Synthesis of the substituted 3-cyclobutene-1,2-diones

Article abstract of DOI:10.1080/00397910701462716

A convenient synthesis of the novel squaric acid derivatives is reported. Unsymmetrically substituted 3,4-diamino-3-cyclobutene-1,2-diones and 3-amino-4-hydroxy-3-cyclobutene-1,2-diones were prepared by interaction of diethyl squarate with different nucle

Full text of DOI:10.1080/00397910701462716

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Synthesis of the Substituted
3‐Cyclobutene‐1,2‐diones
Sergey A. Ivanovsky a , Mikhail V. Dorogov a , Dmitry V. Kravchenko b
Alexandre V. Ivachtchenko c
&
a The Ushinsky Yaroslavl State Pedagogical University, Yaroslavl, Russia
b Chemical Diversity Research Institute, Moscow Reg., Russia
c ChemDiv, Inc., San Diego, CA, USA
Published online: 09 Aug 2007.
To cite this article: Sergey A. Ivanovsky , Mikhail V. Dorogov , Dmitry V. Kravchenko & Alexandre V.
Ivachtchenko (2007) Synthesis of the Substituted 3‐Cyclobutene‐1,2‐diones, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 37:15, 2527-2542, DOI:
10.1080/00397910701462716
To link to this article: http://dx.doi.org/10.1080/00397910701462716
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Synthetic Communicationsw, 37: 2527–2542, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701462716
Synthesis of the Substituted 3-Cyclobutene-
1,2-diones
Sergey A. Ivanovsky and Mikhail V. Dorogov
The Ushinsky Yaroslavl State Pedagogical University, Yaroslavl, Russia
Dmitry V. Kravchenko
Chemical Diversity Research Institute, Moscow Reg., Russia
Alexandre V. Ivachtchenko
ChemDiv, Inc., San Diego, CA, USA
Abstract: A convenient synthesis of the novel squaric acid derivatives is reported.
Unsymmetrically substituted 3,4-diamino-3-cyclobutene-1,2-diones and 3-amino-4-
hydroxy-3-cyclobutene-1,2-diones were prepared by interaction of diethyl squarate
with different nucleophilic reagents such as alkali, primary and secondary amines
and amino acids. Substituted 3-amino-4-aryl-3-cyclobutene-1,2-diones were synthe-
sized by interaction of squaryl dichloride with different arenes followed by arylsquar-
ylation of amines. Efficient procedures were developed for consequent substitution of
ethoxy groups in diethyl squarate and chlorine atoms in squaryl dichloride. The syn-
thesized compounds have a great potential of bioactivity and are useful objects for bio-
medicinal screening.
Keywords: Friedel-Crafts alkylation, squarates, squaric acid, squarylation
INTRODUCTION
The 3-cyclobutene-1,2-dione structural motif can be found in a large number
of pharmaceutical agents with a diverse range of biological properties. The
majority of bioactive 3-cyclobutene-1,2-diones are substituted 3,4-diamino
Received in Poland, August 4, 2006
Address correspondence to Alexandre V. Ivachtchenko, ChemDiv, Inc., 11558
Sorrento Valley Rd., Suite 5, San Diego, CA 92121, USA. E-mail: av@chemdiv.com
2527

2528
S. A. Ivanovsky et al.
derivatives. They are documented as inhibitors of transactivation responsive
RNA of HIV-1,[1] antagonists of VLA-4 integrin[2] and histamine H2,[3,4]
K(ATP) channel activators[5] and NMDA antagonists.[6] Some squaric acid
peptide conjugates were reported as inhibitors of matrix metalloprotease-1.[7]
Ability of some 3-cyclobutene-1,2-diones to give colored complexes
with transition metal cations causes their use as dyes[8] and chemosensors
for iron (III).[9]
A number of 3-aryl-3-cyclobutene-1,2-diones were
described in literature as inhibitors of protein tyrosine phosphatases.[10] The
3-cyclobutene-1,2-dione fragment (“squaryl”) containing substituted amino
groups can be considered as a bioisostere of various fragments in amino
acids.[1,2] Combination of squaryl and amino acid fragments can be very
useful approach in the design of novel bioactive compounds.
In this article, we describe the results of our systematic studies in the area of
synthesis and characterization of amino- and aryl-substituted 3-cyclobutene-
1,2-diones.
As a part of our studies of chemistry of substituted 3-cyclobutene-1,2-
diones, we explored two different approaches to the synthesis of the novel
3-cyclobutene-1,2-diones. The first approach features generation of diethyl
squarate (2) from squaric acid (1) (Scheme 1) followed by interaction of the
resulting diethyl squarate with different nucleophilic reagents (Schemes 2, 3).
This approach leads to unsymmetrical 3,4-diamino derivatives.
Diethyl squarate (2) was obtained by interaction of squaric acid (1) with
triethyl orthoformate in a solution of boiling ethanol in 80% yield and served
as a precursor for the synthesis of amino derivatives. Substitution of the first
ethoxy group with amines (3a–c) proceeded in parallel in ethanol solution at
room temperature for 24 h or with amino acid ethyl esters (6a–d) at the same
reaction conditions. The resulting compounds (4a–c) were transformed into
3-substituted squaric acids (5a–c) by alkaline hydrolysis of the remaining
ethoxy group. The hydrolysis proceeded in a water solution of NaOH
at 908C. The resulting solutions of the corresponding sodium salts were
neutralized with hydrochloric acid to afford the desired acids (5a–c).
Ethyl ethers (7a–d) were used as precursors for the synthesis of the
substituted squaryl diamines (9a–h) by interaction with amines (8a,b) in
parallel. This interaction proceeds smoothly in alcohol solution in the presence
of triethylamine (TEA) at room temperature. At higher temperature, the yields
of the desired 3,4-diamino derivatives were decreased because of side reactions.
Scheme 1. Synthesis of 3,4-diethoxy-3-cyclobutene-1,2-dione.

Substituted 3-Cyclobutene-1,2-diones
2529
Scheme 2. Substitution of ethoxy groups in 3,4-diethoxy-3-cyclobutene-1,2-dione
with amines (a—ethanol, 208C, 24 h; b—water, NaOH, 1008C, 15 min; c—TEA,
ethanol, 208C, 24 h).
Scheme 3. Substitution of ethoxy group with amino acids (a—ethanol, 208C, 24 h;
b—TEA, ethanol, reflux, 24 h; c—dry DMF, reflux, 3 h).

2530
S. A. Ivanovsky et al.
Reaction of diethyl squarate (2) with pyrrolidine proceeded at the same
reaction conditions as with primary amines (3a–c) and afforded compound
(10). We explored its interaction with zwitterionic amino acids (11a–c) and
developed an efficient procedure for preparation of the corresponding car-
boxylic acids (12a–c). The desired reaction products were obtained in good
yields by reaction of 10 with amino acids (11a–c) in refluxing ethanol
solution in the presence of TEA as a deprotonating agent for 24 h. The
resulting acids (12a–c) were used as precursors for the synthesis of amides
(14a–f) in parallel.
A second synthetic approach features transformation of squaric acid (1) to
the corresponding dichloride, 3,4-dichloro-3-cyclobutene-1,2-dione (15), by
treatment of squaric acid (1) with thionyl chloride under reflux for 2 h
(Scheme 4). The resulting dichloro derivative (15) was used for squarylation
of arenes (16a–g) in the presence of AlCl3 in chloroform solution. The
resulting chlorides (17a–g) were treated with amines (18a,b) in parallel to
obtain the substituted 3-amino-4-aryl-3-cyclobutene-1,2-diones (19a–n),
which are novel and useful objects for biomedicinal screening.
All the squaric acid derivatives within these series were characterized by
1
1H NMR and LC MS analysis. The H NMR spectra were clean, and mass
Scheme 4. Squarylation of arenes (a—reflux, 2 h; b—AlCl3, chloroform, 10–208C,
3 h; c—ethanol, 208C, 24 h).

Substituted 3-Cyclobutene-1,2-diones
2531
spectral data obtained on an liquid chromatography/mass spectrometry
(LC/MS) instrument were also satisfactory. The suggested direction of the
1
squarylation was confirmed by H NMR spectral data.
EXPERIMENTAL
Melting points were measured with a Buchi B-520 melting-point apparatus
1
and are not corrected. H NMR spectra were recorded on Bruker DRX-500
spectroscope in DMSO-d6 using TMS as an internal standard. LC MS
spectra were recorded with PE SCIEX API 150EX liquid chromatograph
equipped with a UV detector (lmax 215 and 254 nm) and using a C18
column (100 ꢀ 4 mm). Elution started with water, ended with acetonitrile/
water (95:5, v/v) and used a linear gradient at a flow rate of 0.15 mL/min
and an analysis cycle time of 25 min.
3,4-Diethoxy-3-cyclobutene-1,2-dione (2) was obtained using the
procedure introduced by Liu et al.[11]
General Procedure for Synthesis of 3-Amino-4-ethoxy-3-cyclobutene-
1,2-diones (4a–c, 10)
A solution of 2 mmol of corresponding amine (3a–c) or pyrrolidine and
0.34 g (2 mmol) of diethyl squarate (2) in ethanol (5 mL) was stirred at
room temperature for 24 h and then evaporated to dryness. The residue was
treated with water; the white precipitate was collected by filtration, washed
with diethyl ether, and dried to afford pure reaction product (4a–c, 10).
3-Ethoxy-4-(3-methoxy-phenylamino)-3-cyclobutene-1,2-dione (4a)
This compound was obtained in 85% yield, mp 227–2298C (2-propanol). LC
MS m/z 247 (M þ 1); 1H NMR (500 MHz, DMSO-d6): 1.50 (t, 3H,
J ¼ 7.4 Hz, CH3), 3.78 (s, 3H, OCH3), 4.83 (q, 2H, J ¼ 7.4 Hz, OCH2),
6.55 (d, 1H, J ¼ 8.1 Hz, ArH), 6.92–6.99 (m, 2H, ArH), 7.15 (dd, 1H,
J1 ¼ 8.1 Hz, J2 ¼ 8.3 Hz, ArH), 10.57 (s, 1H, NH).
3-(Cyclopentylamino)-4-ethoxy-3-cyclobutene-1,2-dione (4b)
This compound was obtained in 78% yield, mp 90–928C (2-propanol). LC
MS m/z 209 (M þ 1); 1H NMR (500 MHz, DMSO-d6): 1.41 (t, 3H,
J ¼ 7.4 Hz, CH3), 1.72–1.78 (m, 8H, 4CH2), 3.92–4.02 (m, 1H, NCH),
4.65 (q, 2H, J ¼ 7.4 Hz, OCH2), 8.64 (d, 1H, J ¼ 5.3 Hz, NH).

2532
S. A. Ivanovsky et al.
3-Ethoxy-4-(4-ethyl-phenylamino)-3-cyclobutene-1,2-dione (4c)
This compound was obtained in 92% yield, mp 192–1958C (2-propanol).
1
LC MS m/z 245 (M þ 1); H NMR (500 MHz, DMSO-d6): 1.21 (t, 3H,
J ¼ 7.8 Hz, CH3), 1.48 (t, 3H, J ¼ 7.4 Hz, CH3), 2.52 (q, 2H, J ¼ 7.8 Hz,
ArCH2), 4.80 (q, 2H, J ¼ 7.4 Hz, OCH2), 7.05 (d, 2H, J ¼ 7.3 Hz, ArH),
7.22 (d, 2H, J ¼ 7.3 Hz, ArH), 10.54 (s, 1H, NH).
3-Ethoxy-4-pyrrolidino-3-cyclobutene-1,2-dione (10)
This compound was obtained in 82% yield, mp 175–1788C (2-propanol).
1
LC MS m/z 195 (M þ 1); H NMR (500 MHz, DMSO-d6): 1.46 (t, 3H,
J ¼ 7.4 Hz, CH3), 1.95–1.99 (m, 4H, 2CH2), 3.60–3.67 (m, 2H, NCH2),
3.72–7.77 (m, 2H, NCH2), 4.70 (q, 2H, J ¼ 7.4 Hz, OCH2).
General Procedure for Synthesis of 3-Amino-4-hydroxy-3-
cyclobutene-1,2-diones (5a–c)
Compound (4a–c) (1 mmol) was suspended in a solution of NaOH
(2.5 mmol) and ethanol (2 mL) in water (10 mL). The mixture was stirred at
908C until the solid was completely dissolved. The resulting solution was
cooled down to room temperature and acidified with 5% hydrochloric acid.
The formed precipitate was collected by filtration, washed with water,
dried, and crystallized from 1,4-dioxane to afford the pure reaction product
(5a–c).
3-Hydroxy-4-(3-methoxy-phenylamino)-3-cyclobutene-1,2-dione (5a)
This compound was obtained in 75% yield, mp 275–2778C (2-propanol). LC
1
MS m/z 219 (M þ 1); H NMR (500 MHz, DMSO-d6): 3.78 (s, 3H, OCH3),
6.55 (d, 1H, J ¼ 8.1 Hz, ArH), 6.92–6.99 (m, 2H, ArH), 7.15 (dd, 1H,
J1 ¼ 8.1 Hz, J2 ¼ 8.3 Hz, ArH), 10.57 (s, 1H, NH); OH is in exchange.
3-(Cyclopentylamino)-4-hydroxy-3-cyclobutene-1,2-dione (5b)
This compound was obtained in 79% yield, mp 180–1838C (2-propanol). LC
1
MS m/z 181 (M þ 1); H NMR (500 MHz, DMSO-d6): 1.72–1.78 (m, 8H,
4CH2), 3.92–4.02 (m, 1H, NCH), 8.64 (d, 1H, J ¼ 5.3 Hz, NH); OH is in
exchange.
3-(4-Ethyl-phenylamino)-4-hydroxy-3-cyclobutene-1,2-dione (5c)
This compound was obtained in 88% yield, mp 255–2578C (2-propanol). LC
MS m/z 217 (M þ 1); 1H NMR (500 MHz, DMSO-d6): 1.48 (t, 3H,

Substituted 3-Cyclobutene-1,2-diones
2533
J ¼ 7.4 Hz, CH3), 2.52 (q, 2H, J ¼ 7.8 Hz, ArCH2), 7.05 (d, 2H, J ¼ 7.3 Hz,
ArH), 7.22 (d, 2H, J ¼ 7.3 Hz, ArH), 10.54 (s, 1H, NH); OH is in exchange.
General Procedure for Synthesis of 4-Ethoxy-3-cyclobutene-1,2-
dione-3-amino Acids Ethyl Ethers (7a–d)
A solution of 2 mmol of corresponding amino acid ethyl ether (6a–d) and
0.34 g (2 mmol) of diethyl squarate (2) in ethanol (5 mL) was stirred at
room temperature for 24 h and then evaporated to dryness. The residue was
treated with water; the white precipitate was collected by filtration, washed
with diethyl ether, and dried to afford the pure reaction product (7a–d).
Ethyl 1-(2-Ethoxy-3,4-dioxo-cyclobut-1-enyl)-piperidine-4-carboxylate (7a)
This compound was obtained in 71% yield, mp 98–1008C (2-propanol).
1
LC MS m/z 281 (M þ 1); H NMR (500 MHz, DMSO-d6): 1.23 (t, 3H,
J ¼ 7.4 Hz, CH3), 1.49 (t, 3H, J ¼ 6.8 Hz, CH3), 1.71–1.78 (m, 4H, 2CH2),
3.55–3.61 (m, 2H, NCH2), 3.69–3.71 (m, 1H, CH) 3.82–3.88 (m, 2H,
NCH2), 4.04 (q, 2H, J ¼ 6.8 Hz, OCH2), 4.73 (q, 2H, J ¼ 7.4 Hz, OCH2).
Ethyl 1-(2-Ethoxy-3,4-dioxo-cyclobut-1-enyl)-piperidine-3-carboxylate (7b)
This compound was obtained in 69% yield, mp 94–978C (2-propanol).
1
LC MS m/z 281 (M þ 1); H NMR (500 MHz, DMSO-d6): 1.23 (t, 3H,
J ¼ 7.4 Hz, CH3), 1.48 (t, 3H, J ¼ 6.8 Hz, CH3), 1.67–1.72 (m, 4H, 2CH2),
3.55–3.61 (m, 2H, NCH2), 3.65–3.69 (m, 1H, CH) 3.85–3.89 (m, 2H,
NCH2), 4.05 (q, 2H, J ¼ 6.8 Hz, OCH2), 4.73 (q, 2H, J ¼ 7.4 Hz, OCH2).
Ethyl 4-[(2-Ethoxy-3,4-dioxo-1-cyclobutenyl)amino]-piperidine-1-
carboxylate (7c)
This compound was obtained in 69% yield, mp 102–1048C (2-propanol). LC
MS m/z 296 (M þ 1); 1H NMR (500 MHz, DMSO-d6): 1.25 (t, 3H,
J ¼ 7.4 Hz, CH3), 1.47 (t, 3H, J ¼ 6.8 Hz, CH3), 1.55–1.59 (m, 2H, CH2),
1.84–1.89 (m, 2H, CH2), 2.95–3.02 (m, 2H, CH2), 3.59–3.62 (m, 1H,
NCH), 4.02–4.11 (m, 2H, CH2), 4.06 (q, 2H, J ¼ 6.8 Hz, OCH2), 4.71
(q, 2H, J ¼ 7.4 Hz, OCH2), 8.82 (d, 1H, J ¼ 7.5 Hz, NH).
Ethyl 4-(2-Ethoxy-3,4-dioxo-1-cyclobutenyl)-piperazine-1-
carboxylate (7d)
This compound was obtained in 73% yield, mp 119–1228C (2-propanol).
1
LC MS m/z 282 (M þ 1); H NMR (500 MHz, DMSO-d6): 1.26 (t, 3H,
J ¼ 7.2 Hz, CH3), 1.45 (t, 3H, J ¼ 6.8 Hz, CH3), 3.52–3.59 (m, 6H, 3CH2),

2534
S. A. Ivanovsky et al.
3.79–3.84 (m, 2H, CH2), 4.08 (q, 2H, J ¼ 6.8 Hz, OCH2), 4.72 (q, 2H,
J ¼ 7.2 Hz, OCH2).
General Procedure for Synthesis of 3-Amino-3-cyclobutene-1,2-
dione-4-amino Acids Ethyl Ethers (9a–h)
Corresponding amine (8a,b) (1 mmol) was added to a solution of 1 mmol of
compound (7a–d) and 0.17 mL (1.2 mmol) of TEA in 10 mL of ethanol.
The mixture was stirred at room temperature for 24 h. The formed precipitate
was collected by filtration, dried, and crystallized from a mixture of ethanol
and hexane to afford the pure reaction product (9a–h).
Ethyl 1-(3,4-Dioxo-2-phenylamino-cyclobut-1-enyl)-piperidine-4-
carboxylate (9a)
This compound was obtained in 81% yield, mp 205–2078C (2-propanol).
1
LC MS m/z 328 (M þ 1); H NMR (500 MHz, DMSO-d6): 1.48 (t, 3H,
J ¼ 6.8 Hz, CH3), 1.71–1.78 (m, 4H, 2CH2), 3.55–3.61 (m, 2H, NCH2),
3.69–3.71 (m, 1H, CH), 3.82–3.88 (m, 2H, NCH2), 4.05 (q, 2H,
J ¼ 6.8 Hz, OCH2), 7.51–7.57 (m, 5H, Ph), 10.11 (s, 1H, NH).
Ethyl 1-(2-Dimethylamino-3,4-dioxo-cyclobut-1-enyl)-piperidine-4-
carboxylate (9b)
This compound was obtained in 78% yield, mp 198–2008C (2-propanol).
LC MS m/z 280 (M þ 1); 1H NMR (500 MHz, DMSO-d6): 1.49 (t, 3H,
J ¼ 6.8 Hz, CH3), 1.71–1.78 (m, 4H, 2CH2), 3.52 (s, 6H, 2NCH3), 3.55–3.61
(m, 2H, NCH2), 3.69–3.71 (m, 1H, CH) 3.82–3.88 (m, 2H, NCH2),
4.05 (q, 2H, J ¼ 6.8 Hz, OCH2).
Ethyl 1-(3,4-Dioxo-2-phenylamino-cyclobut-1-enyl)-piperidine-3-
carboxylate (9c)
This compound was obtained in 79% yield, mp 195–1978C (2-propanol).
1
LC MS m/z 328 (M þ 1); H NMR (500 MHz, DMSO-d6): 1.48 (t, 3H,
J ¼ 6.8 Hz, CH3), 1.67–1.72 (m, 4H, 2CH2), 3.55–3.61 (m, 2H, NCH2),
3.65–3.69 (m, 1H, CH), 3.85–3.89 (m, 2H, NCH2), 4.05 (q, 2H,
J ¼ 6.8 Hz, OCH2), 7.51–7.57 (m, 5H, Ph), 10.12 (s, 1H, NH).
Ethyl 1-(2-Dimethylamino-3,4-dioxo-cyclobut-1-enyl)-piperidine-4-
carboxylate (9d)
This compound was obtained in 75% yield, mp 164–1668C (2-propanol). LC
MS m/z 280 (M þ 1); 1H NMR (500 MHz, DMSO-d6): 1.47 (t, 3H,

Substituted 3-Cyclobutene-1,2-diones
2535
J ¼ 6.8 Hz, CH3), 1.67–1.72 (m, 4H, 2CH2), 3.54 (s, 6H, 2NCH3), 3.55–3.61
(m, 2H, NCH2), 3.65–3.69 (m, 1H, CH) 3.85–3.89 (m, 2H, NCH2),
4.08 (q, 2H, J ¼ 6.8 Hz, OCH2).
Ethyl 4-(3,4-Dioxo-2-phenylamino-cyclobut-1-enylamino)-piperidine-
1-carboxylate (9e)
This compound was obtained in 84% yield, mp 237–2398C (2-propanol). LC
MS m/z 343 (M þ 1); 1H NMR (500 MHz, DMSO-d6): 1.46 (t, 3H,
J ¼ 6.8 Hz, CH3), 1.55–1.59 (m, 2H, CH2), 1.84–1.89 (m, 2H, CH2),
2.95–3.02 (m, 2H, CH2), 3.59–3.62 (m, 1H, NCH), 4.02–4.11 (m, 2H,
CH2), 4.09 (q, 2H, J ¼ 6.8 Hz, OCH2), 7.51–7.57 (m, 5H, Ph), 8.82 (d, 1H,
J ¼ 7.5 Hz, NH), 10.21 (s, 1H, NH).
Ethyl 4-(2-Dimethylamino-3,4-dioxo-cyclobut-1-enylamino)-
piperidine-1-carboxylate (9f)
This compound was obtained in 77% yield, mp 221–2248C (2-propanol). LC MS
1
m/z 295 (M þ 1); H NMR (500 MHz, DMSO-d6): 1.47 (t, 3H, J ¼ 6.8 Hz,
CH3), 1.55–1.59 (m, 2H, CH2), 1.84–1.89 (m, 2H, CH2), 2.95–3.02 (m, 2H,
CH2), 3.53 (s, 6H, 2NCH3), 3.59–3.62 (m, 1H, NCH), 4.02–4.11 (m, 2H,
CH2), 4.06 (q, 2H, J ¼ 6.8 Hz, OCH2), 8.82 (d, 1H, J ¼ 7.5 Hz, NH).
Ethyl 4-(3,4-Dioxo-2-phenylamino-cyclobut-1-enyl)-piperazine-1-
carboxylate (9g)
This compound was obtained in 87% yield, mp 287–2898C (2-propanol). LC
MS m/z 329 (M þ 1); 1H NMR (500 MHz, DMSO-d6): 1.47 (t, 3H,
J ¼ 6.8 Hz, CH3), 3.52–3.59 (m, 6H, 3CH2), 3.79–3.84 (m, 2H, CH2), 4.08
(q, 2H, J ¼ 6.8 Hz, OCH2), 7.51–7.57 (m, 5H, Ph), 10.12 (s, 1H, NH).
Ethyl 4-(2-Dimethylamino-3,4-dioxo-cyclobut-1-enyl)-piperazine-1-
carboxylate (9h)
This compound was obtained in 81% yield, mp 263–2678C (2-propanol). LC
MS m/z 281 (M þ 1); 1H NMR (500 MHz, DMSO-d6): 1.47 (t, 3H,
J ¼ 6.8 Hz, CH3), 3.50 (s, 6H, 2NCH3), 3.52–3.59 (m, 6H, 3CH2),
3.79–3.84 (m, 2H, CH2), 4.08 (q, 2H, J ¼ 6.8 Hz, OCH2).
General Procedure for Synthesis of 3-Amino-3-cyclobutene-1,2-
dione-4-amino Acids (12a–c)
Amino acid (11a–c) (0.11 mol) was added to a solution of compound (10)
(0.1 mol) and 17 mL (0.12 mol) of TEA in 100 mL of ethanol. The reaction

2536
S. A. Ivanovsky et al.
mixture was refluxed for 24 h and then evaporated to dryness. The residue was
treated with diethyl ether. The formed precipitate was collected by filtration
and dried to afford pure reaction product (12a–c).
4-(f[3,4-Dioxo-2-(1-pyrrolidinyl)-1-cyclobutenyl]aminogmethyl)-1-
cyclohexanecarboxylic Acid (12a)
This compound was obtained in 81% yield, mp 278–2828C (2-propanol).
LC MS m/z 306 (M þ 1); 1H NMR (500 MHz, DMSO-d6): 0.95–1.11 (m, 2H,
CH2), 1.32–1.42 (m, 2H, CH2), 1.87–1.93 (m, 8H, 4CH2), 2.06–2.12
(m, 1H, CH), 3.38–3.43 (m, 2H, NCH2), 3.69–3.74 (m, 4H, 2NCH2), 7.35
(t, 1H, J ¼ 5.1 Hz, NH), 11.62 (s, 1H, COOH).
4-[(2-Pyrrolidino-3,4-dioxo-1-cyclobutenyl)amino]methylbenzoic Acid (12b)
This compound was obtained in 64% yield, mp 232–2348C (2-propanol).
LC MS m/z 302 (M þ 1); 1H NMR (500 MHz, DMSO-d6): 1.65–1.71
(m, 4H, 2CH2), 4.08–4.13 (m, 4H, 2CH2), 4.84 (d, 2H, J ¼ 6.2 Hz, NCH2),
7.40 (d, 2H, J ¼ 7.3 Hz, ArH), 7.92 (d, 2H, J ¼ 7.3 Hz, ArH), 7.95 (t, 1H,
J ¼ 6.2 Hz, NH); OH is in exchange.
3-(3,4-Dioxo-2-pyrrolidin-1-yl-cyclobut-1-enylamino)-propionic Acid (12c)
This compound was obtained in 71% yield, mp 212–2158C (2-propanol).
LC MS m/z 238 (M þ 1); 1H NMR (500 MHz, DMSO-d6): 1.60–1.70
(m, 4H, 2CH2), 4.02 (t, 2H, J ¼ 5.3 Hz, CH2), 4.06–4.11 (m, 4H, 2CH2),
4.15 (m, 2H, NCH2), 7.35 (t, 1H, J ¼ 5.0 Hz, NH); OH is in exchange.
General Procedure for Synthesis of 3-Amino-3-cyclobutene-1,2-
dione-4-amino Acids Amides (14a–f)
Acid (12a–c) (1 mmol) was added to a solution of CDI (1 mmol) in dry DMF
(5 mL). The mixture was stirred at 808C for 1 h. Then corresponding amine
(13a,b) (1 mmol) was added to the reaction mixture. The solution was
refluxed for 2 h, cooled down to room temperature, and poured into water.
The formed precipitate was collected by filtration, washed with water,
dried, and purified by crystallization from a mixture of ethanol and DMF to
afford pure reaction product (14a–f).
4-[(3,4-Dioxo-2-pyrrolidin-1-yl-cyclobut-1-enylamino)-methyl]-
cyclohexanecarboxylic acid tert-butylamide (14a)
This compound was obtained in 45% yield, mp 245–2478C (2-propanol).
LC MS m/z 361 (M þ 1); 1H NMR (500 MHz, DMSO-d6): 0.95–1.11

Substituted 3-Cyclobutene-1,2-diones
2537
(m, 2H, CH2), 1.32–1.42 (m, 2H, CH2), 1.78 (s, 9H, 3CH3), 1.87–1.93
(m, 8H, 4CH2), 2.06–2.12 (m, 1H, CH), 3.38–3.43 (m, 2H, NCH2), 3.69–
3.74 (m, 4H, 2NCH2), 7.35 (t, 1H, J ¼ 5.1 Hz, NH), 8.11 (s, 1H, NH).
4-[(3,4-Dioxo-2-pyrrolidin-1-yl-cyclobut-1-enylamino)-methyl]-
cyclohexanecarboxylic Acid Benzylamide (14b)
This compound was obtained in 53% yield, mp 259–2618C (2-propanol).
LC MS m/z 395 (M þ 1); 1H NMR (500 MHz, DMSO-d6): 0.95–1.11
(m, 2H, CH2), 1.32–1.42 (m, 2H, CH2), 1.87–1.93 (m, 8H, 4CH2), 2.06–
2.12 (m, 1H, CH), 3.38–3.43 (m, 2H, NCH2), 3.69–3.74 (m, 4H, 2NCH2),
4.83 (d, 2H, J ¼ 6.1 Hz, NCH2), 7.35 (t, 1H, J ¼ 5.1 Hz, NH), 7.50–7.54
(m, 5H, Ph), 7.97 (t, 1H, J ¼ 6.1 Hz, NH).
N-tert-Butyl-4-[(3,4-dioxo-2-pyrrolidin-1-yl-cyclobut-1-enylamino)-
methyl]-benzamide (14c)
This compound was obtained in 62% yield, mp 221–2238C (2-propanol).
LC MS m/z 355 (M þ 1); 1H NMR (500 MHz, DMSO-d6): 1.65–1.71
(m, 4H, 2CH2), 1.78 (s, 9H, 3CH3), 4.08–4.13 (m, 4H, 2CH2), 4.84 (d, 2H,
J ¼ 6.2 Hz, NCH2), 7.40 (d, 2H, J ¼ 7.3 Hz, ArH), 7.92 (d, 2H, J ¼ 7.3 Hz,
ArH), 7.95 (t, 1H, J ¼ 6.2 Hz, NH), 8.13 (s, 1H, NH).
N-Benzyl-4-[(3,4-dioxo-2-pyrrolidin-1-yl-cyclobut-1-enylamino)-methyl]-
benzamide (14d)
This compound was obtained in 67% yield, mp 234–2378C (2-propanol).
LC MS m/z 389 (M þ 1); 1H NMR (500 MHz, DMSO-d6): 1.65–1.71
(m, 4H, 2CH2), 4.08–4.13 (m, 4H, 2CH2), 4.81 (d, 2H, J ¼ 6.1 Hz, NCH2),
4.84 (d, 2H, J ¼ 6.2 Hz, NCH2), 7.40 (d, 2H, J ¼ 7.3 Hz, ArH), 7.50–7.54
(m, 5H, Ph), 7.92 (d, 2H, J ¼ 7.3 Hz, ArH), 7.95 (t, 1H, J ¼ 6.2 Hz, NH),
7.97 (t, 1H, J ¼ 6.1 Hz, NH).
N-tert-Butyl-3-(3,4-dioxo-2-pyrrolidin-1-yl-cyclobut-1-enylamino)-
propionamide (14e)
This compound was obtained in 53% yield, mp 211–2138C (2-propanol).
LC MS m/z 293 (M þ 1); 1H NMR (500 MHz, DMSO-d6): 1.65–1.71
(m, 4H, 2CH2), 1.78 (s, 9H, 3CH3), 4.02 (t, 2H, J ¼ 5.3 Hz, CH2), 4.08–
4.13 (m, 4H, 2CH2), 4.15 (m, 2H, NCH2), 7.35 (t, 1H, J ¼ 5.0 Hz, NH),
8.10 (s, 1H, NH).

2538
S. A. Ivanovsky et al.
N-Benzyl-3-(3,4-dioxo-2-pyrrolidin-1-yl-cyclobut-1-enylamino)-
propionamide (14f)
This compound was obtained in 57% yield, mp 231–2338C (2-propanol). LC
1
MS m/z 327 (M þ 1); H NMR (500 MHz, DMSO-d6): 1.65–1.71 (m, 4H,
2CH2), 4.02 (t, 2H, J ¼ 5.3 Hz, CH2), 4.08–4.13 (m, 4H, 2CH2), 4.15
(m, 2H, NCH2), 4.81 (d, 2H, J ¼ 6.1 Hz, NCH2), 7.35 (t, 1H, J ¼ 5.0 Hz,
NH), 7.50–7.54 (m, 5H, Ph), 7.99 (t, 1H, J ¼ 6.1 Hz, NH).
3,4-Dichloro-3-cyclobutene-1,2-dione (15) was obtained using the
procedure introduced by Masatomi et al.[12]
General Procedure for Synthesis of 3-Aryl-4-chloro-3-cyclobutene-
1,2-diones (17a–g)
Compound (16a–g) (0.1 mol) was added to a solution of 1.51 g (0.1 mol) of
compound (15) in 10 mL of dry chloroform. The mixture was cooled down
to 108C. Then 13.4 g (0.1 mol) of anhydrous AlCl3 was added to the
reaction mixture. The suspension was stirred at room temperature for 3 h
and then poured onto crushed ice. The formed precipitate was extracted
with chloroform (three portions per 15 mL). The organic layers were
combined, dried over CaCl2, and evaporated to dryness. The residue was
treated with diethyl ether, collected by filtration, and dried to afford
reaction product (17a–g) in 70–80% yields.
General Procedure for Synthesis of 3-Amino-4-aryl-3-cyclobutene-
1,2-diones (19a–n)
Compound (17a–g) (1 mmol) was added to a solution of corresponding amine
(18a,b) (1 mmol) and TEA (1.2 mmol) in dioxane (3 mL) at 0–58C under
stirring. The mixture was stirred at 45–508C for 4 h, cooled down to room
temperature, and poured into water. The formed precipitate was collected
by filtration, washed with water, dried, and purified by crystallization from
a mixture of ethanol and DMF to afford pure reaction product (19a–n).
3-Phenyl-4-phenylamino-cyclobut-3-ene-1,2-dione (19a)
This compound was obtained in 78% yield, mp 177–1798C (2-propanol).
LC MS m/z 249 (M þ 1); 1H NMR (500 MHz, DMSO-d6): 7.51–7.54
(m, 5H, Ph), 7.58–7.61 (m, 5H, Ph), 10.12 (s, 1H, NH).
3-Cyclohexylamino-4-phenyl-cyclobut-3-ene-1,2-dione (19b)
This compound was obtained in 72% yield, mp 157–1598C (2-propanol).
LC MS m/z 255 (M þ 1); 1H NMR (500 MHz, DMSO-d6): 0.95–1.11

Substituted 3-Cyclobutene-1,2-diones
2539
(m, 2H, CH2), 1.32–1.44 (m, 8H, 4CH2), 3.59–3.62 (m, 1H, NCH),
7.51–7.54 (m, 5H, Ph), 8.54 (d, 1H, J ¼ 5.8 Hz, NH).
3-Phenylamino-4-p-tolyl-cyclobut-3-ene-1,2-dione (19c)
This compound was obtained in 81% yield, mp 197–1998C (2-propanol).
1
LC MS m/z 263 (M þ 1); H NMR (500 MHz, DMSO-d6): 1.87 (s, 3H,
CH3), 7.13 (d, 2H, J ¼ 8.2 Hz, ArH), 7.50–7.58 (m, 5H, Ph), 7.65 (d, 2H,
J ¼ 8.2 Hz, ArH), 10.12 (s, 1H, NH).
3-Cyclohexylamino-4-p-tolyl-cyclobut-3-ene-1,2-dione (19d)
This compound was obtained in 74% yield, mp 155–1588C (2-propanol).
LC MS m/z 269 (M þ 1); 1H NMR (500 MHz, DMSO-d6): 0.95–1.11
(m, 2H, CH2), 1.32–1.44 (m, 8H, 4CH2), 1.87 (s, 3H, CH3), 3.59–3.62
(m, 1H, NCH), 7.13 (d, 2H, J ¼ 8.2 Hz, ArH), 7.65 (d, 2H, J ¼ 8.2 Hz,
ArH), 8.54 (d, 1H, J ¼ 5.8 Hz, NH).
3-(3,4-Dimethyl-phenyl)-4-phenylamino-cyclobut-3-ene-1,2-dione (19e)
This compound was obtained in 71% yield, mp 151–1538C (2-propanol).
1
LC MS m/z 277 (M þ 1); H NMR (500 MHz, DMSO-d6): 1.86 (s, 3H,
CH3), 1.89 (s, 3H, CH3), 6.95 (d, 1H, J ¼ 8.1 Hz, ArH), 7.36 (s, 1H, ArH),
7.50–7.58 (m, 5H, Ph), 7.80 (d, 1H, J ¼ 8.1 Hz, ArH), 10.21 (s, 1H, NH).
3-Cyclohexylamino-4-(3,4-dimethyl-phenyl)-cyclobut-3-ene-1,2-dione (19f)
This compound was obtained in 68% yield, mp 164–1678C (2-propanol).
LC MS m/z 283 (M þ 1); 1H NMR (500 MHz, DMSO-d6): 0.95–1.11
(m, 2H, CH2), 1.32–1.44 (m, 8H, 4CH2), 1.86 (s, 3H, CH3), 1.89 (s, 3H,
CH3), 3.62 (m, 1H, NCH), 6.95 (d, 1H, J ¼ 8.1 Hz, ArH), 7.36 (s, 1H,
ArH), 7.80 (d, 1H, J ¼ 8.1 Hz, ArH), 8.54 (d, 1H, J ¼ 5.8 Hz, NH).
3-Phenylamino-4-(2,4,5-trimethyl-phenyl)-cyclobut-3-ene-1,2-dione (19g)
This compound was obtained in 67% yield, mp 193–1958C (2-propanol).
1
LC MS m/z 291 (M þ 1); H NMR (500 MHz, DMSO-d6): 1.86 (s, 6H,
2CH3), 1.89 (s, 3H, CH3), 6.95 (s, 1H, ArH), 7.36 (s, 1H, ArH), 7.50–7.58
(m, 5H, Ph), 10.18 (s, 1H, NH).
3-Cyclohexylamino-4-(2,4,5-trimethyl-phenyl)-cyclobut-3-ene-1,2-
dione (19h)
This compound was obtained in 62% yield, mp 171–1738C (2-propanol).
LC MS m/z 297 (M þ 1); 1H NMR (500 MHz, DMSO-d6): 0.95–1.11

2540
S. A. Ivanovsky et al.
(m, 2H, CH2), 1.32–1.44 (m, 8H, 4CH2), 1.86 (s, 6H, 2CH3), 1.89 (s, 3H,
CH3), 3.62 (m, 1H, NCH), 6.95 (s, 1H, ArH), 7.36 (s, 1H, ArH), 8.54
(d, 1H, J ¼ 5.8 Hz, NH).
3-Phenylamino-4-(5,6,7,8-tetrahydro-naphthalen-2-yl)-cyclobut-3-
ene-1,2-dione (19i)
This compound was obtained in 58% yield, mp 161–1628C (2-propanol).
LC MS m/z 303 (M þ 1); 1H NMR (500 MHz, DMSO-d6): 1.77–1.82
(m, 4H, 2CH2), 2.20–2.26 (m, 2H, CH2), 2.55–2.59 (m, 2H, CH2), 6.50
3
(dd, 1H, J3–4 ¼ 6.7 Hz, J3–1 ¼ 0.8 Hz, CH), 6.77 (d, 1H, J4–3 ¼ 6.7 Hz,
4CH), 6.96 (d, 1H, J1–3 ¼ 0.8 Hz, 1CH), 7.50–7.58 (m, 5H, Ph), 10.22
(s, 1H, NH).
3-Cyclohexylamino-4-(5,6,7,8-tetrahydro-naphthalen-2-yl)-cyclobut-3-
ene-1,2-dione (19j)
This compound was obtained in 51% yield, mp 142–1458C (2-propanol).
LC MS m/z 309 (M þ 1); 1H NMR (500 MHz, DMSO-d6): 0.95–1.11
(m, 2H, CH2), 1.32–1.44 (m, 8H, 4CH2), 1.77–1.82 (m, 4H, 2CH2), 2.20–
2.26 (m, 2H, CH2), 2.55–2.59 (m, 2H, CH2), 3.62 (m, 1H, NCH), 6.50 (dd,
3
4
1H, J3–4 ¼ 6.7 Hz, J3–1 ¼ 0.8 Hz, CH), 6.77 (d, 1H, J4–3 ¼ 6.7 Hz, CH),
1
6.96 (d, 1H, J1–3 ¼ 0.8 Hz, CH), 8.54 (d, 1H, J ¼ 5.8 Hz, NH).
3-(4-Chloro-phenyl)-4-phenylamino-cyclobut-3-ene-1,2-dione (19k)
This compound was obtained in 84% yield, mp 201–2038C (2–propanol).
1
LC MS m/z 283 (M þ 1); H NMR (500 MHz, DMSO-d6): 7.13 (d, 2H,
J ¼ 8.0 Hz, ArH), 7.50–7.58 (m, 5H, Ph), 8.12 (d, 2H, J ¼ 8.0 Hz, ArH),
10.24 (s, 1H, NH).
3-(4-Chloro-phenyl)-4-cyclohexylamino-cyclobut-3-ene-
1,2-dione (19l)
This compound was obtained in 74% yield, mp 197–1998C (2-propanol).
LC MS m/z 289 (M þ 1); 1H NMR (500 MHz, DMSO-d6): 0.95–1.11
(m, 2H, CH2), 1.32–1.44 (m, 8H, 4CH2), 3.59–3.62 (m, 1H, NCH), 7.12
(d, 2H, J ¼ 8.2 Hz, ArH), 8.11 (d, 2H, J ¼ 8.2 Hz, ArH), 8.53 (d, 1H,
J ¼ 5.8 Hz, NH).
3-(4-Methoxy-phenyl)-4-phenylamino-cyclobut-3-ene-1,2-dione (19m)
This compound was obtained in 71% yield, mp 200–2038C (2-propanol).
1
LC MS m/z 279 (M þ 1); H NMR (500 MHz, DMSO-d6): 3.97 (s, 3H,

Substituted 3-Cyclobutene-1,2-diones
2541
CH3), 7.13 (d, 2H, J ¼ 8.2 Hz, ArH), 7.50–7.58 (m, 5H, Ph), 8.42 (d, 2H,
J ¼ 8.2 Hz, ArH), 10.12 (s, 1H, NH).
3-Cyclohexylamino-4-(4-methoxy-phenyl)-cyclobut-3-ene-
1,2-dione (19n)
This compound was obtained in 69% yield, mp 185–1878C (2-propanol).
LC MS m/z 285 (M þ 1); 1H NMR (500 MHz, DMSO-d6): 0.95–1.11
(m, 2H, CH2), 1.32–1.44 (m, 8H, 4CH2), 3.96 (s, 3H, CH3), 3.59–3.62
(m, 1H, NCH), 7.13 (d, 2H, J ¼ 8.2 Hz, ArH), 7.65 (d, 2H, J ¼ 8.2 Hz,
ArH), 8.54 (d, 1H, J ¼ 5.8 Hz, NH).
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