Practical Method for the Preparation of 2,2-Dimethyl-5-{aryl[(hetero)aryl]methyl}-1,3-dioxane-4,6-diones: Synthesis and Mechanistic Study

Article abstract of DOI:10.1055/s-0035-1561656

An efficient practical synthetic procedure has been developed for the synthesis of 2,2-dimethyl-5-{aryl[(hetero)aryl]methyl}-1,3-dioxane-4,6-diones through Friedel-Crafts alkylation. The scope and limitation of the reaction of 2,2-dimethyl-5-arylidene-1,3

Full text of DOI:10.1055/s-0035-1561656

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–H
paper
A
E. Najda et al.
Paper
Synthesis
Practical Method for the Preparation of 2,2-Dimethyl-5-
{aryl[(hetero)aryl]methyl}-1,3-dioxane-4,6-diones: Synthesis and
Mechanistic Study
R1
R1
Ewelina Najda
Anna Zakaszewska
Karolina Janikowska*
Sławomir Makowiec*
ZnCl2, CH2Cl2
0.5–24 h
Ar(Het)
O
(Het)Ar–H
+
O
O
O
up to 92%
20 examples
O
O
O
O
Department of Organic Chemistry, Faculty of Chemistry,
Gdansk University of Technology, Narutowicza 11/12,
80-233 Gdansk, Poland
R1 = Me, H, Cl, F, NO2
(Het)Ar = p-excess aromatic system
mak@pg.gda.pl
Received: 17.02.2016
Accepted after revision: 02.05.2016
Published online: 10.06.2016
The simplest strategy for the preparation of 2,2-dimeth-
yl-5-{aryl[(hetero)aryl]methyl}-1,3-dioxane-4,6-diones 3 is
based on the addition of nucleophilic aromatic species to
electron-deficient 2,2-dimethyl-5-arylidene-1,3-dioxane-
4,6-diones 2 (Scheme 1).
DOI: 10.1055/s-0035-1561656; Art ID: ss-2016-t0119-op
Abstract An efficient practical synthetic procedure has been devel-
oped for the synthesis of 2,2-dimethyl-5-{aryl[(hetero)aryl]methyl}-
1,3-dioxane-4,6-diones through Friedel–Crafts alkylation. The scope
and limitation of the reaction of 2,2-dimethyl-5-arylidene-1,3-dioxane-
4,6-diones with π-excess aromatic systems have been delineated.
R2
R1
R1
R3
R2
X
+
Key words heterocycles, indoles, pyrroles, electrophilic aromatic sub-
stitution, Lewis acids
R3
O
O
O
O
X
O
O
O
O
1
2
3
Functionalized derivatives of Meldrum’s acid have
gained an established position in organic synthesis. Most
practical applications are related to the use of various acyl
derivatives of 1,3-dioxane-4,6-diones, which are easily
formed by the acylation of Meldrum’s acid with activated
acyl compounds or isocyanates.1 These acyl derivatives are
important in that under moderately mild thermolysis con-
ditions they are converted into β-oxoketenes – a broadly
exploited chemical species. In comparison, alkyl or aryl-
methyl derivatives of Meldrum’s acid belong to a less ex-
plored class of compounds; however, these reagents could
also be a starting point for various syntheses, particularly
those leading to bioactive species.2
Recently, we focused our research efforts on the synthe-
sis and application of 2,2-dimethyl-5-{aryl[(hete-
ro)aryl]methyl}-1,3-dioxane-4,6-diones, which could be
considered as the starting molecules for a broad scope of
bioactive compounds possessing a heteroaromatic ring
fused with cyclic ketones, for example, strigolactone ana-
logues,3 antitumor agents,4 aurora kinase inhibitors,5
necroptosis inhibitors,6 acetylcholinestrase inhibitors,7 ox-
indole alkaloids,8 or Uhle ketones.9
R1 = Me, H, Cl, F, NO2
R2, R3 = H, -CH=CH-CH=CH-
X = O, S, NH, NMe
Scheme 1 Formation of 2,2-dimethyl-5-{aryl[(hetero)aryl]methyl}-
1,3-dioxane-4,6-diones through Friedel–Crafts alkylation
Since the α,β-unsaturated system of vinyl derivatives of
Meldrum’s acid are rather moderate electrophiles, the
method of choice for the preparation of 3 is usually the ad-
dition of organometallic reagent to 2,2-dimethyl-5-het-
eroarylideno-1,3-dioxane-4,6-diones.10 Such an approach is
also used for the formation of 2,2-dimethyl-5-(homodiaryl-
methyl)-1,3-dioxane-4,6-diones with Cu(I) as catalyst11 or
without catalyst.12 In the case of heteroaromatic highly π-
excess donors, one would expect to obtain 3 in a Friedel–
Crafts type of reaction with α,β-unsaturated electrophiles.
However, in the chemical literature there is a lack of general
and simple procedures for the preparation of such com-
pounds. Only narrow specialized methods could be found:
as reaction of indoles in three-component process in the
presence of L-proline described by Laronze and co-work-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

B
E. Najda et al.
Paper
Synthesis
ers,13 enantioselective addition of 2-furfuryl ketones to 2,2-
dimethyl-5-arylidene-1,3-dioxane-4,6-diones 2,14 or addi-
tion of organoboron compounds.15
beginning, a reaction between benzaldehyde, Meldrum’s
acid, and pyrrole or N-methylpyrrole in acetonitrile was
performed in the presence of L-proline. As a result, the de-
sired product 3 was not obtained (Scheme 3), even if more
acidic conditions, such as tetrafluroboric acid in acetic acid,
were applied.
In this article, we describe a general method for the
preparation of 3 that allows the formation of the target
compounds independently of the type of heteroaromatic
reagent used. As mentioned earlier, Laronze has described
an effective method for the preparation of 3 with indole as
a heteroatomic moiety; however, when this method was
applied for the slightly less π-excess aromatic donors such
as pyrrole or furan, the desired 3 was not obtained. There-
fore, we were forced to find a more universal methodology
for the effective preparation of 3, which would exploit the
widest possible range of aromatic substrates and electro-
L-Pro, MeCN
or
HBF4•Et2O, AcOH
O
O
Ph
+
+
n. r.
N
O
O
H
O
R
1
R = H, Me
Scheme 3 Attempts towards the preparation of 2,2-dimethyl-5-
[aryl(1H-pyrrol-2-yl)methyl]-1,3-dioxane-4,6-diones in the three-com-
ponent process
philic
2,2-dimethyl-5-arylidene-1,3-dioxane-4,6-diones.
Next, the mechanism of the reaction between a benzalde-
hyde derivative, Meldrum’s acid, and π-nucleophile in the
presence of a catalyst was investigated. From the theoretical
point of view, there are two possible routes: First, the previ-
ous formation of the Knoevenagel product and then the
Fridel–Crafts alkylation to yield 3 (path a, Scheme 2). Sec-
ond, the initial hydroxyalkylation of aromatic ring by alde-
hyde in the presence of an acid or base catalyst. The first
initial steps for both types of reactions are possible and
known processes16,17 in the two-component reactions. To
distinguish the plausible reaction mechanism from others,
we planned and performed a series of experiments. At the
However, in the reaction of benzaldehyde, Meldrum’s
acid, and N-methylpyrrole in acetonitrile in the presence of
L-proline, we observed the formation of 2, but the subse-
quent addition to the aromatic ring of N-methylpyrrole was
not effective in these conditions and the reaction resulted
in the formation of a complex mixture of products. Howev-
er, when we used the previously prepared 2 and indole in
the presence of L-proline, the product 3 was formed in a
similar yield as was reported by Laronze13d for a three-com-
ponent reaction. Also, the use of 2a, N-methylpyrrole, and
L-proline in acetonitrile resulted in the formation of the de-
sired product (Table 1, entries 18–20). The above facts
strongly suggests (path a, Scheme 2) as a plausible mecha-
nism for the investigated process. Additionally, we checked
whether indole can be hydroxylated with an aldehyde in
the presence of L-proline. In the reaction of indole and
benzaldehyde, the formation of 4 was not observed, in fact,
for the effective hydroxyalkylation of indole, tetramethyl-
guanidine is required.17 Moreover, independently formed 3-
(1-hydroxybenzyl)-1H-indole or 3-(1-hydroxybenzyl)pyr-
role did not react with Meldrum’s acid in the presence of L-
proline. On the basis of these experiments, we conclude
that the first step of the reaction is the formation of 2,
which, in the further course of the reaction, plays the role
of electrophile in the reaction with the aromatic ring. To re-
duce the number of variables during the search for the opti-
mal conditions for the preparation of 1, we decided to use
the previously prepared 2 as substrates. It should also be
added that use of the mixture of Meldrum’s acid and alde-
hyde for in situ formation of 2 is the source of problems as-
sociated with dimer formation.18 At the beginning, we tried
to find the most effective catalyst for the reaction between
1 and 2. At first, tetrafluoroboric acid diethyl etherate in di-
chloromethane was tested at room temperature in the reac-
tion of 1 equivalent of 2a with 5 equivalents of N-methylpy-
role, resulting in a moderate yield of 3ba (entry 15), proba-
bly due to the decomposition of previously formed product
in acidic media. In another combination of reagents,
Y
O
O
+
+
O
O
N
H
H
O
path a
path b
Y
Y
HO
O
O
O
O
+
N
H
+
O
O
O
O
N
H
4
2
Y = Me, H, Cl, F, NO2
Y
HN
O
O
O
O
3
Scheme 2 Possible ways for formation of 2,2-dimethyl-5-{aryl[(hete-
ro)aryl]methyl}-1,3-dioxane-4,6-diones in the three-component reac-
tion
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

C
E. Najda et al.
Paper
Synthesis
HBF4·OEt2 proved to be ineffective. The next catalyst investi-
gated was ZrCl4. In the reaction of 2a with N-methylindole,
a complex mixture of products were obtained that were
difficult to separate. Furthermore, SnCl4 was used in the re-
action of 2a and pyrrole, but this approach was also unsuc-
cessful, as was the approach with TMSCl (entry 16). Finally,
we took anhydrous ZnCl2 under consideration as a moder-
ately strong Lewis acid. We carried out an experiment
where 1 equivalent of 2a and 10 equivalents of N-meth-
ylpyrrole were treated with ZnCl2 in DCE at 40 °C for 0.5
hour. From the reaction mixture the product 3ba was iso-
lated in 50% yield (entry 12). The obtained yield was similar
to the reaction with L-proline as a catalyst, but the reaction
time was shorter (entry 19). Therefore, we tried to optimize
this reaction; however, increasing the temperature of the
process to the boiling point of DCE resulted in the forma-
tion of a complex mixture of products, while decreasing the
temperature led to a drop in yield (entry 8). In most cases
with ZnCl2 as a catalyst, the use of a large excess of volatile
heteroaromatic compound furnished good yields (entries 4,
5, 7, 10, 21–23). Nevertheless, we had to pay attention to
the fact that two different catalysts such as ZnCl2 in di-
chloromethane and L-proline in acetonitrile led to similar
results (entries 12 and 19). Control experiments were per-
formed with dichloromethane as solvent between: pyrrole
and 2a (entry 2); N-methylpyrrole and 2a,e (entries 9, 11,
13, 14, 25); indole and 2a–e (entries 28, 30, 32, 34, 36);
N,N-dimethylaniline and 2a,c,e (entries 38, 41, 44) without
any additional catalyst. These experiments led to surprising
results: in the case of the combination nitrogen heteroaro-
matic substrates and acceptors 2a–d, the best results were
obtained without a catalyst in the reaction mixture, where-
as in the case of the reaction of N-methylpyrrole with 2d,
furan with 2e, and N,N-dimethylaniline with 2a–d the addi-
tion of ZnCl2 caused higher yields of 3. It must be noted that
3 are not very stable compounds and particularly in a solu-
tion containing protic acids,12a they undergo slow decom-
1
position, which was proven by H NMR monitoring of the
solution of 3aa after the addition of a catalytic amount of
TFA. Therefore, purification on silica gel must be done as
quickly as possible, otherwise a significant drop in yield oc-
curs.
Table 1 Results of Friedel–Crafts Alkylation of Aromatic Species 1 with 2,2-Dimethyl-5-arylidene-1,3-dioxane-4,6-diones 2 – Experimental Optimiza-
tion of Conditions
R1
R1
Ar(Het)
O
(Het)Ar–H +
O
O
O
1
O
O
O
O
3
2
Entry
1
ArH
pyrrole
2
R1
Product 3
Catalyst
Temp (°C) Solvent
Time (h)
Yield (%)
Ratio 1:2
1
2a
3
a
a
a
a
a
a
a
b
b
b
b
b
b
b
b
b
b
a
a
a
c
H
H
H
Cl
F
3aa
3aa
3aa
3ac
3ad
3ad
3ae
3ba
3ba
3ba
3ba
3ba
3ba
3ba
3ba
3ba
3ba
ZnCl2
–
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
40
40
r.t.
r.t.
r.t.
40
CH2Cl2
CH2Cl2
MeCN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeNO2
2
6
30
17
58
45
38
84
32
78
51
74
50
79
40
32
15
20
100:1
10:1
1:1
pyrrole
0.5
1
pyrrole
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
–
4a
5a
6
pyrrole
0.5
1
100:1
100:1
10:1
100:1
10:1
10:1
100:1
100:1
10:1
10:1
1:1
pyrrole
d
d
e
a
a
a
a
a
a
a
a
a
a
pyrrole
F
0.5
0.5
1
7a
8
pyrrole
NO2
H
H
H
H
H
H
H
H
H
H
N-methylpyrrole
N-methylpyrrole
N-methylpyrrole
N-methylpyrrole
N-methylpyrrole
N-methylpyrrole
N-methylpyrrole
N-methylpyrrole
N-methylpyrrole
N-methylpyrrole
9
1
10
11
12
13a
14
15
16
17
ZnCl2
–
0.5
1
ZnCl2
–
0.5
1
–
1
HBF4
TMSCl
ZnCl2
2
5:1
1
5:1
2
5:1
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

D
E. Najda et al.
Paper
Synthesis
Table 1 (continued)
Entry
1
ArH
N-methylpyrrole
2
R1
Product 3
Catalyst
Temp (°C) Solvent
Time (h)
Yield (%)
Ratio 1:2
18
b
b
b
b
b
b
b
b
c
a
a
a
b
c
H
3ba
3ba
3ba
3bb
3bc
3bd
3be
3be
3ce
3da
3da
3db
3db
3dc
3dc
3dd
3dd
3de
3de
3ea
3ea
3eb
3ec
3ec
3ed
3ee
3ee
L-Pro
L-Pro
L-Pro
ZnCl2
ZnCl2
ZnCl2
ZnCl2
–
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
40
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
40
80
r.t.
r.t.
80
r.t.
40
r.t.
MeCN
MeCN
MeCN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DCE
2
2
32
50
76
59
92
64
60
32
23
35
71
17
65
62
85
57
83
32
44
21
17
46
22
20
15
17
19
1:1
10:1
100:1
100:1
100:1
100:1
5:1
19
N-methylpyrrole
N-methylpyrrole
N-methylpyrrole
N-methylpyrrole
N-methylpyrrole
N-methylpyrrole
N-methylpyrrole
furan
H
20
H
2
21a
22a
23a
24a
25
Me
Cl
0.5
0.5
0.5
0.5
1
d
e
e
e
a
a
b
b
c
F
NO2
NO2
NO2
H
10:1
10:1
1:1
26a
27
ZnCl2
ZnCl2
–
7.5
0.25
1
d
d
d
d
d
d
d
d
d
d
e
e
e
e
e
e
e
e
indole
28a
29
indole
H
1:1
indole
Me
Me
Cl
ZnCl2
–
0.25
1
1:1
30a
31
indole
1:1
indole
ZnCl2
–
2
1:1
32a
33
indole
c
Cl
1
1:1
indole
d
d
e
e
a
a
b
c
F
ZnCl2
–
0.25
1
1:1
34a
35
indole
F
1:1
indole
NO2
NO2
H
ZnCl2
–
2
1:1
36a
37a
38
indole
2.5
7
1:1
N,N-dimethylaniline
N,N-dimethylaniline
N,N-dimethylaniline
N,N-dimethylaniline
N,N-dimethylaniline
N,N-dimethylaniline
N,N-dimethylaniline
N,N-dimethylaniline
ZnCl2
–
1:1
H
3
1:1
39a
40a
41
Me
Cl
ZnCl2
ZnCl2
–
CH2Cl2
CH2Cl2
DCE
20
2
100:1
100:1
1:1
c
Cl
5
42a
43
d
e
e
F
ZnCl2
ZnCl2
–
CH2Cl2
CH2Cl2
CH2Cl2
1,5
7
100:1
1:1
NO2
NO2
44a
7
1:1
a For the specific combination of reagents the best yield of 3 was obtained.
In conclusion, extensive studies to develop effective
methods for the preparation of 2,2-dimethyl-5-{aryl[(hete-
ro)aryl]methyl}-1,3-dioxane-4,6-diones 3 were carried out
with a wide range of variables such as type of substrates,
process temperature, solvents, and catalyst. We proved the
undeniable superiority of the use of 2,2-dimethyl-5-
arylidene-1,3-dioxane-4,6-diones 2 that has been previous-
ly prepared and purified, rather than the in situ formation
of 2 in a three-component reaction. From the tested cata-
lysts, ZnCl2 proved to be most universal for all types of re-
agent combinations; however, for highly π-excess aromatic
reagents, better results were acquired without the addition
of a catalyst.
under argon and stored over 4 Å molecular sieves. MeCN and nitro-
methane were distilled from 4 Å molecular sieves and stored over
them. Analytical TLC was performed on aluminum sheets of silica gel
UV-254 Merck and visualized with UV lamp at 254 nm. Flash chroma-
tography was performed using 40–63 microns of Zeochem silica gel.
1H and 13C NMR spectra were recorded at Varian Gemini 200 and Vari-
an Unity Plus 500; chemical shifts (δ) are expressed in ppm. Melting
points are uncorrected.
2,2-Dimethyl-5-(4-fluorophenyl)methyl-1,3-dioxane-4,6-dione
(2d)
Prepared according to a literature procedure.16b 4-Fluorobenzalde-
hyde (0.62 g, 5 mmol, 1 equiv) was added to a stirred solution of
Meldrum’s acid (0.79 g, 5.5 mmol, 1.1 equiv) in anhyd benzene (25
mL). To this mixture was added AcOH (28 μL, 0.5 mmol, 10 mol %) and
pyrrolidine (30 μL, 0.5 mmol, 10 mol %). The resulting mixture was
stirred for 16 h. After diluting with EtOAc (50 mL), the reaction mix-
ture was washed with sat. aq NaHCO3, and dried (MgSO4). Solvent
Commercially available reagents were purchased from Sigma-Aldrich.
5-Arylidene-1,3-dioxa-4,6-diones 2a–c,e16b were prepared according
to the literature procedure. CH2Cl2 and DCE were distilled from P4O10
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

E
E. Najda et al.
Paper
Synthesis
was removed under reduced pressure and the residue was crystalized
from EtOH to give 2d; yellow crystals, yield: 0.25 g (20%); mp 138–
140 °C.
1H NMR (CDCl3, 500 MHz): δ = 8.39 (s, 1 H), 8.16–8.19 (m, 2 H), 7.15–
2,2-Dimethyl-5-[4-nitrophenyl(1H-pyrrol-2-yl)methyl]-1,3-diox-
ane-4,6-dione (3ae)
Purification by flash column chromatography (EtOAc/hexanes, 4:1);
yellow oil; yield: 144 mg (84%).
1H NMR (CDCl3, 200 MHz): δ = 9.15 (s, 1 H), 8.11 (d, J = 8.8 Hz, 2 H),
7.28 (d, J = 8.8 Hz, 2 H), 6.83–6.81 (q, J = 2.9 Hz, 1 H), 6.24–6.20 (m, 1
H), 6.18–6.19 (m, 1 H), 5.53 (d, J = 2.0 Hz, 1 H), 4.25 (d, J = 2.0 Hz, 1 H),
1.81 (s, 3 H), 1.73 (s, 3 H).
7.19 (m, 2 H), 1.80 (s, 6 H).
13C NMR (CDCl3, 125 MHz): δ = 166.0 (d, J = 259.0 Hz), 163.5, 160.1,
156.9, 137.0 (d, J = 9.6 Hz), 128.3, 116.4 (d, J = 21.5 Hz), 114.3, 104.9,
27.9.
13C NMR (CDCl3, 125 MHz): δ = 165.4, 165.0, 147.0, 146.9, 129.0,
HRMS (ESI+): m/z [M + H]+ calcd for C13H12FO4: 251.0720; found:
128.3, 123.8, 119.4, 109.8, 108.5, 106.1, 52.1, 41.5, 28.4, 27.3.
251.0701.
HRMS (ESI+): m/z [M + H]+ calcd for C17H17N2O6: 345.1087; found:
2,2-Dimethyl-5-[(hetero)aryl(aryl)methyl]-1,3-dioxane-4,6-di-
ones 3aa–ee; General Procedure
345.1080.
A solution of 5-arylidene-1,3-dioxane-4,6-dione 2a–e (0.5 mmol), ar-
omatic compound 1a–e (amount specified in Table 1), and catalyst
10% mol in anhyd solvent (5 mL) was stirred under argon (catalyst,
solvent, reaction time, and temperature are specified in Table 1). After
completion of the reaction the solvent was removed under vacuum,
and the residue was purified.
2,2-Dimethyl-5-[phenyl(1-methyl-1H-pyrrol-2-yl)methyl]-1,3-di-
oxane-4,6-dione (3ba)
Purification by flash column chromatography (EtOAc/hexanes, 1:2);
white solid; yield: 123 mg (79%).
1H NMR (CDCl3, 400 MHz): δ = 7.32–7.24 (m, 5 H), 6.60–6.59 (m, 1 H),
6.29–6.27 (m, 1 H), 6.14–6.11 (m, 1 H), 5.34 (d, J = 2.5 Hz, 1 H), 4.24
(d, J = 2.5 Hz, 1 H), 3.36 (s, 3 H), 1.77 (s, 3 H), 1.64 (s, 3 H).
13C NMR (CDCl3, 125 MHz): δ = 165.0, 164.2, 139.0, 130.5, 129.3,
128.6, 127.5, 122.6, 108.6, 107.0, 105.3, 52.3, 41.5, 34.3, 28.5, 27.8.
2,2-Dimethyl-5-[phenyl(1H-pyrrol-2-yl)methyl]-1,3-dioxane-4,6-
dione (3aa)
Purification by flash column chromatography (EtOAc/hexanes, 1:2);
brown oil; yield: 44 mg (30%).
1H NMR (CD2Cl2, 500 MHz): δ = 9.13 (s, 1 H), 7.30–7.22 (m, 3 H), 7.14–
7.13 (m, 2 H), 6.78–6.77 (m, 1 H), 6.18–6.17 (m, 1 H), 6.14 (q, J = 2.9
Hz, 1 H), 5.44 (d, J = 1.4 Hz, 1 H), 4.26 (d, J = 1.4 Hz, 1 H), 1.79 (s, 3 H),
1.67 (s, 3 H).
13C NMR (CD2Cl2, 125 MHz): δ = 166.0, 165.6, 140.0, 130.1, 128.9,
128.3, 127.5, 118.7, 109.1, 108.3, 106.0, 52.4, 42.3, 28.5, 27.5.
HRMS (ESI+): m/z [M + H]+ calcd for C17H18NO4: 300.1236; found:
300.1258.
HRMS (ESI+): m/z [M + H]+ calcd for C18H20NO4: 314.1391; found:
314.1388.
2,2-Dimethyl-5-[p-tolyl(1-methyl-1H-pyrrol-2-yl)methyl]-1,3-di-
oxane-4,6-dione (3bb)
Purification by flash column chromatography (EtOAc/hexanes, 1:3);
yellow solid; yield: 96 mg (59%).
1H NMR (CDCl3, 200 MHz): δ = 7.16–7.02 (m, 4 H), 6.57 (s, 1 H), 6.25–
6.23 (m, 1 H), 6.13–6.10 (m, 1 H), 5.29 (s, 1 H), 4.22 (d, J = 2.5 Hz, 1 H),
3.34 (s, 3 H), 2.30 (s, 3 H), 1.77 (s, 3 H), 1.62 (s, 3 H).
13C NMR (CDCl3, 125 MHz): δ = 165.1, 164.2, 137.1, 135.9, 130.7,
129.3, 129.2, 122.5, 108.4, 106.9, 105.2, 52.3, 41.2, 34.2, 28.4, 27.7,
21.3.
HRMS (ESI+): m/z [M + H]+ calcd for C19H22NO4: 328.1548; found:
348.1572.
2,2-Dimethyl-5-[4-chlorophenyl(1H-pyrrol-2-yl)methyl]-1,3-diox-
ane-4,6-dione (3ac)
Purification by flash column chromatography (EtOAc/hexanes, 1:1);
brown oil; yield: 96 mg (58%).
1H NMR (CDCl3, 400 MHz): δ = 9.22 (s, 1 H), 7.25 (d, J = 8.8 Hz, 2 H),
7.09 (d, J = 8.8 Hz, 2 H), 6.80–6.71 (m, 1 H), 6.26–6.18 (m, 2 H), 5.47
(d, J = 2.1 Hz, 1 H), 4.16 (d, J = 2.1 Hz, 1 H), 1.80 (s, 3 H), 1.70 (s, 3 H).
13C NMR (CDCl3, 125 MHz): δ = 165.6, 165.2, 137.9, 133.2, 129.5,
128.9, 128.9, 118.9, 109.1, 108.3, 105.8, 52.1, 41.4, 28.4, 27.4.
2,2-Dimethyl-5-[4-chlorophenyl(1-methyl-1H-pyrrol-2-yl)meth-
yl]-1,3-dioxane-4,6-dione (3bc)
Purification by flash column chromatography (EtOAc/hexanes, 1:1);
yellow oil; yield: 159 mg (92%).
1H NMR (CDCl3, 200 MHz): δ = 7.26–7.17 (m, 4 H), 6.57–6.54 (m, 1 H),
6.24–6.22 (m, 1 H), 6.13–6.10 (m, 1 H), 5.30 (d, J = 2.5 Hz, 1 H), 4.22
(d, J = 2.5 Hz, 1 H), 3.33 (s, 3 H), 1.77 (s, 3 H), 1.63 (s, 3 H).
13C NMR (CDCl3, 125 MHz): δ = 164.9, 163.8, 137.4, 133.4, 130.9,
130.0, 128.7, 122.8, 108.6, 107.1, 105.3, 52.2, 40.6, 34.2, 28.4, 27.6.
HRMS (ESI+): m/z [M + H]+ calcd for C17H17ClNO4: 334.0845; found:
334.0848.
2,2-Dimethyl-5-[4-fluorophenyl(1H-pyrrol-2-yl)methyl]-1,3-diox-
ane-4,6-dione (3ad)
Purification by flash column chromatography (EtOAc/hexanes, 1:1);
yellow oil; yield: 71 mg (45%).
1H NMR (CD2Cl2, 500 MHz): δ = 9.14 (s, 1 H), 7.18–7.14 (m, 2 H), 7.00–
6.97 (m, 2 H), 6.79–6.78 (m, 1 H), 6.17–6.15 (m, 1 H), 6.15–6.13 (m, 1
H), 5.43 (s, 1 H), 4.24 (d, J = 2.4 Hz, 1 H), 1.78 (s, 3 H), 1.68 (s, 3 H).
13C NMR (CD2Cl2, 125 MHz): δ = 165.9, 165.4, 162.2 (d, J = 245.0 Hz),
135.8, 130.3 (d, J = 7.9 Hz), 129.9, 118.8, 115.3 (d, J = 21.5 Hz), 109.1,
108.4, 106.1, 52.5, 41.6, 28.5, 27.5.
HRMS (ESI+): m/z [M + H]+ calcd for C18H19ClNO4: 348.1003; found:
348.0999.
2,2-Dimethyl-5-[4-fluorophenyl(1-methyl-1H-pyrrol-2-yl]meth-
yl)-1,3-dioxane-4,6-dione (3bd)
Purification by flash column chromatography (EtOAc/hexanes, 1:3);
white solid; yield: 105 mg (64%).
HRMS (ESI+): m/z [M + Na]+ calcd for C17H16FNO4Na: 340.0960; found:
340.0961.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

F
E. Najda et al.
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Synthesis
1H NMR (CDCl3, 200 MHz): δ = 7.26–7.22 (m, 2 H), 6.97–6.94 (m, 2 H),
6.58–6.57 (m, 1 H), 6.25–6.24 (m, 1 H), 6.12–6.11 (m, 1 H), 5.31 (d, J =
2.0 Hz, 1 H), 4.22 (d, J = 2.0 Hz, 1 H), 3.33 (s, 3 H), 1.77 (s, 3 H), 1.66 (s,
3 H).
13C NMR (CDCl3, 125 MHz): δ = 165.0, 163.9, 162.2 (d, J = 245.9 Hz),
134.5, 131.1 (d, J = 7.9 Hz), 130.5, 122.7, 115.4 (d, J = 21.5 Hz), 108.6,
107.0, 105.3, 52.3, 40.6, 34.2, 28.4, 27.7.
13C NMR (CDCl3, 125 MHz): δ = 165.8, 164.9, 137.0, 136.9, 136.0,
129.5, 129.3, 129.1, 124.3, 122.5, 119.9, 119.3, 115.4, 111.4, 105.4,
52.1, 41.6, 28.4, 28.2, 27.8.
HRMS (ESI+): m/z [M + H]+ calcd for C22H22NO4: 364.1549; found:
364.1572.
2,2-Dimethyl-5-[4-chlorophenyl(1H-indol-3-yl)methyl]-1,3-diox-
ane-4,6-dione (3dc)
HRMS (ESI+): m/z [M + H]+ calcd for C18H19FNO4: 332.1297; found:
332.1294.
Purification by flash column chromatography (EtOAc/hexanes, 1:3);
yellow oil; yield: 162 mg (85%).
1H NMR (CDCl3, 500 MHz): δ = 8.20 (s, 1 H), 7.40–7.34 (m, 5 H), 7.26–
7.18 (m, 3 H), 7.07 (t, J = 7.3 Hz, 1 H), 5.64 (d, J = 2.4 Hz, 1 H), 4.28 (d,
J = 2.4 Hz, 1 H), 1.73 (s, 3 H), 1.52 (s, 3 H).
13C NMR (CDCl3, 125 MHz): δ = 165.5, 164.7, 138.6, 136.0, 133.2,
130.8, 128.7, 127.0, 124.2, 122.7, 120.1, 119.1, 114.8, 111.4, 105.4,
52.0, 40.7, 28.4, 27.9.
2,2-dimethyl-5-(4-nitrophenyl(1-methyl-1H-pyrrol-2-yl)methyl]-
1,3-dioxane-4,6-dione (3be)
Purification by flash column chromatography, (EtOAc/hexanes, 4:1);
yellow oil; yield: 107 mg (60%).
1H NMR (CDCl3, 400 MHz): δ = 8.13 (d, J = 9.1 Hz, 2 H), 7.45 (d, J = 9.1
Hz, 2 H), 6.63–6.61 (m, 1 H), 6.26–6.23 (m, 1 H), 6.16–6.13 (m, 1 H),
5.42 (d, J = 2.5 Hz, 1 H), 4.29 (d, J = 2.5 Hz, 1 H), 3.38 (s, 3 H), 1.82 (s, 3
H), 1.73 (s, 3 H).
HRMS (ESI+): m/z [M + H]+ calcd for C21H19ClNO4: 384.1002; found:
384.0988.
13C NMR (CDCl3, 125 MHz): δ = 164.6, 163.6, 147.3, 146.7, 130.4,
128.9, 123.7, 123.2, 108.9, 107.5, 105.6, 52.2, 40.5, 34.2, 28.4, 27.6.
HRMS (ESI+): m/z [M + H]+ calcd for C18H19N2O6: 359.1242; found:
2,2-Dimethyl-5-[4-fluorophenyl(1H-indol-3-yl)methyl]-1,3-diox-
ane-4,6-dione (3dd)
359.1240.
Purification by flash column chromatography (EtOAc/hexanes, 1:2);
yellow oil; yield: 152 mg (83%).
1H NMR (CDCl3, 500 MHz): δ = 8.17 (s, 1 H), 7.40–7.36 (m, 5 H), 7.19
(t, J = 7.3 Hz, 1 H), 7.06 (t, J = 7.8 Hz, 1 H), 6.97–6.94 (m, 1 H), 5.64 (d,
J = 2.4 Hz, 1 H), 4.28 (d, J = 2.4 Hz, 1 H), 1.73 (s, 3 H), 1.49 (s, 3 H).
13C NMR (CDCl3, 125 MHz): δ = 165.7, 164.8, 162.1 (d, J = 245.9 Hz),
136.1, 135.7 (d, J = 3.0 Hz), 131.1 (d, J = 7.9 Hz), 127.0, 124.2, 122.6,
120.0, 119.2, 115.3 (d, J = 21.5 Hz), 115.0, 111.5, 105.5, 52.2, 40.9,
28.4, 27.9.
2,2-Dimethyl-5-[4-nitrophenyl(furan-2-yl)methyl]-1,3-dioxane-
4,6-dione (3ce)
Purification by flash column chromatography (EtOAc/hexanes, 4:1);
yellow oil; yield: 40 mg (23%).
1H NMR (CDCl3, 500 MHz): δ = 8.17 (d, J = 8.8 Hz, 2 H), 7.65 (d, J = 8.8
Hz, 2 H), 7.38 (s, 1 H), 6.37 (t, J = 4.4 Hz, 1 H), 6.09 (d, J = 2.9 Hz, 1 H),
5.41 (d, J = 2.4 Hz, 1 H), 4.29 (d, J = 2.4 Hz, 1 H), 1.80 (s, 3 H), 1.68 (s, 3
H).
HRMS (ESI+): m/z [M + H]+ calcd for C21H19FNO4: 367.1297 found:
368.1287.
13C NMR (CDCl3, 125 MHz): δ = 163.9, 163.8, 151.7, 145.2, 142.2,
131.1, 129.9, 123.9, 111.1, 108.8, 105.7, 50.4, 43.2, 28.4, 27.6.
HRMS (ESI+): [M + H]+ calcd for C17H16NO7: 346.0927; found:
346.0925.
2,2-Dimethyl-5-[4-nitrophenyl(1H-indol-3-yl)methyl]-1,3-diox-
ane-4,6-dione (3de)
Purification by flash column chromatography (EtOAc/hexanes, 4:1);
yellow oil; yield: 87 mg (44%).
1H NMR (CDCl3, 500 MHz): δ = 8.33 (s, 1 H), 8.10 (d, J = 8.7 Hz, 2 H),
7.58 (d, J = 8.7 Hz, 2 H), 7.38–7.35 (m, 3 H), 7.22–7.19 (m, 1 H), 7.08 (t,
J = 7.8 Hz, 1 H), 5.76 (d, J = 2.4 Hz, 1 H), 4.35 (d, J = 2.4 Hz, 1 H), 1.78 (s,
3 H), 1.60 (s, 3 H).
13C NMR (CDCl3, 125 MHz): δ = 165.1, 164.3, 147.8, 147.1, 135.9,
130.7, 130.3, 124.3, 123.6, 122.9, 120.3, 118.9, 113.8, 111.6, 105.6,
52.1, 40.4, 28.4, 27.7.
2,2-Dimethyl-5-[phenyl(1H-indol-3-yl)methyl]-1,3-dioxane-4,6-
dione (3da)19
Purification by flash column chromatography (EtOAc/hexanes, 1:2);
yellow oil; yield: 124 mg (71%).
1H NMR (CDCl3, 500 MHz): δ = 8.18 (s, 1 H), 7.44–7.35 (m, 5 H), 7.30–
7.17 (m, 4 H), 7.08–7.05 (m, 1 H), 5.65 (d, J = 2.0 Hz, 1 H), 4.31 (d, J =
2.4 Hz, 1 H), 1.71 (s, 3 H), 1.42 (s, 3 H).
13C NMR (CDCl3, 125 MHz): δ = 165.8, 164.9, 140.0, 136.0, 129.3,
128.6, 127.4, 127.2, 124.4, 122.5, 119.9, 119.3, 115.2, 111.4, 105.4,
52.1, 41.9, 28.3, 28.2.
HRMS (ESI+): m/z [M + H]+ calcd for C21H19N2O6: 395.1243; found:
395.1268.
2,2-Dimethyl-5-[p-tolyl(1H-indol-3-yl)methyl]-1,3-dioxane-4,6-
dione (3db)
2,2-Dimethyl-5-{phenyl[4-(dimethylamino)phenyl]methyl}-1,3-
dioxane-4,6-dione (3ea)
Purification by flash column chromatography (EtOAc/hexanes, 1:2);
yellow oil; yield: 118 mg (65%).
Purification by flash column chromatography (EtOAc/hexanes, 1:1);
yellow oil; yield: 37 mg (21%).
1H NMR (CDCl3, 500 MHz): δ = 8.18 (s, 1 H), 7.44 (d, J = 7.8 Hz, 1 H),
7.37–7.34 (m, 2 H), 7.30–7.25 (m, 2 H), 7.21–7.14 (m, 2 H), 7.09–7.05
(m, 2 H), 5.61 (d, J = 1.9 Hz, 1 H), 4.29 (d, J = 2.5 Hz, 1 H), 2.30 (s, 3 H),
1.71 (s, 3 H), 1.43 (s, 3 H).
1H NMR (acetone-d6, 400 MHz): δ = 7.34–7.26 (m, 4 H), 7.23–7.13 (m,
1 H), 7.14 (d, J = 8.8 Hz, 2 H), 6.68 (d, J = 8.8 Hz, 2 H), 5.23–5.21 (m, 1
H), 4.90 (d, J = 3.2 Hz, 1 H), 2.93 (s, 6 H), 1.87 (s, 3 H), 1.58 (s, 3 H).
13C NMR (CDCl3, 125 MHz): δ = 165.2, 165.0, 140.8, 130.6, 129.2,
128.6, 127.1, 113.7, 105.3, 51.5, 48.8, 41.4, 28.5, 27.9.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

G
E. Najda et al.
Paper
Synthesis
HRMS (ESI+): m/z [M + H]+ calcd for C21H24NO4: 354.1705; found:
354.1756.
from the European Union under the European Regional Development
Fund.
2,2-Dimethyl-5-{(p-tolyl)[4-(dimethylamino)phenyl]methyl}-1,3-
dioxane-4,6-dione (3eb)
Supporting Information
Purification by flash column chromatography (EtOAc/hexanes, 1:1);
yellow oil; yield: 85 mg (46%).
1H NMR (acetone-d6, 400 MHz): δ = 7.20–7.18 (m, 2 H), 7.17–7.08 (m,
4 H), 6.68 (d, J = 8.8 Hz, 2 H), 5.18–17 (m, 1 H), 4.86 (d, J = 3.2 Hz, 1 H),
2.92 (s, 6 H), 2.29 (s, 3 H), 1.86 (s, 3 H), 1.57 (s, 3 H).
13C NMR (CDCl3, 125 MHz): δ = 165.3, 165.1, 137.8, 136.7, 130.5,
129.3, 129.1, 113.8, 105.3, 51.6, 48.6, 41.4, 28.5, 27.9, 21.3.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561656.
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References
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Purification by flash column chromatography (EtOAc/hexanes, 1:1);
yellow oil; yield: 42 mg (22%).
1H NMR (CDCl3, 500 MHz): δ = 7.27 (s, 4 H), 7.17 (d, J = 8.8 Hz, 2 H),
6.68 (d, J = 8.8 Hz, 2 H), 5.29 (d, J = 2.4 Hz, 1 H), 4.26 (d, J = 2.4 Hz, 1 H),
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130.4, 129.4, 128.6, 113.3, 105.4, 51.5, 48.0, 41.2, 28.5, 27.8.
HRMS (ESI+): m/z [M + H]+ calcd for C21H23ClNO4: 388.1316; found:
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2,2-Dimethyl-5-{(4-fluorophenyl)[4-(dimethylamino)phe-
nyl]methyl}-1,3-dioxane-4,6-dione (3ed)
Purification by flash column chromatography (EtOAc/hexanes, 1:1);
yellow oil; yield: 28 mg (15%).
1H NMR (CDCl3, 500 MHz): δ = 7.30–7.26 (m, 2 H), 7.16 (d, J = 8.8 Hz, 2
H), 6.95–6.99 (m, 2 H), 6.67 (d, J = 8.8 Hz, 2 H), 5.28 (s, 1 H), 4.25 (d, J =
2.4 Hz, 1 H), 2.93 (s, 6 H), 1.74 (s, 3 H), 1.53 (s, 3 H).
13C NMR (CDCl3, 125 MHz): δ = 164.9, 161.9 (d, J = 245.9 Hz), 131.0,
130.9, 130.4, 115.1 (d, J = 21.5 Hz), 105.4, 51.6, 47.9, 41.7, 28.5, 27.8.
HRMS (ESI+): m/z [M + H]+ calcd for C21H23FNO4: 372.1610; found:
372.1607.
2,2-Dimethyl-5-{(4-nitrophenyl)[4-(dimethylamino)phe-
nyl]methyl}-1,3-dioxane-4,6-dione (3ee)
Purification by flash column chromatography (EtOAc/hexanes, 1:1);
yellow oil; yield: 38 mg (19%).
1H NMR (CDCl3, 400 MHz): δ = 8.14 (d, J = 7.8 Hz, 2 H), 7.47 (d, J = 8.7
Hz, 2 H), 7.17 (d, J = 8.7 Hz, 2 H), 6.72 (d, J = 7.8 Hz, 2 H), 5.38 (d, J = 2.4
Hz, 1 H), 4.32 (d, J = 2.4 Hz, 1 H), 2.96 (s, 6 H), 1.80 (s, 3 H), 1.60 (s, 3
H).
13C NMR (CDCl3, 125 MHz): δ = 164.7, 164.6, 148.8, 146.9, 130.7,
130.1, 123.6, 113.5, 105.7, 51.4, 48.1, 41.2, 28.5, 27.7.
HRMS (ESI+): m/z [M + H]+ calcd for C21H23N2O6: 399.1555; found:
399.1550.
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Acknowledgment
The project was carried-out within the PARENT-BRIDGE programme
of the Foundation for Polish Science (POMOST/2013-8/6), co-financed
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

H
E. Najda et al.
Paper
Synthesis
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H