Annulations of α-Carbamoyl Ketene Dithioacetals with Dicarboxylic Acid Dichlorides: Synthesis of Functionalized Pyrrolidinetriones and Piperidinetriones

Article abstract of DOI:10.1002/ejoc.201301227

An annulation strategy based on ketene dithioacetals is described. Under very mild conditions, a number of pyrrolidinetriones 2 and piperidinetriones 3 have been synthesized by the cycloaddition reaction of α-carbamoyl ketene dithioacetals 1 with di-carboxylic acid dichlorides in good to excellent yields. Further application of this protocol is highlighted by the synthesis of a set of fused pyrimidine derivatives 4/5 from 2/3 and amidines.

Full text of DOI:10.1002/ejoc.201301227

FULL PAPER
DOI: 10.1002/ejoc.201301227
Annulations of α-Carbamoyl Ketene Dithioacetals with Dicarboxylic Acid
Dichlorides: Synthesis of Functionalized Pyrrolidinetriones and
Piperidinetriones
Ying Dong,[a] Yaru Guo,[a] Jun Liu,*[a] Gang Zheng,[a] and Mang Wang*[a]
Keywords: Synthetic methods / Nitrogen heterocycles / Annulation
An annulation strategy based on ketene dithioacetals is de-
scribed. Under very mild conditions, a number of pyrrol-
idinetriones 2 and piperidinetriones 3 have been synthesized
by the cycloaddition reaction of α-carbamoyl ketene di-
thioacetals 1 with di-carboxylic acid dichlorides in good to
excellent yields. Further application of this protocol is high-
lighted by the synthesis of a set of fused pyrimidine deriva-
tives 4/5 from 2/3 and amidines.
idine-2,3,5-triones
2
and piperidine-2,4,6-triones 3.
Introduction
Furthermore, fused pyrimidine derivatives,[10] including 6H-
pyrrolo[3,4-d]pyrimidine-5,7-diones 4 and pyrido[4,3-d]pyr-
imidine-5,7(6H,8H)-diones 5 were prepared through facile
condensation reactions of 2/3 with amidines in high to ex-
cellent yields.
Rapid assembly of acyclic molecules provides an efficient
method for the construction of cyclic compounds. Ketene
dithioacetals are important organic intermediates.[1,2] Al-
though the cyclization strategies based on them, including
[3 + 2],[3] [3 + 1 + 1],[4] [3 + 3],[5] [4 + 2],[6] [5 + 1][7] and [7
+ 1][8] annulation reactions, have been well documented and
become powerful tools for the synthesis of a wide variety
of carbo- and heterocyclic compounds,[1] new types of cycli-
zation processes are still sought after in this field.
Among [3 + n] annulation reactions, ketene dithioacetals
have been extensively used as 3-carbon (C1, C2 and C3)
1,3-bielectrophilic fragments for constructing five- and six-
membered cyclic compounds (Scheme 1, Part 1)[3b–3d,3g,3h,5]
Alternatively, Rao and co-workers described a cyclization
reaction with ketene dithioacetals as 1,3-binucleophilic (C2
and S atom) components (Scheme 1, Part 2).[3f] Recently, α-
cinnamoyl ketene dithioacetals were also reported as 1,3-
binucleophilic reagents (C1 and carbonyl oxygen) in a tan-
dem three-component [3 + 2] cycloaddition reaction under
basic conditions (Scheme 1, Part 3).[9] During our con-
tinuous interest in developing a synthetic strategy based on
ketene dithioacetals,[2] we designed a new [3 + n] cyclization
mode, in which the C2 and N atoms of α-carbamoyl ketene
dithioacetals 1 act as 1,3-binucleophilic centers (Scheme 1,
Part 4). Herein, we report these [3 + 2] and [3 + 3] annu-
lation reactions of α-carbamoyl ketene dithioacetals 1 with
dicarboxylic acid dichlorides leading efficiently to pyrrol-
Scheme 1. [3 + n] Cyclization reaction strategies based on ketene
dithioacetals.
Results and Discussion
We first examined the reaction of 3,3-bis(ethylthio)-N-
phenylacrylamide (1f) with oxalyl dichloride under the
same conditions as the previous report[9] [in tetra-
hydrofuran (THF), at room temperature, Et3N as base;
Table 1, Entry 1]. To our delight, 4-[bis(ethylthio)methyl-
ene]-1-phenylpyrrolidine-2,3,5-trione (2f) was obtained af-
ter 1 h in 98% yield. The structure of 2f was successfully
confirmed by NMR and MS spectroscopy, and further in
a single-crystal X-ray diffraction study (Figure 1).[11] The
annulation reaction rate appears to be temperature depend-
ent and 2f was isolated in 89% yield after 18 h at 0 °C
[a] Department of Chemistry, Northeast Normal University,
Renmin Street No. 5268, Changchun, Jilin, China
E-mail: liuj975@nenu.edu.cn
wangm452@nenu.edu.cn
http://en.nenu.edu.cn/
http://chem.nenu.edu.cn/teacher_show.php?teacher_id=40&
typeid=43
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301227.
Eur. J. Org. Chem. 2014, 797–801
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Y. Dong, Y. Guo, J. Liu, G. Zheng, M. Wang
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(Table 1, Entry 2). Notably, α-carbamoyl ketene dithioacet-
al (1f) proved to be reactive enough to react with oxalyl
dichloride leading to 2f in excellent yield even in the ab-
sence of Et3N under identical conditions (Table 1, Entry 3).
Other solvents proved to be less efficient than THF for the
reaction and no reaction occurred in dimethylformamide
(DMF; Table 1, Entries 4–6).
Table 1. Optimization of the [3 + 2] cyclization reaction of 1f with
oxalyl dichloride.[a]
Entry Base
[equiv.]
Solvent
T
[°C]
Time
[h]
2f Yield
[%][b]
1
2
3
4
5
6
Et3N (2.0) THF
Et3N (2.0) THF
room temp.
0
room temp.
room temp.
room temp.
room temp.
1
18
1
2
9
98
89
97
93
92
–
–
–
–
THF
CH2Cl2
toluene
DMF
10
n.r.
[a] The reactions were carried out with 1f (0.5 mmol) and oxalyl
dichloride (0.6 mmol). [b] Isolated yield.
Figure 1. ORTEP diagram of 2f.
The above process indicates a simple and efficient route
to pyrrolidine-2,3,5-trione derivatives, which are of impor-
tance in biological and pharmaceutical compounds,[12]
starting from readily available acyclic precursors under very
mild conditions. Thus, we set out to explore the scope of α-
carbamoyl ketene dithioacetals 1 through the [3 + 2] cycli-
zation reaction. As shown in Scheme 2, both acyclic and
cyclic ketene dialkylthioacetals tested afforded products 2
in good to excellent yields. α-Carbamoyl ketene dithioacet-
als with N-protecting groups containing either an electron-
donating or electron-withdrawing aryl group successfully
provided pyrrolidine-2,3,5-triones 2a–2d and 2f–2i in good
to excellent yields. In addition, the mild conditions were
also compatible with substrates 1e and 1j with free NH2.
Compounds 2e and 2j were isolated in 98% and 95% yields,
respectively. Next, we selected malonyl dichloride, phthaloyl
Scheme 2. Cyclization of α-carbamoyl ketene dithioacetals 1 with
acid dichlorides. Reaction conditions: 1 (0.5 mmol), dicarboxylic
acid dichloride (0.6 mmol), THF (1 mL), room temperature. Iso-
lated yield. [a] Et3N (1.2 mmol) was used.
798
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Synthesis of Functionalized Pyrrolidinetriones and Piperidinetriones
dichloride and maleoyl dichloride for the annulation reac- and the yield of 4a reached 98% when 2.0 equiv. NaH was
tion. However, complex mixtures were often obtained and used (Table 2, Entry 8).
no desired product was isolated under identical reaction
Table 2. Optimization of the [3 + 3] cyclization reaction of 2a with
conditions. All attempts to optimize the reaction failed.
Next, we turned our investigation to non-enolizable diacid
dichlorides. Pleasingly, 2,2-dimethylmalonyl dichloride
proved to be compatible with this protocol. As described in
Scheme 2, a variety of α-carbamoyl ketene dithioacetals 1
reacted well with 2,2-dimethylmalonyl dichloride to give
corresponding piperidine-2,4,6-triones 3[13] in 88–98%
yields, although longer reaction times were often required.
Pyrrolidine-2,3,5-triones 2 and piperidine-2,4,6-triones 3
possess the structural characters of ketene dithioacetals that
may provide synthetic potential in the construction of fused
heterocycles. In connection with previous reports,[14] we at-
tempted to identify the condensation reactions of 2/3 with
amidines. Initially, we chose pyrrolidinetrione 2a with an
acyclic dithioacetal functional as the model substrate, and
various bases were tested in different solvents at different
temperatures (Table 2). The reaction afforded desired prod-
uct 4a in 37% yield when NaOH was used as base in THF
at room temperature (Table 2, Entry 2). Screening of vari-
ous bases revealed that the yield of 4a could be improved
to 67% yield by using NaH (Table 2, Entry 5). Switching
the solvent from THF to DMF identified DMF as the opti-
mum solvent. Pleasingly, it was found that increasing the
acetamidine hydrochloride.[a]
Entry Base
[equiv.]
Solvent
T
[°C]
4a Yield
[%][b]
1
2
3
4
5
6
7
8
Na2CO3 (1.2)
NaOH (1.2)
tBuOK (1.2)
EtONa (1.2)
NaH (1.2)
NaH (1.2)
NaH (2.0)
THF
THF
THF
THF
THF
DMF
DMF
DMF
room temp.
room temp.
room temp.
room temp.
room temp.
50
n.r.
37
14
40
67
81
82
98
50
90
NaH (2.0)
[a] The reactions were carried out with 2f (0.5 mmol), acetamidine
hydrochloride (0.6 mmol). [b] Isolated yield.
Under the optimized conditions, the reactions between
reaction temperature resulted in an improved yield (Table 2, pyrrolidine-2,3,5-triones 2a/2d and acetamidine hydro-
Entry 6). We settled on 90 °C as the optimal temperature chloride or benzamidine hydrochloride were carried out
Scheme 3. Condensation reactions of 2 and 3 with amidines. Reaction conditions: 2/3 (0.5 mmol), amidine hydrochloride (0.6 mmol), NaH
(1.0 mmol), DMF (1 mL), 90 °C. Isolated yield.
Eur. J. Org. Chem. 2014, 797–801
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Y. Dong, Y. Guo, J. Liu, G. Zheng, M. Wang
FULL PAPER
Scheme 4. Proposed mechanism for the synthesis of 2 and 4 (by using 1a as example).
(134 mg, 0.5 mmol) in anhydrous THF (1 mL), oxalyl dichloride
(0.057 mL, 0.6 mmol) in 1 mL of anhydrous THF was added drop-
wise over 10 min. After the reaction mixture was stirred at room
temperature for 1.5 h, 1a was consumed as indicated by TLC. The
reaction was quenched with iced water (10 mL) and then saturated
NaHCO3 (25 mL) was added before extraction with CH2Cl2 (3ϫ
15 mL). The combined organic extracts were dried with anhydrous
MgSO4, filtered and concentrated under reduced pressure to pro-
vide the crude product, which was purified by flash chromatog-
raphy (silica gel; eluent, petroleum ether/ethyl acetate: 16:1, v/v) to
(Scheme 3). The reaction proceeded smoothly and corre-
sponding 6H-pyrrolo[3,4-d]pyrimidine-5,7-diones 4 were
formed in excellent yields in all cases. Notably, purification
of 4 only required recrystallization in diethyl ether that
demonstrates the simplicity of the annulation strategy.
When piperidinetriones 3a and 3c were tested in the con-
densation reaction with amidines under identical condi-
tions, desired pyrido[4,3-d]pyrimidine-5,7(6H,8H)-diones 5
could be obtained with benzamidine as substrates. Simi-
larly, acetamidine gave pyrimidine-5-carboxamides 6 as the give 2a (156 mg, 97%) as a yellow crystalline solid.
sole products, which resulted from the hydrolyzation of
piperidinetrione and subsequent decarboxylation, in good
to excellent yields (Scheme 3).
4-[Bis(ethylthio)methylene]-1-phenylpyrrolidine-2,3,5-trione
(2a):
157 mg, 97%, Rf = 0.4 (petroleum ether/ethyl acetate, 4:1), yellow
1
crystalline solid, m.p. 149–150 °C. H NMR (500 MHz, CDCl3): δ
On the basis of the above experimental results and our
previous report,[9] we proposed a mechanism for the annu-
lation reaction of 1a with oxalyl dichloride and condensa-
tion reaction of 2a with acetamidine, as depicted in
Scheme 4. It was clear that α-acylation intermediate I was
first formed and then intramolecular cyclization afforded
2a. In the condensation of 2a with acetamidine, intermedi-
ate II was firstly formed through nucleophilic attacked the
ketyl of 2a with acetamidine, followed by an intramolecular
addition-elimination and dehydration reaction to afford 4a.
= 1.39 (t, J = 7.5 Hz, 6 H), 3.30 (q, J = 7.5 Hz, 4 H), 7.40 (q, J =
7.5 Hz, 3 H), 7.48 (t, J = 7.5 Hz, 2 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 13.5 (2 C), 31.7, 34.2, 110.9, 126.0 (2 C), 128.3, 128.8
(2 C), 130.8, 160.5, 165.3, 174.1, 186.3 ppm. HRMS (ESI-TOF):
calcd. for C15H16NO3S2 [M + H+] 322.0566; found 322.0562.
General Procedure for the Preparation of 3: The procedure for the
synthesis of 3 is the same as for 2.
5-[Bis(ethylthio)methylene]-3,3-dimethyl-1-phenylpiperidine-2,4,6-
trione (3a): 163 mg, 90%, Rf = 0.3 (petroleum ether/ethyl acetate,
1
5:1), yellow solid, m.p. 125–126 °C. H NMR (500 MHz, CDCl3):
δ = 1.34 (t, J = 7.5 Hz, 6 H), 1.58 (s, 6 H), 3.07 (q, J = 7.5 Hz, 4
H), 7.14 (d, J = 8.0 Hz, 2 H), 7.41 (d, J = 7.5 Hz, 1 H), 7.47 (t, J
= 7.5, 8.0 Hz, 2 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 13.1
(2 C), 24.3 (2 C), 33.1 (2 C), 52.5, 113.9, 128.4 (2 C), 128.8, 129.1
(2 C), 135.8, 162.6, 174.6, 190.3, 190.4 ppm. HRMS (ESI-TOF):
calcd. for C18H22NO3S2 [M + H+] 364.1036; found 364.1045.
Conclusions
In summary, new annulations of α-carbamoyl ketene di-
thioacetals with dicarboxylic acid dichlorides have been de-
scribed to provide a simple and general method for the syn-
thesis of functionalized pyrrolidinetriones and piper-
idinetriones. The utilization of this annulation strategy is
highlighted by efficient synthesis of 6H-pyrrolo[3,4-d]-
pyrimidine-5,7-diones, and pyrido[4,3-d]pyrimidine-5,7-
(6H,8H)-diones.
General Procedure for the Preparation of 4 (4a as example): To a
well-stirred solution of acetamidine hydrochloride (56.7 mg,
0.6 mmol) in anhydrous DMF (1 mL), sodium hydride (24 mg,
1.0 mmol) was added. After stirring at room temperature for 5 min,
4-[bis(ethylthio)methylene]-1-phenylpyrrolidine-2,3,5-trione
2a
(160 mg, 0.5 mmol) was added. Then, the reaction mixture was
stirred at 90 °C for 1.5 h. After 2a was consumed as indicated by
TLC, the reaction mixture was quenched with iced water (50 mL)
whilst stirring and the precipitate was collected by filtration,
washed with water (3ϫ 50 mL) and recrystallized from diethyl
ether to give 4-(ethylthio)-2-methyl-6-phenyl-6H-pyrrolo[3,4-d]pyr-
imidine-5,7-dione (4a, 147 mg, 98%) as a white crystalline solid.
Experimental Section
General Procedure for the Preparation of 2 (2a as example): To a
well-stirred solution of 3,3-bis(ethylthio)-N-phenylacrylamide 1a
800
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Eur. J. Org. Chem. 2014, 797–801

Synthesis of Functionalized Pyrrolidinetriones and Piperidinetriones
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4-(Ethylthio)-2-methyl-6-phenyl-6H-pyrrolo[3,4-d]pyrimidine-5,7-di-
one (4a): 147 mg, 98%, Rf = 0.3 (petroleum ether/ethyl acetate, 2:1),
white crystalline solid, m.p. 161–162 °C. 1H NMR (500 MHz,
CDCl3): δ = 1.45 (t, J = 7.0 Hz, 3 H), 2.89 (s, 3 H), 3.38 (q, J =
7.0 Hz, 2 H), 7.40–7.43 (m, 3 H), 7.49–7.52 (m, 2 H) ppm. 13C
NMR (125 MHz, CDCl3): δ = 14.0, 23.6, 26.8, 116.8, 126.4 (2 C),
128.5, 129.2 (2 C), 130.8, 158.2, 164.5, 164.8, 168.9, 173.6 ppm.
HRMS (ESI-TOF): calcd. for C15H14N3O2S [M + H+] 300.0801;
found 300.0810.
General Procedure for the Preparation of 5 and 6: The procedure
for the synthesis of 5 and 6 is the same as for 4.
[4]
[5]
4-(Ethylthio)-8,8-dimethyl-2,6-diphenylpyrido[4,3-d]pyrimidine-5,7-
(6H,8H)-dione (5a): 163 mg, 81%, Rf = 0.3 (petroleum ether/ethyl
acetate, 3:2), white crystalline solid, m.p. 207–208 °C. 1H NMR
(500 MHz, CDCl3): δ = 1.47 (t, J = 7.0 Hz, 3 H), 1.84 (s, 6 H),
3.36 (q, J = 7.0 Hz, 2 H), 7.21 (d, J = 7.0 Hz, 2 H), 7.44 (t, J =
7.0 Hz, 1 H), 7.49–7.59 (m, 5 H), 8.59–8.61 (m, 2 H) ppm. 13C
NMR (125 MHz, CDCl3): δ = 13.5, 24.9, 27.3 (2 C), 46.9, 112.1,
128.5 (2 C), 128.69 (2 C), 128.7, 129.2 (2 C), 129.3 (2 C), 132.1,
134.6, 136.6, 163.1, 163.9, 171.1, 174.6, 175.6 ppm. HRMS (ESI-
TOF): calcd. for C23H22N3O2S [M + H+] 404.1427; found
404.1435.
[6]
[7]
4-(Ethylthio)-6-isopropyl-2-methyl-N-phenylpyrimidine-5-carbox-
amide (6a): 153 mg, 97%, Rf = 0.4 (petroleum ether/ethyl acetate,
4:1), white solid, m.p. 130–131 °C. 1H NMR (500 MHz, CDCl3): δ
= 1.27 (d, J = 6.5 Hz, 6 H), 1.35 (t, J = 7.0 Hz, 3 H), 2.65 (s, 3 H),
3.12–3.17 (m, 1 H), 3.22 (q, J = 7.0 Hz, 2 H), 7.19 (t, J = 7.0,
8.0 Hz, 1 H), 7.38 (t, J = 8.0 Hz, 2 H), 7.51 (s, 1 H), 7.61 (d, J =
7.0 Hz, 2 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 14.26, 21.82
(2 C), 24.09, 26.23, 32.89, 120.11 (2 C), 124.10, 125.09, 129.14 (2
C), 137.29, 164.43, 166.13, 167.34, 170.02 ppm. HRMS (ESI-TOF):
calcd. for C17H22N3OS [M + H+] 316.1478; found 316.1470.
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Acknowledgments
[11] Crystallographic data for 2f is available as Supporting Infor-
mation or as CCDC-947174. These data can be obtained free
of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
The authors acknowledge the National Nature Science Foundation
of China (NSFC) (grant number NNSFC21172031/21202017),
New Century Excellent Talents in Chinese University (grant
number NCET-11-0613) and the Research Fund for the Doctoral
Program of Higher Education of China (20120043110004) for
funding support of this research.
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Received: August 15, 2013
Published Online: November 28, 2013
Eur. J. Org. Chem. 2014, 797–801
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