the reaction path that leads to the formation of
these heterocyclic products.
EXPERIMENTAL SECTION
1
General. NMR spectroscopic data were recorded with 400 spectrometer (400.13 MHz for H
13
1
1
13
1
and 100.61 MHz for C{ H} ) and 500 spectrometer (500.03 for H and 125 MHz for C{ H} )
in DMSO-d and in CDCl and were referenced to residual solvent proton signals (δH = 2.50 and
6
3
7.26 ppm, respectively) and solvent carbon signals (δC = 39.5 and 77.0 ppm, respectively). Mass
spectra were recorded with a HRMS-ESI-qTOF spectrometer (electrospray ionization mode,
positive ions detection). Flash column chromatography on silica was performed with Biotage
Isolera Prime instrument using Biotage SNAP KP-Sil 25g cartridges. TLC was performed with
Macherey- Nagel «Alugram Sil G/UV254» plates. Melting points were determined with a Stuart
SMP50 instrument in open capillary tubes and are uncorrected. All reactions were performed in
air, unless otherwise noted. Toluene was distilled from sodium and stored over MS 4Å. Ethyl
acetate and DMSO were dried over MS 4Å.
General procedure for synthesis of 4-aryl-2H-pyran-2,6(3H)-diones (4a-j).
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Method A. Corresponding dicarboxylic acid (5 mmol) was suspended in toluene (100 mL) and
heated at reflux in an oil bath with azeotropic removal of water using a Dean-Stark trap. After
2
4 h, the reaction mixture was concentrated in vacuo and the residue was thoroughly washed
with hexane. The solid residue thus obtained was separated by filtration and dried in vacuo to
give analytically pure compounds 4a-c.
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Method B. To a stirred suspension of dicarboxylic acid (5 mmol) in dry ethyl acetate (30 mL)
trifluoroacetic anhydride (12.5 mmol, 2.5 equiv.) was added in one portion at room temperature.
After stirring for 2 days, the resulting mixture was concentrated in vacuo and the residue was
thoroughly washed with hexane, followed by filtration and drying of the solids in vacuo to
afford pure compounds 4d-j. All compounds 4 were stored at 5 °C in sealed screw-cap vials.
4-Phenyl-2H-pyran-2,6(3H)-dione (4a)
1
13
12
Yield 0.94 g, 100%. Beige solid. The H and C NMR spectra matched literature data.
4-(4-Methoxyphenyl)-2H-pyran-2,6(3H)-dione (4b).
1
13
13
Yield 0.98 g, 90%. Beige solid. The H and C NMR spectra matched literature data.
4
-(4-Chlorophenyl)-2H-pyran-2,6(3H)-dione (4c)
1
Yield 1.04 g, 94%; beige solid. H NMR (400 MHz, DMSO-d ) δ 7.85 (d, J = 8.3 Hz, 2H), 7.65
6
13
1
–
7.50 (m, 2H), 6.84 (s, 1H), 4.16 (s, 2H). C{ H} NMR (101 MHz, DMSO-d ) δ 166.4, 161.7,
6
153.3, 136.7, 133.4, 129.4, 129.1, 111.9, 33.9.
4
-(2-Chlorophenyl)-2H-pyran-2,6(3H)-dione (4d)
1
Yield 1.01 g, 91%; beige solid. H NMR (400 MHz, CDCl ) δ 7.50 (dd, J = 7.7, 1.6 Hz, 1H),
3
7.47 – 7.37 (m, 2H), 7.31 – 7.26 (m, 1H), 6.35 (t, J = 1.9 Hz, 1H), 3.93 (d, J = 1.8 Hz, 2H).
1
3
1
C{ H} NMR (101 MHz, CDCl ) δ 164.4, 159.8, 154.1, 134.7, 131.4, 131.4, 130.7, 129.1,
3
1
27.6, 117.8, 35.3.
4
-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-2H-pyran-2,6(3H)-dione (4e)
1
Yield 1.14 g, 93%; beige solid. H NMR (400 MHz, CDCl ) δ 7.13 – 7.08 (m, 2H), 6.98 (d, J =
3
1
3
1
9
.3 Hz, 1H), 6.52 (t, J = 1.7 Hz, 1H), 4.39 – 4.29 (m, 4H), 3.87 (d, J = 1.6 Hz, 2H). C{ H}
NMR (101 MHz, CDCl ) δ 164.9, 160.4, 151.8, 147.2, 144.1, 126.8, 119.8, 118.2, 115.3, 110.1,
3
6
4.7, 64.2, 33.2.
4
-(4-(Trifluoromethoxy)phenyl)-2H-pyran-2,6(3H)-dione (4f)
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9
1
Yield 1.24 g, 91%; beige solid. H NMR (400 MHz, CDCl ) δ 7.68 – 7.60 (m, 2H), 7.42 – 7.34
3
1
3
1
(
m, 2H), 6.62 (t, J = 1.7 Hz, 1H), 3.93 (d, J = 1.6 Hz, 2H). C{ H} NMR (101 MHz, CDCl ) δ
3
1
64.2, 159.9, 151.7 (q, J = 1.8 Hz), 151.1 (d, J = 65.2 Hz), 132.1, 127.9, 121.4, 112.8, 33.3.
4
-(3-Nitrophenyl)-2H-pyran-2,6(3H)-dione (4g)
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Yield 0.94 g, 81%; beige solid. H NMR (400 MHz, DMSO-d ) δ 8.55 (s, 1H), 8.35 (d, J = 8.2
6
1
3
1
Hz, 1H), 8.25 (d, J = 7.8 Hz,1H), 7.80 (t, J = 8.0 Hz, 1H), 7.00 (s, 1H), 4.27 (s, 2H). C{ H}
NMR (101 MHz, DMSO-d ) δ 166.1, 161.5, 152.4, 148.8, 136.4, 133.5, 131.0, 126.0, 121.9,
6
1
13.8, 34.0.
4
-(3-Acetylphenyl)-2H-pyran-2,6(3H)-dione (4h)
1
Yield 1.12 g, 97%; beige solid. H NMR (400 MHz, CDCl ) δ 8.16 (s, 1H), 8.12 (d, J = 7.8 Hz,
3
1
H), 7.78 (d, J = 7.8 Hz, 1H), 7.66 (t, J = 7.8 Hz, 1H), 6.70 (s, 1H), 3.98 (s, 2H), 2.69 (s, 3H).
13
1
C{ H} NMR (101 MHz, CDCl ) δ 196.9, 164.2, 159.9, 151.7, 138.0, 134.4, 131.6, 130.2,
3
1
29.9, 125.7, 113.3, 33.4, 26.7.
4-(2-Methoxyphenyl)-2H-pyran-2,6(3H)-dione (4i)
1
Yield 0.98 g, 90%; beige solid. H NMR (400 MHz, DMSO-d ) δ 7.55 – 7.43 (m, 2H), 7.17 (d, J
6
=
8.2 Hz, 1H), 7.06 (t, J = 7.5 Hz, 1H), 6.62 (t, J = 1.7 Hz, 1H), 4.12 (d, J = 1.7 Hz, 2H), 3.87
13
1
(
s, 3H). C{ H} NMR (101 MHz, DMSO-d ) δ 166.7, 161.8, 157.8, 154.0, 132.7, 129.8, 124.1,
6
121.3, 114.6, 112.7, 56.2, 35.4.
4
-(4-(Adamantan-1-yl)phenyl)-2H-pyran-2,6(3H)-dione (4j)
1
Yield 1.39 g, 86%; beige solid. H NMR (400 MHz, CDCl ) δ 7.63 – 7.45 (m, 4H), 6.62 (d, J =
3
13
1
1
.8 Hz, 1H), 3.93 (d, J = 1.7 Hz, 2H), 2.15 (s, 3H), 1.95 (s, 6H), 1.90 – 1.71 (m, 6H). C{ H}
NMR (400 MHz, CDCl ) δ 165.0, 160.4, 156.1, 152.6, 130.8, 126.1, 126.0, 110.9, 42.9, 36.7,
3
3
6.6, 33.3, 28.8.
General procedure for synthesis of pyridin-2(3H)-ones 6a-s.
Method A. 3-Arylglutaconic anhydride (1 mmol) was placed in a screw-cap vial and suspended
in dry toluene (2 mL) at room temperature followed by addition of the corresponding imine
o
(
1.05 mmol). The resulting mixture was heated at 110 C in an oil bath for 16 h. After cooling
to room temperature, the reaction mixture was concentrated in vacuo and purified by flash
column chromatography to provide pure compounds 6a-e,h-o,q-s.
Method B. To a stirred solution of arylglutaconic anhydride (1 mmol) in DMSO (2 mL) in a
screw-cap vial the corresponding imine (1.05 mmol) was added at room temperature. The
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o
resulting mixture was heated at 110 C in an oil bath for 16 h. After cooling to room
temperature, the reaction mixture was diluted with ethyl acetate (20 mL) and water (15 mL).
The organic layer was separated, washed with water (2 x 10 mL), dried over Na SO , filtered
2
4
and concentrated in vacuo. The residue was purified by flash column chromatography to
provide pure compounds 6f,g,p.
0
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8
9
0
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2
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1
-Butyl-6-(4-methoxyphenyl)-4-phenyl-1,6-dihydropyridin-2(3H)-one (6a).
Yield 305 mg (91%). Obtained NMR spectra were in accordance with the previously published
1
0
data .
1
-Benzyl-6-isopropyl-4-phenyl-1,6-dihydropyridin-2(3H)-one (6b).
Yield 244 mg (80%), purification by flash chromatography (eluent: acetone+n-hexane, gradient:
1
2
7
3
%−20% of acetone); yellow oil; H NMR (400 MHz, DMSO-d ) δ 7.59 – 7.48 (m, 2H), 7.42 –
6
.23(m, 8H), 6.24 (dd, J = 4.9, 2.6 Hz, 1H), 5.20 (d, J = 15.2 Hz, 1H), 4.21 (d, J = 15.2 Hz, 1H),
.97 (dt, J = 5.0, 2.1 Hz, 1H), 3.46 (dt, J = 21.0, 3.3 Hz, 1H), 3.29 (dd, J = 21.0, 2.3 Hz, 1H),
1
3
1
2.36 – 2.23 (m, 1H), 0.96 (d, J = 7.0 Hz, 3H), 0.72 (d, J = 6.7 Hz, 3H). C{ H} NMR (101
MHz, DMSO-d ) δ 167.9, 138.5, 138.2, 134.4, 129.0, 128.9 (2C), 128.3, 128.0, 127.5, 125.5,
6
+
1
19.0, 62.7, 46.5, 34.6, 31.6, 19.4, 15.8. HRMS (ESI) m/z: [M + H] Calcd for C H NO
2
1
24
306.1852; Found 306.1855
2
-Phenyl-6,7-dihydro-3H-pyrido[2,1-a]isoquinolin-4(11bH)-one (6c).
Yield 209 mg (76%), purification by flash chromatography (eluent: acetone+n-hexane, gradient:
1
2%−20% of acetone); white solid, mp 111-113 °C. H NMR (400 MHz, CDCl ) δ 7.51 – 7.46
3
(
m, 2H), 7.45 – 7.33 (m, 3H), 7.32 – 7.26 (m, 3H), 7.23 (td, J = 7.1, 6.7, 1.9 Hz, 1H), 6.61 (dt, J
=
3.4, 1.6 Hz, 1H), 5.53 (pseudo-q, J = 4.3 Hz, 1H), 4.88 – 4.78 (m, 1H), 3.49 (ddd, J = 21.3,
5
.0, 1.8 Hz, 1H), 3.40 (ddd, J = 21.2, 4.3, 1.5 Hz, 1H), 3.23 – 3.07 (m, 2H), 2.95 – 2.81 (m, 1H).
1
3
1
C{ H} NMR (101 MHz, CDCl ) δ 166.6, 136.7, 135.1, 133.5, 129.2, 129.0, 128.7, 128.2,
3
1
27.2, 126.8, 126.7, 125.2, 124.7, 119.6, 57.2, 40.4, 34.1, 28.4. HRMS (ESI) m/z: [M + Na]+
Calcd for C H NONa 298.1202; Found 298.1202.
1
9
17
8
'-Phenyl-7',9a'-dihydro-6'H-spiro[cyclohexane-1,10'-pyrido[1,2-a]indol]-6'-one (6d).
Yield 240 mg (73%), purification by flash chromatography (eluent: acetone+n-hexane, gradient:
1
2
%−20% of acetone); white solid, mp 181-183 °C; H NMR (400 MHz, DMSO-d ) δ 8.08 (d, J
6
= 8.0 Hz, 1H), 7.54 – 7.48 (m, 2H), 7.41 (d, J = 7.1 Hz, 2H), 7.34 (dd, J = 8.5, 6.6 Hz, 1H), 7.31
7.25 (m, 1H), 7.19 (t, J = 7.8 Hz, 1H), 7.04 (td, J = 7.5, 1.2 Hz, 1H), 6.25 (s, 1H), 4.57 – 4.40
–
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(m, 1H), 3.54 (ddd, J = 20.9, 6.4, 2.6 Hz, 1H), 3.37 (dt, J = 20.7, 2.8 Hz, 1H), 1.98 (dd, J = 21.0,
1
3
1
1
2.1 Hz, 2H), 1.88 – 1.70 (m, 3H), 1.57 – 1.23 (m, 5H). C{ H} NMR (101 MHz, CDCl ) δ
3
1
65.5, 140.6 (d, J = 15.2 Hz), 138.4, 134.9, 128.7, 128.2, 127.5, 125.2, 124.7, 124.2, 71.4, 47.0,
+
3
6.1, 33.0, 32.2, 25.7, 23.2, 21.0. HRMS (ESI) m/z: [M + Na] Calcd for C H NONa
2
3
23
352.1672; Found 352.1672.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
-Ethyl-4-phenyl-6-(p-tolyl)-1,6-dihydropyridin-2(3H)-one (6e).
Yield 207 mg (71%), purification by flash chromatography (eluent: acetone+n-hexane, gradient:
1
2
%−20% of acetone); yellow oil. H NMR (400 MHz, CDCl ) δ 7.45 – 7.38 (m, 2H), 7.36 (ddd,
3
J = 7.6, 6.6, 1.5 Hz, 2H), 7.35 – 7.28 (m, 1H), 7.23 – 7.13 (m, 4H), 6.14 (ddd, J = 4.2, 2.1, 1.1
Hz, 1H), 5.13 (d, J = 4.0 Hz, 1H), 3.92 (dq, J = 14.3, 7.2 Hz, 1H), 3.58 (ddd, J = 21.3, 4.1, 2.1
Hz, 1H), 3.50 (ddd, J = 21.2, 3.6, 1.2 Hz, 1H), 2.90 (dq, J = 14.1, 7.1 Hz, 1H), 2.37 (s, 3H), 1.11
1
3
1
(t, J = 7.1 Hz, 3H). C{ H} NMR (101 MHz, CDCl ) δ 167.0, 138.0, 137.9, 137.5, 130.4, 129.7,
3
1
28.6, 128.0, 127.0, 125.0, 121.8, 62.7, 39.4, 34.0, 21.1, 12.2. HRMS (ESI) m/z: [M + Na]+
Calcd for C H NONa 314.1515; Found 314.1513.
2
0
21
6
-Сyclohexyl-1-ethyl-4-phenyl-1,6-dihydropyridin-2(3H)-one (6f).
Yield 173 mg (61%), purification by flash chromatography (eluent: acetone+n-hexane, gradient:
1
2
%−20% of acetone); orange oil. H NMR (400 MHz, CDCl ) δ 7.45 – 7.37 (m, 4H), 7.35 – 7.31
3
(m, 1H), 6.17 (dd, J = 4.8, 1.5 Hz, 1H), 4.01 (t, J = 4.1 Hz, 1H), 3.89 (dq, J = 14.2, 7.1 Hz, 1H),
3
.37 – 3.31 (m, 2H), 3.21 (dq, J = 14.0, 7.1 Hz, 1H), 1.95 – 1.53 (m, 7H), 1.37 – 0.88 (m, 7H).
1
3
1
C{ H} NMR (101 MHz, CDCl ) δ 168.0, 138.4, 134.2, 128.6, 127.9, 125.0, 119.5, 63.2, 43.1,
3
+
4
0.0, 35.0, 30.1, 26.7, 26.3, 26.0, 25.9, 12.8. HRMS (ESI) m/z: [M + Na] Calcd for
C H NONa 306.1828; Found 306.1836.
1
9
25
6
-(tert-Butyl)-1-(4-methoxybenzyl)-4-phenyl-1,6-dihydropyridin-2(3H)-one (6g).
Yield 157 mg (45%), purification by flash chromatography (eluent: acetone+n-hexane, gradient:
1
2
%−20% of acetone); green oil. H NMR (400 MHz, CDCl ) δ 7.45 – 7.36 (m, 4H), 7.35 – 7.32
3
(m, 1H), 7.15 – 7.09 (m, 2H), 6.89 – 6.82 (m, 2H), 6.29 (dd, J = 5.7, 1.8 Hz, 1H), 5.72 (d, J =
1
3
1
1
5.1 Hz, 1H), 4.03 (d, J = 15.1 Hz, 1H), 3.84 – 3.73 (m, 4H), 3.48 (s, 2H), 1.07 (s, 9H). C{ H}
NMR (101 MHz, CDCl ) δ 170.5, 158.8, 138.4, 134.9, 129.3, 128.6, 127.9, 125.1, 122.2, 114.0,
3
+
66.3, 55.2, 50.2, 41.5, 36.3, 27.4. HRMS (ESI) m/z: [M + Na] Calcd for C H NO Na
2
3
27
2
3
72.1934; Found 372.1933.
4
-(4-(Adamantan-1-yl)phenyl)-6-phenyl-1-propyl-1,6-dihydropyridin-2(3H)-one (6h).
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Yield 268 mg (63%), purification by flash chromatography (eluent: acetone+n-hexane, gradient:
1
2
%−20% of acetone); grey solid, mp 165-167 °C. H NMR (400 MHz, CDCl ) δ 7.42 – 7.34 (m,
3
6
H), 7.27 – 7.23 (m, 2H), 6.15 (dt, J = 3.3, 1.5 Hz, 1H), 5.15 (pseudo-q, J = 3.9 Hz, 1H), 3.89
(
ddd, J = 13.5, 9.7, 6.2 Hz, 1H), 3.64 – 3.47 (m, 2H), 2.71 (ddd, J = 13.6, 9.6, 5.3 Hz, 1H), 2.15
– 2.07 (m, 4H), 1.92 (d, J = 2.9 Hz, 6H), 1.86 – 1.73 (m, 6H), 1.72 – 1.44 (m, 2H), 0.88 (t, J =
0
1
2
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6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
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7
8
9
0
1
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
1
7
1
.4 Hz, 3H). C{ H} NMR (101 MHz, CDCl ) δ 167.5, 151.5, 140.7, 134.9, 130.4, 129.0, 128.1,
3
27.0, 125.1, 124.6, 120.8, 63.3, 46.2, 43.1, 36.7, 36.1, 33.9, 28.9, 20.2, 11.4. HRMS (ESI) m/z:
+
[
M + Na] Calcd for C H NONa 448.2611; Found 448.2630.
3
0
35
4
-(4-(Adamantan-1-yl)phenyl)-1-allyl-6-(thiophen-2-yl)-1,6-dihydropyridin-2(3H)-one (6i).
Yield 234 mg (55%), purification by flash chromatography (eluent: acetone+n-hexane, gradient:
1
2%−20% of acetone); yellow solid, mp 152 – 154 °C. H NMR (400 MHz, CDCl ) δ 7.45 – 7.35
3
(
m, 4H), 7.33 – 7.26 (m, 1H), 7.02 (dd, J = 3.5, 1.3 Hz, 1H), 6.98 (dd, J = 5.0, 3.5 Hz, 1H), 6.23
dt, J = 4.7, 1.5 Hz, 1H), 5.80 (dddd, J = 17.6, 10.1, 7.7, 4.2 Hz, 1H), 5.45 (pseudo-q, J = 3.7 Hz,
(
1
H), 5.28 – 5.14 (m, 2H), 4.85 (ddt, J = 15.4, 3.9, 1.8 Hz, 1H), 3.56 (dt, J = 3.1, 1.8 Hz, 2H),
3.38 (dd, J = 15.4, 7.7 Hz, 1H), 2.18 – 2.07 (m, 3H), 1.93 (d, J = 2.9 Hz, 6H), 1.87 – 1.72 (m,
1
3
1
6
H). C{ H} NMR (101 MHz, CDCl ) δ 167.1, 151.7, 144.4, 134.8, 132.4, 131.5, 126.7, 125.9,
3
1
25.8, 125.2, 124.8, 120.3, 118.0, 56.9, 45.8, 43.1, 36.7, 36.2, 34.0, 28.9. HRMS (ESI) m/z: [M
+
+
Na] Calcd for C H NOSNa 452.2019; Found 452.2005.
2
8
31
4
-(4-(Adamantan-1-yl)phenyl)-1,6-bis(4-methoxyphenyl)-1,6-dihydropyridin-2(3H)-one (6j).
Yield 249 mg (48%), purification by flash chromatography (eluent: acetone+n-hexane, gradient:
1
2%−20% of acetone); grey solid, mp 224 - 226 °C. H NMR (400 MHz, CDCl ) δ 7.47 (d, J =
3
8
.4 Hz, 2H), 7.41 (d, J = 8.5 Hz, 2H), 7.06 – 7.00 (m, 2H), 6.92 – 6.87 (m, 2H), 6.86 – 6.78 (m,
H), 6.30 – 6.25 (m, 1H), 5.35 (pseudo-q, J = 3.8 Hz, 1H), 3.79 (d, J = 3.9 Hz, 6H), 3.77 – 3.64
4
13
1
(
m, 2H), 2.18 – 2.10 (m, 3H), 1.95 (d, J = 2.8 Hz, 6H), 1.81 (qd, J = 12.1, 6.0 Hz, 6H). C{ H}
NMR (101 MHz, CDCl ) δ 167.7, 159.4, 158.5, 151.6, 134.9, 133.4, 132.2, 130.6, 129.2, 128.9,
3
1
25.2, 124.7, 121.0, 114.4, 114.0, 66.8, 55.3, 55.2, 43.1, 36.8, 36.2, 34.4, 28.9. HRMS (ESI)
+
m/z: [M + Na] Calcd for C H NO Na 542.2666; Found 542.2665.
3
5
37
3
4
-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-1-ethyl-6-(p-tolyl)-1,6-dihydropyridin-2(3H)-one (6k).
Yield 297 mg (85%), purification by flash chromatography (eluent: acetone+n-hexane, gradient:
1
2%−20% of acetone); dark yellow oil. H NMR (400 MHz, CDCl ) δ 7.18 (d, J = 8.0 Hz, 2H),
3
7
.14 (d, J = 8.1 Hz, 2H), 6.94 – 6.88 (m, 2H), 6.83 (d, J = 8.3 Hz, 1H), 6.02 (dt, J = 3.1, 1.5 Hz,
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1H), 5.09 (pseudo-q, J = 4.0 Hz, 1H), 4.26 (s, 4H), 3.90 (dq, J = 14.2, 7.2 Hz, 1H), 3.50 (ddd, J =
2
1.3, 4.1, 2.1 Hz, 1H), 3.46 – 3.38 (m, 1H), 2.88 (dq, J = 14.1, 7.1 Hz, 1H), 2.36 (s, 3H), 1.09 (t,
1
3
1
J = 7.1 Hz, 3H). C{ H} NMR (101 MHz, CDCl ) δ 167.1, 143.6, 143.5, 137.9, 137.6, 131.5,
3
1
29.7, 129.6, 127.0, 120.5, 118.1, 117.2, 114.0, 64.4, 64.3, 62.6, 39.4, 34.0, 21.1, 12.2. HRMS
+
(ESI) m/z: [M + Na] Calcd for C H NO Na 372.1570; Found 372.1569.
2
2
23
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
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5
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0
1
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0
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0
1
-Butyl-6-(4-methoxyphenyl)-4-(4-(trifluoromethoxy)phenyl)-1,6-dihydropyridin-2(3H)-one (6l).
Yield 314 mg (75%), purification by flash chromatography (eluent: acetone+n-hexane, gradient:
1
2%−20% of acetone); orange oil. H NMR (400 MHz, CDCl ) δ 7.43 (d, J = 8.8 Hz, 2H), 7.23 –
3
7
1
.14 (m, 4H), 6.91 (d, J = 8.6 Hz, 2H), 6.13 (dt, J = 3.1, 1.5 Hz, 1H), 5.11 (pseudo-q, J = 3.9 Hz,
H), 3.91 (ddd, J = 13.5, 9.5, 6.2 Hz, 1H), 3.83 (s, 3H), 3.54 (ddd, J = 21.2, 4.1, 2.0 Hz, 1H),
3.50 – 3.42 (m, 1H), 2.74 (ddd, J = 13.6, 9.5, 5.3 Hz, 1H), 1.64 – 1.44 (m, 2H), 1.35 – 1.23 (m,
1
3
1
2
H), 0.91 (t, J = 7.3 Hz, 3H). C{ H} NMR (101 MHz, CDCl ) δ 166.8, 159.6, 148.88 (q, J =
3
1
.8 Hz), 136.6, 132.1, 129.9, 128.2, 126.4, 122.7, 121.0, 120.4 (q, J = 257.4 Hz), 114.5, 62.5,
+
5
5.3, 44.1, 33.9, 29.0, 20.2, 13.8. HRMS (ESI) m/z: [M + Na] Calcd for C H F NO Na
2
3
24
3
3
442.1600; Found 442.1597.
Scale-up experiment was performed according to General procedure for preparation of
compounds 6, method A using anhydride 4f (900 mg, 3.3 mmol), N-butyl-1-(4-
methoxyphenyl)methanimine (631 mg, 3.3 mmol) and toluene (5 mL). Purification by column
chromatography in acetone−n-hexane (2-20% of acetone) afforded 992 mg (72 %) of compound
6
l.
6-(4-(Benzyloxy)-3-methoxyphenyl)-1-(prop-2-yn-1-yl)-4-(4-(trifluoromethoxy)phenyl)-1,6-
dihydropyridin-2(3H)-one (6m).
Yield 279 mg (55%), purification by flash chromatography (eluent: acetone+n-hexane, gradient:
1
2
%−20% of acetone); orange oil. H NMR (400 MHz, CDCl ) δ 7.47 – 7.43 (m, 4H), 7.42 – 7.37
3
(m, 2H), 7.36 – 7.31 (m, 1H), 7.25 – 7.20 (m, 2H), 6.90 (d, J = 8.1 Hz, 1H), 6.85 – 6.76 (m, 2H),
6
.17 (dd, J = 3.8, 1.9 Hz, 1H), 5.39 (pseudo-q, J = 4.0 Hz, 1H), 5.17 (s, 2H), 5.09 (dd, J = 17.4,
.6 Hz, 1H), 3.89 (s, 3H), 3.64 – 3.40 (m, 2H), 3.31 (dd, J = 17.3, 2.5 Hz, 1H), 2.26 (t, J = 2.5
2
1
3
1
Hz, 1H). C{ H} NMR (101 MHz, CDCl ) δ 166.4, 150.3, 149.0 (q, J = 1.8 Hz), 148.5, 136.9,
3
1
1
36.4, 131.8, 129.1, 128.6, 128.0, 127.2, 126.4, 122.3, 121.1, 120.3 (q, J = 256.9 Hz), 119.8,
+
14.2, 110.7, 78.3, 72.2, 71.1, 61.7, 56.2, 33.6, 32.5. HRMS (ESI) m/z: [M + H] Calcd for
C H F NO 508.1730; Found 508.1742.
2
9
25
3
4
1
,4-Bis(4-methoxyphenyl)-6-(p-tolyl)-1,6-dihydropyridin-2(3H)-one (6n).
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Yield 307 mg (77%), purification by flash chromatography (eluent: acetone+n-hexane, gradient:
%−20% of acetone); beige foam. Obtained NMR spectra were in accordance to previously
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1
0
published data .
1-Benzyl-4-(3-nitrophenyl)-6-phenyl-1,6-dihydropyridin-2(3H)-one (6o).
Yield 269 mg (70%), purification by flash chromatography (eluent: acetone+n-hexane, gradient:
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
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5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
%−20% of acetone); red oil. H NMR (400 MHz, CDCl ) δ 8.28 (t, J = 2.1 Hz, 1H), 8.16 (ddd,
3
J = 8.2, 2.3, 1.0 Hz, 1H), 7.75 – 7.67 (m, 1H), 7.55 (t, J = 8.0 Hz, 1H), 7.47 – 7.31 (m, 6H), 7.28
– 7.23 (m, 4H), 6.30 – 6.22 (m, 1H), 5.70 (d, J = 14.8 Hz, 1H), 5.06 (pseudo-q, J = 3.9 Hz, 1H),
1
3
1
3
.79 – 3.66 (m, 1H), 3.67 – 3.58 (m, 1H), 3.52 (d, J = 14.9 Hz, 1H). C{ H} NMR (101 MHz,
CDCl ) δ 166.7, 148.6, 139.5, 139.2, 136.4, 130.7, 129.6, 129.4, 128.7, 128.7, 128.6, 128.4,
3
+
1
27.7, 127.1, 124.3, 122.8, 120.0, 61.7, 46.3, 33.7. HRMS (ESI) m/z: [M + Na] Calcd for
C H N O Na 407.1366; Found 407.1370.
2
4
20
2
3
4
-(3-Acetylphenyl)-1-butyl-6-(4-methoxyphenyl)-1,6-dihydropyridin-2(3H)-one (6p).
Yield 207 mg (55%), purification by flash chromatography (eluent: acetone+n-hexane, gradient:
1
2
%−20% of acetone); yellow oil. H NMR (400 MHz, CDCl ) δ 8.01 (d, J = 1.8 Hz, 1H), 7.89
3
(
d, J = 7.7 Hz, 1H), 7.65 – 7.57 (m, 1H), 7.47 (t, J = 7.8 Hz, 1H), 7.22 – 7.16 (m, 2H), 6.94 –
.90 (m, 2H), 6.29 – 6.17 (m, 1H), 5.21 – 5.05 (m, 1H), 3.98 – 3.88 (m, 1H), 3.83 (s, 3H), 3.60 –
3.51 (m, 2H), 2.74 (ddd, J = 14.0, 9.4, 5.4 Hz, 1H), 2.63 (s, 3H), 1.59 (s, 2H), 1.34 – 1.22 (m,
6
1
3
1
2
H), 0.91 (t, J = 7.3 Hz, 3H). C{ H} NMR (101 MHz, CDCl ) δ 197.8, 166.9, 159.6, 138.4,
3
1
37.4, 132.1, 129.6, 129.4, 128.9, 128.2, 127.9, 124.7, 123.1, 114.5, 62.6, 55.3, 44.1, 33.9, 29.7,
+
2
9.0, 26.7, 20.2, 13.8. HRMS (ESI) m/z: [M + Na] Calcd for C H NO Na 400.1883; Found
2
4
27
3
400.1896.
4
-(4-Chlorophenyl)-1-(furan-2-ylmethyl)-6-(pentan-3-yl)-1,6-dihydropyridin-2(3H)-one (6q).
Yield 189 mg (53%), purification by flash chromatography (eluent: acetone+n-hexane, gradient:
1
2
%−20% of acetone); yellow oil. H NMR (400 MHz, CDCl ) δ 7.41 – 7.25 (m, 5H), 6.41 – 6.25
3
(
m, 2H), 6.07 (dd, J = 4.8, 1.9 Hz, 1H), 5.28 (d, J = 15.5 Hz, 1H), 4.29 – 4.16 (m, 2H), 3.45 –
.27 (m, 2H), 1.80 (tq, J = 8.7, 3.9 Hz, 1H), 1.72 – 1.56 (m, 1H), 1.43 – 1.17 (m, 2H), 1.03 (t, J =
3
1
3
1
7.4 Hz, 4H), 0.85 (t, J = 7.4 Hz, 3H). C{ H} NMR (101 MHz, CDCl ) δ 168.1, 150.5, 142.1,
3
1
1
36.8, 133.8, 132.5, 128.7, 126.2, 119.1, 110.5, 109.1, 59.9, 45.0, 39.8, 34.5, 23.2, 21.5, 12.3,
+
2.1. HRMS (ESI) m/z: [M + Na] Calcd for C H ClNO Na 380.1388; Found 380.1391.
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-Cyclohexyl-4-(2-methoxyphenyl)-1,2-dihydro-[2,3'-bipyridin]-6(5H)-one (6r).
Yield 177 mg (49%), purification by flash chromatography (eluent: acetone+n-hexane, gradient:
1
2
%−20% of acetone); orange oil. H NMR (400 MHz, CDCl ) δ 8.62 – 8.58 (m, 1H), 8.55 (dd, J
3
= 4.8, 1.6 Hz, 1H), 7.58 (dt, J = 8.0, 2.0 Hz, 1H), 7.35 – 7.26 (m, 2H), 7.18 – 7.09 (m, 1H), 6.90
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
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3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
–
1
1
6.85 (m, 2H), 6.05 (ddd, J = 5.2, 2.1, 0.9 Hz, 1H), 5.23 (dt, J = 5.4, 2.9 Hz, 1H), 4.14 (tt, J =
1.7, 3.6 Hz, 1H), 3.82 (s, 3H), 3.52 (td, J = 2.9, 2.4, 1.5 Hz, 2H), 1.89 – 1.73 (m, 2H), 1.69 –
1
3
1
.51 (m, 4H), 1.35 – 1.16 (m, 3H), 1.05 (tt, J = 12.8, 3.4 Hz, 1H). C{ H} NMR (101 MHz,
CDCl ) δ 167.9, 159.7, 149.0, 147.8, 138.4, 134.2, 131.1, 129.8, 129.6, 126.2, 124.0, 119.8,
3
+
1
14.0, 58.4, 56.5, 55.3, 35.3, 31.1, 30.0, 26.1, 26.0, 25.4. HRMS (ESI) m/z: [M + H] Calcd for
C H N O 363.2067; Found 363.2065.
2
3
27
2
2
4
-(2-Chlorophenyl)-1-methyl-6-(naphthalen-1-yl)-1,6-dihydropyridin-2(3H)-one (6s).
Yield 149 mg (43%), purification by flash chromatography (eluent: acetone+n-hexane, gradient:
1
2
%−20% of acetone); yellow oil. H NMR (400 MHz, CDCl ) δ 8.25 – 8.08 (m, 1H), 8.01 – 7.89
3
(m, 1H), 7.87 (d, J = 8.1 Hz, 1H), 7.64 – 7.49 (m, 3H), 7.46 (dd, J = 7.2, 1.3 Hz, 1H), 7.38 – 7.32
(m, 1H), 7.24 – 7.17 (m, 2H), 7.15 – 7.10 (m, 1H), 6.01 – 5.88 (m, 2H), 3.63 (ddd, J = 21.7, 4.2,
13
1
1
1
1
3
.8 Hz, 1H), 3.52 (dd, J = 21.8, 3.6 Hz, 1H), 2.95 (s, 3H). C{ H} NMR (101 MHz, CDCl ) δ
3
67.9, 138.6, 135.2, 134.2, 132.4, 132.3, 130.6, 129.9, 129.8, 129.3, 129.0, 128.8, 126.9, 126.7,
+
26.0, 125.9, 124.9, 122.1, 35.3, 32.8. HRMS (ESI) m/z: [M + Na] Calcd for C H ClNONa
22 18
70.0969; Found 370.0980.
1
-Ethyl-6-oxo-4-phenyl-2-(p-tolyl)-1,2,3,6-tetrahydropyridine-3-carboxylic acid and 1-ethyl-6-
oxo-4-phenyl-2-(p-tolyl)-1,2,5,6-tetrahydropyridine-3-carboxylic acid (7e + 8e).
To a stirred solution of of 4-phenyl-2H-pyran-2,6(3H)-dione (188 mg, 1 mmol) in DMSO (0.5
mL) N-ethyl-1-(p-tolyl)methanimine (154 mg, 1.05 mmol) dissolved in DMSO (0.5 mL) was
added dropwise at room temperature (exothermic reaction, temperature should remain below 25
°C). After 24 h the reaction mixture was diluted with ethyl acetate and water. The organic layer
was washed with water twice, dried over Na SO , filtered and concentrated in vacuo at room
2
4
o
temperature (T<25 C to avoid decarboxylation). The residue was washed with cold diethyl ether
(5 mL), filtered and dried to give a 1:1 mixture of compounds 7e and 8e.
1
Yield 215 mg (64%); beige solid. H NMR (500 MHz, CDCl ) δ 7.29 (d, J = 9.9 Hz, 7H), 7.18
3
(td, J = 4.0, 3.4, 1.7 Hz, 5H), 7.12 (d, J = 8.4 Hz, 6H), 6.48 (s, 1H), 5.51 (dd, J = 3.7, 2.0 Hz,
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H), 5.28 – 5.19 (m, 1H), 4.02 (dq, J = 14.3, 7.2 Hz, 1H), 3.90 (d, J = 1.4 Hz, 1H), 3.84 (dq, J =
4.3, 7.2 Hz, 1H), 3.68 (dd, J = 21.9, 3.6 Hz, 1H), 3.29 (dd, J = 21.9, 2.0 Hz, 1H), 2.92 (dq, J =
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14.2, 7.2 Hz, 1H), 2.82 (dq, J = 14.1, 7.1 Hz, 1H), 2.33 (s, 3H), 2.32 (s, 3H), 1.14 – 1.04 (m,
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H). 13C{ H} NMR (126 MHz, CDCl ) δ 173.0, 168.6, 166.8, 164.6, 143.9, 142.0, 139.1, 138.2,
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37.8, 137.1, 136.0, 135.5, 129.7, 129.6, 129.4, 128.7, 128.3, 127.3, 126.8, 126.5, 126.2, 126.1,
21.3, 65.9, 62.6, 60.8, 50.5, 40.6, 40.0, 39.1, 21.1, 21.0, 15.2, 12.9, 12.3. (7e + 8e): HRMS
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(ESI) m/z: [M + Na] Calcd for C H NO Na 358.1414; Found 358.1425. The structure of these
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compounds was also confirmed by HMBC and HSQC spectra.
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-Ethyl-4-phenyl-6-(p-tolyl)-3,6-dihydropyridin-2(1H)-one-3-d (9) and 1-ethyl-4-phenyl-6-(p-
tolyl)-3,6-dihydropyridin-2(1H)-one-3,3,5-d (10)
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(
9)+(10): H NMR (400 MHz, DMSO-d ) δ 7.51 – 7.38 (m, 9H), 7.34 (dd, J = 8.4, 6.5 Hz, 9H),
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.31 – 7.24 (m, 4H), 7.22 – 7.13 (m, 17H), 6.25 – 6.15 (m, 2H), 5.21 (s, 4H), 3.71 – 3.57 (m,
4H), 3.55 (d, J = 3.8 Hz, 1H), 3.25 (d, J = 3.1 Hz, 1H), 2.77 (dq, J = 14.0, 7.0 Hz, 4H), 2.26 (s,
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2H), 0.94 (t, J = 7.1 Hz, 12H). (9)+(10): C NMR (101 MHz, DMSO-d ) δ 166.9, 138.2, 138.0,
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37.9, 137.7, 129.9, 129.8, 129.0, 128.4, 127.5, 125.3, 124.7, 122.5, 62.1, 62.1, 21.1, 12.6.
+
(
9): HRMS (ESI) m/z: [M + H] Calcd for C H DNO 293.1759; Found 293.1749
20 21
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(
10): HRMS (ESI) m/z: [M + H] Calcd for C H D NO 295.1884; Found 295.1883
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ASSOCIATED CONTENT
Supporting Information
1
13
1
Schemes S1-S4 and copies of H and C{ H} NMR spectra for compounds 4a-j, 6a-s, 7e+8e,
9
+10. This material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*
E-mail: m.krasavin@spbu.ru.
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGEMENTS
This research was supported by the Russian Science Foundation (project grant 18-73-0074). We
are grateful to the Research Centre for Magnetic Resonance, the Centre for Chemical Analysis
and Materials Research, and the Centre for X-ray Diffraction Methods of Saint Petersburg State
University Research Park for the analytical data.
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