Application of the Cleavable Isocyanide in Efficient Approach to Pyroglutamic Acid Analogues with Potential Biological Activity

Article abstract of DOI:10.1134/S1070363219120363

Two efficient procedures have been developed for the synthesis of pyroglutamic acid analogues 28, 29, and 34. According to the first method the Ugi (4C3C) reaction is followed by a post-transformation reaction, and the second method involves the Michael a

Full text of DOI:10.1134/S1070363219120363

ISSN 1070-3632, Russian Journal of General Chemistry, 2019, Vol. 89, No. 12, pp. 2562–2570. © Pleiades Publishing, Ltd., 2019.
Application of the Cleavable Isocyanide in Efficient Approach
to Pyroglutamic Acid Analogues with Potential Biological Activity
a,
b
a
c
A. M. Jassem *, H. M. Al-Ajely , F. A. K. Almashal , and B. Chen
a
College of Education for Pure Sciences, Department of Chemistry, Basrah University, Basrah, 61004 Iraq
b
College of Science, Department of Chemistry, Mosul University, Mosul, 41002 Iraq
c
Department of Chemistry, University of Sheffield, Sheffield, S3 7HF United Kingdom
*
e-mail: ahmed.majedd@uobasrah.edu.iq
Received October 15, 2019; revised November 27, 2019; accepted November 27, 2019
Abstract—Two efficient procedures have been developed for the synthesis of pyroglutamic acid analogues 28, 29,
and 34. According to the first method the Ugi (4C3C) reaction is followed by a post-transformation reaction, and
the second method involves the Michael addition reaction. The present methodologies demonstrate the applicability
of 1-(2,2-dimethoxyethyl)-2-isocyanobenzene (15) as a cleavable isocyanide in the Ugi/ post-transformation reac-
tion and a strong nucleophile in the Michael addition reaction. The framework of pyroglutamic acid analogues has
been constructed by the selective cleavage of the C-terminal amide bond and nucleophilic addition to the activated
α,β-unsaturated carbonyl group.
Keywords: cleavable isocyanide, Ugi (4C3C) reaction, Michael addition, pyroglutamic acid analogues
DOI: 10.1134/S1070363219120363
Pyroglutamic acid is a core-structure of many bio-
active compounds [1]. Examples of biological activities
of pyroglutamic acid analogues include antibiotics such
as omuralide 1 which shows an inhibitory effect toward
access to biologically active molecules.Among the cleav-
able isocyanides are (β-isocyanoethyl) ethyl carbonate 7
[13], 1-cyclohexenylisonitrile 8 [14–16], tert-butyliso-
nitrile 9 [17], p-methoxy phenyl isocyanide 10 [18, 19],
diphenyl methyl isocyanide 11 [20], 1-isocyanomethyl
benzotriazoles 12 [21], 4-isocyanopermethyl-butane-
1,1,3-triol 13 [22], 2-nitrophenyl isocyanide 14 [23],
and 1-(2,2-dimethoxyethyl)-2-isocyanobenzene 15 [24].
2
2
0S proteasome in bacterial cells [2, 3]. Lactacystin
, salinosporamide A 3 [4, 5], and dysibetaine 4 are
currently used in treatment of human cancer. In addition,
–)-Pramanicin 5 and (+)-epolactaene 6 can induce
(
apoptosis in a human leukemia B-cell line [6] (see the
figure).
Although it has not been possible to cleave the
hindered C-terminal amides of some α -acyloxyamide
derivatives generated from multicomponent products,
1-(2,2-dimethoxyethyl)-2-isocyanobenzene (15) has
been synthesized for a selective cleavage of the resultant
C-terminal amide bond as well as it's applicability in the
stereocontrolled synthesis [25–27]. In our ongoing ap-
proach to efficient methods of synthesis of biologically
active pyroglutamic acid analogues, we have synthesized
isocyanide 15 and studied its application in Ugi–post-
transformation and Michael addition reaction in the
synthesis of new pyroglutamic acid analogues 28, 29,
Multicomponent reactions (MCRs) are character-
ized by the unique ability to generate highly complex
molecular structures from various starting materials in
one-pot processes [7]. A combination of reactions with
other strategies (such as Ugi–post-transformations) has
been extensively used in synthesis of biologically active
products [8, 9] and structures of multitude functionality
[10, 11].
Isocyanide-based multicomponent reactions (IMCRs)
have attracted close attention due to their applicability to
generate biologically active molecules in a single step.
Although isocyanides have demonstrated the utility in
multicomponent reactions, they have not been demon-
strated as “cleavable” in cleavage of α-acyloxyamide
derivatives [12]. Therefore, the design and synthesis of
cleavable isocyanides are required to provide an efficient
3
4 (Scheme 1).
RESULTS AND DISCUSSION
In Ugi–post-transformations, the Ugi products were
used efficiently in the approach to structurally complex
molecules [28, 29]. The key objective for synthesis of
2
562

APPLICATION OF THE CLEAVABLE ISOCYANIDE IN EFFICIENT APPROACH
2563
OH
OH
OH
H
O
S
O
H
N
O
N
HN
O
O
O
O
O
CO H
2
OH
NHAc
1
2
Cl
Salinosporamide A
3
Omuralide
Lactacystin
N
H
O
O
OH
N
O
COO
6
NH
OH
HO
HO
4
5
(ꢀ)-Dysibetaine
(ꢀ)-Pramanicin
O
O
OH
H CO C
3
2
NH
O
6
(+)-Epolactaene
Some pharmacologically active pyroglutamic acid analogues.
cleavable isocyanide 15 was its application in modifica-
tion of the products derived from the Ugi reaction. The
Ugi products 24, 25 derived from keto acids 21, 22,
addition of a nucleophile to an activated α,β-unsaturated
carbonyl compound [30]. The new chalcone 33 acted
as the core in synthesis of pyroglutamic acid analogue
2
-phenylethanamine 23, and a cleavable isocyanide 15
3
4 in four steps. The first step involved bromination of
were converted to the pyroglutamic acid analogues 28, 29
via N-acylindoles 26, 27 under mild conditions. Such abil-
ity of N-acylindoles 26, 27 was proven to be an efficient
access to new pyroglutamic acid analogues. The achieved
results demonstrated that addition of 4Å molecular sieves
alcohol 30 with formation of compound 31 which was
reacted with 1H-pyrazole to form intermediate 32. Its
following treatment with acetophenone using ZrCl4
(10 mol %) gave chalcone 33. Finally, the pyroglutamic
acid analogue 34 was successfully obtained via 1,4-addi-
tion reaction of isocyanide 15 to chalcone 33. The reaction
was first tested both in the presence MeOH and without a
solvent. The reaction yielded 55% of pyroglutamic acid
analogue 34 was achieved in MeOH medium at room
temperature. The same reaction was also carried out under
solvent-free conditions at 150°C for 6 h leading to 78%
yield of product 34.
(20–25 mg/mmol) influenced upon yield of Ugi products
2
4, 25. Although the Ugi products could be smoothly
proceeded in the media of MeOH, our results indicated
that using 2,2,2-trifluoroethanol (TFE) as a solvent led
to higher yields. Heating the Ugi products 24, 25 with dl
camphorsulphonic acid (CSA) in toluene for less than 2 h
resulted in the respective N-acylindoles derivatives 26 and
2
7. Subsequently, N-acylindole derivatives 26, 27 were
treated with a catalytic amount of Cs CO in DMF–H O
2
3
2
EXPERIMENTAL
(
1 : 1) to afford the corresponding pyroglutamic acid
analogues (28 and 29) in high yields.
All starting compounds and solvents were purchased
from Sigma Aldrich. All reactions were carried out un-
der the atmosphere of nitrogen. TLC was performed on
The Michael reaction (1,4-addition) refers to forma-
tion of carbon-carbon bonds that include base-catalyzed
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 12 2019

2564
JASSEM et al.
Scheme 1. Use of isocyanide 15 in Ugi/post transformation and Michael addition reactions
OEt
Me
Me N
OEt
NO2
NO2
NH2
2
TMSCl
or PTSA
Pd
MeOH
NO2
Pyrrolidine
OMe
OMe
MeOH
DMF
0°C
H2
N
OMe
OMe
8
16
17
18
19
OMe
MeO
Ugi strategy
CHO POCl3
O
N
NC
OMe
PhCH
2
CH
23
NH
2 2
HCO Et
H
2
Et N
3
N
OMe
OMe
O
O
DCM
n
N
H
OMe
CH CH Ph
OH
2
2
n
20
15
2
2
4, n = 2
5, n = 3
O
2
1, n= 2
2, n= 3
2
TFE, 48 h,
room temperature
O
O
CSA
0°C
N
HO
O
n
8
n
O
N
N
Cs CO3
2
CH C Ph
CH CH Ph
2
2
2
2
DMFꢀH O
2
room temperature
2
2
6, n = 2
7, n = 3
2
8, n = 2
9, n = 3
2
H
O
N
O
N
PBr ·CHCl
3
3
Br
O
HO
MeO
N
room temperature
K CO3
N
MeO
3
MeO
DMF
30
31
32
N
Ph
O
N
HO
Michael
strategy
OMe
PhCOCH3
N
N
Ph
N
ZrCl4
15
O
MeO
MeOH
33
OMe
MeO
34
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 12 2019

APPLICATION OF THE CLEAVABLE ISOCYANIDE IN EFFICIENT APPROACH
2565
plates precoated with silica gel 60 UV 254 (Merck). An
(2,2-Dimethoxyethyl)-2-nitrobenzene (18). A solu-
tion of enamine 17 (4.5 g, 4.4 mmol) in MeOH (40 mL)
was added to a solution of para-toluenesulfonic acid
(4.70 g, 24.5 mmol) in MeOH (25 mL). The reaction
mixture was refluxed for 12 h to full conversation
according to TLC. The reaction mixture was cooled
down, Na CO (0.7 g, 6.3 mmol) was carefully added
alkaline aqueous solution of KMnO was used to visual-
4
ize the chromatograms.All synthesized compounds were
purified by flash chromatography with SiO (60 Å, 230–
2
4
00 mesh, Merck). Majority of the synthesized com-
1
13
pounds was isolated in >95% purity. H and C NMR
spectra were measured on a BrukerAV-400 spectrometer
at 400 MHz ( H) and 100.5 MHz ( C) at room tempera-
2
3
1
13
to it, and the mixture was stirred for 15 min. An
excess solvent was removed and the resulting mixture
ture (Sheffield, UK). CDCl and DMSO-d were used as
3
6
1
the internal references ( H NMR, CDCl , δ 7.26 ppm;
DMSO-d , δ 2.50 ppm; C NMR, CDCl , δ 77.16 ppm;
was separated between toluene (20 mL) and H O
3
2
1
3
(20 mL). The aqueous layer was then extracted with
toluene (3×50 mL). The combined organic layers were
dried over Na SO , filtered and concentrated under
6
3
DMSO-d , δ 39.52 ppm). Melting points were determined
6
on a Gallenkamp melting point apparatus in capillary
tubes. HRMS were performed on a Micro Mass LCT
operating in Electrospray mode (ES) (Sheffield, UK).
IR spectra were recorded on a Perkin Elmer Paragon 100
FTIR spectrophotometer (Sheffield, UK).
2
4
reduced pressure. Purification was performed by flash
chromatography (petroleum ether–ethyl acetate, 4 : 1,
R 0.24) to give compound 18 as an orange oil. Yield
f
–
1
60%. FTIR spectrum, ν, cm : 1510 (C=C, C H ), 1355
C–H), 1120 (C–O), 980 (N–C). H NMR spectrum, δ,
6
5
1
(
Synthesis of convertible isocyanide 15 was carried
ppm: 7.91–7. 87 m (1H, CH, C H ), 7.57–7. 52 m (1H,
out according to the developed earlier method [31, 32].
6
5
CH, C H ), 7.45–7. 38 m (2H, CH, C H ), 4.59 t (1H,
6
5
6
5
1
-[(E)-2-(2-Nitrophenyl)vinyl]pyrrolidine
(17).
J = 5.4 Hz, CH), 3.38 s (6H, 2OCH ), 3.24 d (2H, J =
3
A solution of 2-nitrotoluene (16) (5.0 g, 36.2 mmol),
dimethylformamide diethyl acetal (5.1 g, 42 mmol)
and pyrrolidine (3.0 g, 42.2 mmol) in DMF (25 mL)
was refluxed under the atmosphere of nitrogen for
h, during that time the mixture turned dark. H NMR
spectra of a reaction aliquot exhibited a 3 : 1 ratio of
-nitrotoluene (16) to the desired product 17. Therefore,
the temperature of reaction was increased to 180°C for
9 h. After that time, H NMR spectra demonstrated no
-nitrotoluene (16) present. The resulting dark mixture
1
3
5
.5 Hz, CH ). C NMR spectrum, δ , ppm: 37.0 (CH ),
2 C 2
5
4.4 (OCH ), 104.6 (CH), 124.5 (CH, C H ), 127.6 (CH,
3
6
5
C H ), 131.6 (CH, C H ); 132.6 (CH, C H ), 133.7 (CH,
6
5
6
5
6
5
+
C H ), 150.0 (C, C H ). HRMS (EI ): 234.0742 [M +
1
6
5
+
6
5
5
Na] , calculated for C H NO Na: 234.0732.
1
0
13
4
2
2-(2,2-Dimethoxyethyl)aniline (19). The H-cube
reactor of ThalesNano system was fitted with a 10%
Pd/C cartridge and hydrogen mode was primed at
1 mL/min using MeOH for 5 min. A 0.1 M solution of
compound 18 (0.42 g, 2.0 mmol) in MeOH (40 mL) was
passed through the H-cube reactor at a rate of 0.5 mL/min
under hydrogen pressure of 80 bar and temperature
1
1
2
was evaporated to dryness on a rotary evaporator and the
residue was poured in H O (50 mL). After the extraction
with ethyl acetate (5×200 mL), the combined organic
layers were dried over Na SO , filtered and concentrated
2
o
80 C. The output stream was collected and the solvent
2
4
under reduced pressure. Purification was performed by
flash chromatography (petroleum ether–ethyl acetate,
was removed under reduced pressure to yield a 5 : 1
mixture of 19 and 18 respectively. Purification was
performed by flash chromatography (petroleum ether–
4
: 1, R 0.28) to give enamine 17 as a red oil. Yield 70%,
f
–
1
FTIR spectrum, ν, cm : 3010 (C–H, C H ), 1615 (C=C,
C H ), 1510 (C=C), 982 (N–C). H NMR spectrum, δ,
ethyl acetate, 4 : 1, R 0.35) to give the product 19 as
6
5
f
1
–1
yellow oil. Yield 80%. FTIR spectrum, ν, cm : 3430
(N–H), 1121 (C–O), 980 (N–C). H NMR spectrum, δ,
6
5
1
ppm: 8.01–7.79 m (1H, CH, C H ), 7.87–7. 84 m (1H,
6
5
CH, C H ), 6.93 d (1H, J = 12.9 Hz, CH), 5.85 d (1H,
ppm: 7.10–7. 06 m (2H, CH, C H ), 6.78–6.69 m (2H,
6
5
6
5
J = 13.5 Hz, CH), 3.41–3.35 m (4H, 2CH ), 2.00–1.95
CH, C H ), 4.52 t (1H, J = 5.34 Hz, CH), 4.08 br.s (2H,
2
6 5
m (4H, 2CH2). 13C NMR spectrum, δ , ppm: 25.3
NH ), 3.42 s (6H, 2OCH ), 2.89 d (2H, J = 5.5 Hz, CH ).
C
2
3
2
1
3
(
CH ), 49.2 (CH ), 91.0 (CH), 122.0 (CH), 125.5 (CH,
C NMR spectrum, δ , ppm: 36.5 (CH ), 54.0 (OCH ),
2
2
C 2 3
C H ), 126.8 (CH, C H ), 128.9 (C, C H ), 132.7 (CH,
106.6 (CH), 116.3 (CH, C H ), 118.7 (CH, C H ), 122.4
6 5 6 5
6
5
6
5
6
5
C H ), 133.0 (CH, C H ), 140.0 (C, C H ). HRMS
(C, C H ), 127.8 (CH, C H ), 131.3 (CH, Ar C H ),
6 5 6 5 6 5
6
5
6
5
6
5
+
+
+
(
ESI): 219.1110 [M + H] ,calculated for C H N O H :
146.0 (CH, C H ). HRMS (ESI): 182.1776 [M + H] ,
6 5
1
2
14
2
2
+
2
19.
calculated for C H NO H : 182.1176.
10 15 2
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 12 2019

2566
JASSEM et al.
N-[2-(2,2-Dimethoxyethyl)phenyl]formamide
20). To a solution of hexamethyldisilazane (4.6 mL,
(CH), 103.8 (C, C H ), 124.0 (CH, C H ), 126.9 (CH,
6 5 6 5
(
C H ), 127.5 (CH, C H ), 129.4 (CH, C H ), 131.4 (C,
6 5 6 5 6 5
+
22.0 mmol) in THF (40 mL), n-butyl lithium (25 mL,
1.0 M in hexane) was added at 0°C over a period
30 min. Addition of solution of 19 (2.0 g, 11.0 mmol) in
C H ). HRMS (ESI): 192.0927 [M + H] , calculated for
6 5
+
C H NO H : 192.1025.
11
13
2
Synthesis of ketoacids was carried out according to
the method [33].
THF (40 mL) was followed by ethyl formate (1.4 mL,
6.6 mmol). The mixture was further refluxed for 18 h
1
4
-Oxooct-7-enoic acid (21). 4-Bromo-1-butene
until TLC (diethyl ether–petroleum ether, 1 : 1) detected
(2.0 mL, 16.8 mmol) in dry THF (20 mL) was added
full conversion. A saturated aqueous solution of NH Cl
4
dropwise to a vigorously stirred suspension of
magnesium (0.534 g, 22.0 mmol) in dry THF (20 mL)
(100 mL) was added and the resulting mixture was
extracted with ethyl acetate (3×50 mL). The combined
over a period 1 h under the atmosphere of N . The
2
organic layers were dried over Na SO , filtered and
2
4
resulting Grignard reagent was immediately transferred
dropwise to a solution of succinic anhydride (1.69 g,
concentrated under reduced pressure. Purification was
performed by flash chromatography (petroleum ether–
1
6.8 mmol) and copper iodide (0.09 g, 0.49 mmol) in
ethyl acetate, 7 : 3, R 0.5) to give compound 20 as brown
f
dry THF (40 mL) at –20°C. Thus formed mixture was
warmed up to 0°C and stirred for 3 h then quenched
with 2M HCl (40 mL) and concentrated under reduced
pressure. The organic layer was extracted with DCM
(2×100 mL). The combined organic layers were washed
with 2 M NaOH (2×100 mL). The combined aqueous
layers were re-extracted with DCM (3×100 mL) after
acidification with conc. HCl to pH 2. The combined
–
1
oil. Yield 50%. FTIR spectrum, ν, cm : 1650 (C=O),
116 (C–O), 995 (N–C). H NMR spectrum, δ, ppm:
1
1
8
.79 s (1H, CHO), 8.52–8.44 m (1H, CH, C H ), 7.94
6 5
d (1H, J = 8.04 Hz, CH), 7.74–7. 71 m (1H, CH, C H ),
6
5
7
3
6
5
.56–7. 54 m (1H, CH, C H ), 4.48–4.40 m (1H, CH),
6 5
.44 s (3H, OCH ), 3.41 s (3H, OCH ), 2.96 d (2H, J =
3
3
13
.0 Hz, CH ). C NMR spectrum, δ , ppm: 36.2 (CH ),
2
C
2
5.0 (OCH ), 100.5 (CH), 102.9 (C, C H ), 123.2 (CH,
3
6
5
organic layers were dried over MgSO , filtered and
4
C H ), 126.4 (CH, C H ), 127.9 (CH, C H ), 129.5 (CH,
6
5
6
5
6
5
concentrated under reduced pressure. Purification by
flash chromatography (petroleum ether–ethyl acetate–
+
C H ), 130.2 (C, C H ). HRMS (ESI ): 232.0950 [M +
6
5
+
6
5
Na] , calculated for C H NO Na: 232.0943.
1
1
15
3
acetic acid, 6.95 : 3 : 0.05, R 0.4) gave ketoacid 21
f
1
-(2,2-Dimethoxyethyl)-2-isocyano benzene (15).
as yellow viscous oil. Yield 50%. FTIR spectrum, ν,
–
1
To a solution of compound 20 (1.2 g, 5.8 mmol) in dry
THF (20 mL), TEA(2.0 mL, 14.6 mmol) was added, and
the mixture was cooled down to –60°C in an EtOH–dry
cm : 3078 (O–H); 2983 (C–H, C H ), 2918 (C–H),
6 5
1
2668 (C=C), 1711 (C=O). H NMR spectrum, δ, ppm:
5.87–5.74 m (1H, CH), 5.16–4.98 m (2H, CH ), 2.76–
2
ice bath. POCl (0.8 mL, 8.6 mmol) was added dropwise.
2.72 m (2H, CH ), 2.70–2.62 m (2H, CH ), 2.58 t (2H,
3
2
2
J = 7.4 Hz, CH ), 2.43–2.34 m (2H, CH ). 13C NMR
Subsequently, the mixture was allowed to warm up to
room temperature and stirred until TLC (diethyl ether–
petroleum ether, 1 : 1) indicated full conversion (ca
2
2
spectrum, δ , ppm: 27.7 (CH ), 29.0 (CH ), 36.9 (CH ),
C
2
2
2
41.8 (CH2), 115.4 (CH2), 136.9 (CH), 178.3 (C=O),
-
1
h). The resulting mixture was poured into an ice water
208 (C=O). HRMS (ESI ): 155.0716, calculated for
(150 mL) then extracted with diethyl ether (3×100 mL).
C8H12O3: 155.0714.
The combined organic layers were washed with NaCl
sat. solution (100 mL). The combined organic layers
were dried over Na SO , filtered and concentrated under
4-Oxonon-8-enoic acid (22) was synthesized by the
method similar to that for 4-oxooct-7-enoic acid 21 and
obtained as pale oil. Yield 58%. FTIR spectrum, ν, cm–1:
2
4
reduced pressure. Purification was performed by flash
chromatography (petroleum ether–ethyl acetate, 7 : 3,
3084 (O–H), 2979 (C–H, Ar), 2940 (C–H), 1699 (C=O).
H NMR spectrum, δ, ppm: 1.72–1.70 m (2H, CH2),
1
R 0.6) to give compound 15 as brown oil. Yield 77%.
2.11–2.05 m (2H, CH ), 2.48 t (2H, J = 7.5 Hz, CH ),
f
2
2
–
1
FTIR spectrum, ν, cm : 2987 (C–H, C H ), 2853 (C–
2.66–2.63 m (2H, CH ), 2.73 t (2H, J = 6.2 Hz, CH ),
6
5
2
2
1
5.06–4.98 m (2H, CH ), 5.83–5.73 m (1H, CH). 13C
H), 2834 (C–H), 1590 (C=C, C H ). H NMR spectrum,
6
5
2
δ, ppm: 7.37–7. 34 m (2H, CH, C H ), 7.28–7. 23 m
NMR spectrum, δ , ppm: 27.8 (CH ), 22.8 (CH ), 33.0
6
5
C
2
2
(
(
2H, CH, C H ), 4.62 t (1H, J = 4.9 Hz, CH), 3.4 s
(CH ), 36.9 (CH ), 41.8 (CH ), 115 (CH ), 137.9 (CH),
2 2 2 2
6
5
6H, 2OCH ), 3.2 d (2H, J = 5.3 Hz, CH ). 13C NMR
178.5 (C=O), 208.7 (C=O). HRMS (ESI ): 169.0876,
calculated for C H O : 169.0870.
-
3
2
spectrum, δ , ppm: 36.0 (CH ), 54.0 (OCH ), 100.4
C
2
3
9
14
3
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 12 2019

APPLICATION OF THE CLEAVABLE ISOCYANIDE IN EFFICIENT APPROACH
2567
1
3
Synthesis of the Ugi products. a. A solution of
keto acid (1.0 mmol) in TFE (5 mL) was added to a
solution of 2-phenylethanamine 23 (1.25 mmol) in TFE
C NMR spectrum, δ , ppm: 27.5 (CH ), 28.3 (CH ),
C
2
2
29.2 (CH ), 29.7 (CH ), 33.8 (CH ), 34.5 (CH ), 36.9
(CH ), 44.2 (CH ), 53.9 (OCH ), 54.5 (OCH ), 70.4 (C),
2
2
2
2
2
2
3
3
(5 mL) and stirred for 45 min. 1-(2,2-Dimethoxyethyl)-
106.5 (CH), 115.5 (CH ), 124.5 (CH, C H ), 125.5 (CH,
2 6 5
2
-isocyano benzene 15 (1.0 mmol) was then added and
C H ), 126.6 (CH, C H ), 127.6 (CH, C H ), 128.6 (CH,
6 5 6 5 6 5
the mixture was stirred at room temperature for 48 h.
The excess solvent was removed under reduced pressure
and the residue re-dissolved in ethyl acetate (20 mL).
The organic phase was washed with 2 M HCl (10 mL),
C H ), 128.7 (C, C H ), 131.2 (CH, C H ), 136.2 (C,
6 5 6 5 6 5
C H ), 137 (CH, C H ), 138.8 (C, C H ), 172.0 (C=O),
6
5
6
5
6
5
+
+
175.5 (C=O). HRMS (ESI ): 487.2567 [M + Na] ,
calculated for C H N O Na: 487.2570.
2
8
36
2
4
NaHCO sat. solution (10 mL) and brine (10 mL), dried
3
Synthesis of N-acylindole derivatives. b. To a
solution of an Ugi product (1.0 mmol) in toluene (5 mL),
dl camphorsulphonic acid (0.5 mmol) was added. The
reaction mixture was stirred at 80°C for 2 h, then cooled
down, quenched with a saturated solution of NaHCO3
(10 mL) and extracted with ethyl acetate (3×20 mL).
The organic layers were dried over Na SO , filtered
and concentrated under reduced pressure. Purification
was performed by a flash chromatography to obtain the
corresponding N-acylindole derivatives.
over MgSO , and concentrated under reduced pressure.
4
The corresponding crude Ugi products were purified by
flash chromatography.
2
-(But-3-en-1-yl)-N-[2-(2,2-dimethoxyethyl)-
phenyl]-5-oxo-1-phenethylpyrrolidine-2-carbox-
amide (24). Brown oil, yield 75%. FTIR spectrum, ν,
2
4
–
1
cm : 3331 (N–H), 3065 (C–H, C H ), 2937 (C–H),
2
6
5
1
836 (C–H), 1686 (C=O), 1585 (C=C), 1515 (C–H). H
NMR spectrum, δ, ppm: 9.04 s (1H, NH), 7.75 d (1H,
J = 7.4 Hz, CH, C H ), 7.32–7.11 m (8H, CH, C H ),
6
5
6
5
5-(But-3-en-1-yl)-5-(1H-indole-1-carbonyl)-1-
phenethylpyrrolidin-2-one (26). Yellow viscous oil,
5
.92–5.82 m (1H, CH), 5.15–5.04 m (2H, CH ), 4.47
2
t (1H, J = 5.2 Hz, CH), 3.61 d.d (1H, J = 16.1 Hz, 6.7
–1
yield 82%. FTIR spectrum, ν, cm : 3065 (C–H, C H ),
6
5
Hz, CH), 3.40 s (3H, OCH ), 3.35 s (3H, OCH ), 3.08
3029 (C–H, C H ), 2932 (C–H), 1691 (C=O), 1537
3
3
6 5
d.d (1H, J = 16.9 Hz, 6.1 Hz, CH), 2.92–2.81 m (2H,
(C=C), 1450 (C–H). 1H NMR spectrum, δ, ppm: 8.53
d (1H, J = 8.3 Hz, CH, C H ), 7.58 d (1H, J = 7.5 Hz,
CH ), 2.71–2.51 m (4H, 2CH ), 2.46–2.37 m (4H,
2
2
3
6
5
1
2
CH ), 2.1–1.99 m (2H, CH ). C NMR spectrum, δ ,
CH, C H ), 7.41 t (1H, J = 7.4 Hz, CH, C H ), 7.34–
2
2
C
6 5 6 5
ppm: 27.5 (CH ), 29.2 (CH ), 29.8 (CH ), 33.8 (CH ),
7. 14 m (6H, CH, C H ), 6.67 d (1H, J = 3.6 Hz, CH,
6 5
2
2
2
2
3
4.5 (CH ), 36.8 (CH ), 44.2 (CH ), 53.9 (OCH ), 54.4
C H ), 5.92–5.84 m (1H, CH), 3.49–3.30 m (2H, CH ),
2
2
2
3
6
5
2
(
OCH ), 60.3 (CH), 70.3 (C), 106.4 (CH), 115.5 (CH ),
2.86–2.79 m (2H, CH ), 2.73–2.61 m (4H, 2CH ), 2.43–
2 2
3
2
1
1
1
1
24.2 (CH, C H ), 124.4 (CH, C H ), 125.5 (CH, C H ),
2.18 m (4H, 2 CH ), 2.02–1.99 m (2H, CH ). 13C NMR
6
5
6
5
6
5
2 2
26.5 (CH, C H ), 127.7 (CH, C H ), 128.5 (CH, C H ),
spectrum, δ , ppm: 27.0 (CH ), 27.6 (CH ), 29.6 (CH ),
C 2 2 2
6
5
6
5
6
5
28.6 (C, C H ), 131.2 (CH, C H ), 136.1 (C, C H ),
33.7 (CH ), 35.7 (CH ), 44.5 (CH ), 71.5 (CH ), 110.5
6
5
6
5
6
5
2 2 2 2
37.1 (CH, C H ), 138.8 (C, C H ), 172.1 (C=O), 175.6
(CH, C H ), 115.8 (CH ), 117.1 (CH, C H ), 120.9 (CH,
6 5 2 6 5
6
5
6
5
+
+
(C=O). HRMS (ESI ): 473.2414 [M + Na] , calculated
C H ), 123.7 (CH, C H ), 124.4 (CH, C H ), 125.8 (CH,
6 5 6 5 6 5
for C H N O Na: 473.2411.
C H ), 126.5 (CH, C H ), 128.5 (C, C H ), 128.7 (CH,
27
34
2
4
6
5
6
5
6
5
C H ), 129.4 (C, C H ), 136.5 (CH), 136.7 (C, C H ),
N-[2-(2,2-Dimethoxyethyl)phenyl]-5-oxo-2-(pent-
-en-1-yl)-1-phenethylpyrrolidine-2-carboxamide
25). Dark brown oil, yield 60%. FTIR spectrum, ν,
6
5
6
5
6
5
1
38.5 (C, C H ), 171.6 (C=O), 175.1 (C=O). HRMS
6 5
4
(
+
+
(ESI ): 387.2067 [M + H] , calculated for C H N O :
25 26 2 2
–
1
387.2067.
cm : 3333 (N–H), 3027 (C–H, C H ), 2937 (C–H),
6
5
1
2
845 (C–H), 1684 (C=O), 1587 (C=C), 1520 (C–H). H
5-(1H-Indole-1-carbonyl)-5-(pent-4-en-1-yl)-1-
phenethyl pyrrolidin-2-one (27). Yellow viscous oil,
NMR spectrum, δ, ppm: 8.99 m (1H, NH), 7.75 d (1H,
J = 8 Hz, CH, C H ), 7.33–7. 12 m (8H, CH, C H ),
–
1
yield 70%. FTIR spectrum, ν, cm : 3060 (C–H, C H ),
6
5
6
5
6
5
5
.87–5.77 m (1H, CH), 5.1–5.0 m (2H, CH ), 4.46 t
3029 (C–H, C H ), 2932 (C–H), 1696 (C=O), 1542
6 5
2
1
(1H, J = 5.4 Hz, CH), 3.56 d.d (1H, CH, J = 17.9 Hz,
(C=C), 1450 (C–H). H NMR spectrum, δ, ppm: 8.53
d (1H, J = 8.4 Hz, CH, C H ), 7.52 d (1H, J = 7.6 Hz,
6
3
.8 Hz, CH), 3.40 s (3H, OCH ), 3.36 s (3H, OCH ),
3 3
6
5
.06 d.d (1H, J = 17.1 Hz, 6.2 Hz, CH), 2.92–2.85 m
CH, C H ), 7.4 t (1H, J = 7.2 Hz, CH, C H ), 7.35–7. 14
6 5 6 5
(
2H, CH ), 2.65–2.54 m (4H, 2CH ), 2.45–2.38 m (4H,
m (5H, CH, C H ), 6.66 d (1H, J = 3.8 Hz, CH, C H ),
6 5 6 5
2
2
2
CH ), 2.25–2.12 m (2H, CH ), 1.94–1.54 m (2H, CH ).
5.88–5.77 m (1H, CH), 5.12–5.04 m (2H, CH ), 3.42–
2
2
2
2
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 12 2019

2568
JASSEM et al.
3
.30 m (2H, CH ), 2.86–2.76 m (2H, CH ), 2.72–2.60 m
(CH ), 34.6 (CH ), 45.6 (CH ), 71.0 (C), 115.5 (CH ),
2 2 2 2
2
2
(
2
(
2H, CH ), 2.40–2.32 m (4H, 2CH ), 1.60–1.27 m (4H,
125.9 (CH, C H ), 128.4 (CH, C H ), 129.2 (CH, C H ),
2
2
6 5 6 5 6 5
13
CH ). C NMR spectrum, δ , ppm: 22.2 (CH ), 24.3
138.2 (CH), 138.8 (C, C H ), 167.8 (C=O), 181.1
6 5
2
C
2
+
+
CH ), 27.8 (CH ), 29.7 (CH ), 33.7 (CH ), 36.1 (CH ),
(C=O). HRMS (ESI ): 302.1796 [M + H] , calculated
2
2
2
2
2
4
4.6 (CH ), 71.7 (C), 110.4 (CH, C H ), 115.9 (CH ),
for C H NO : 302.1774.
2
6
5
2
18 23
3
1
1
1
1
17.2 (CH, C H ), 120.9 (CH, C H ), 123.8 (CH, C H ),
6 5 6 5 6 5
3-(Bromomethyl)-4-methoxybenzaldehyde (31).
To a solution of 3-(hydroxymethyl)-4-methoxybenz-
24.3 (CH, C H ), 125.7 (CH, C H ), 126.5 (CH, C H ),
6
5
6
5
6
5
28.5 (CH, C H ), 128.8 (CH, C H ), 129.5 (C, C H ),
6
5
6
5
6
5
aldehyde (30) (1.66 g, 10.0 mmol) in CHCl (20 mL),
3
36.7 (CH), 137.5 (C, C H ), 138.6 (C, C H ), 171.8
6
5
6
5
PBr (3.24 g, 12.0 mmol) was added. The mixture was
3
+
(C=O), 175.2 (C=O). HRMS (ESI ): 401.2219 [M +
stirred at room temperature for 3 h. After the reaction
+
H] , calculated for C H N O : 401.2224.
2
6
28
2
2
was completed (TLC), H O (5 mL) was added to the
2
Synthesis of pyroglutamic acid analogues. c. To a
solution of N-acylindole products (1.0 mmol) in DMF–
H O (1 : 1, 4 mL), Cs CO (1.0 mmol) was added. The
mixture. The organic layer was separated and the
aqueous layer was extracted with DCM (3×20 mL).
The combined organic layers were dried over MgSO4,
filtered and evaporated. The pure product 31 was
obtained as a colorless oil by flash chromatography
2
2
3
mixture was stirred at 22°C for 6 h, then diluted with
H O (10 mL), made basic with 1M solution of NaOH
2
and extracted with ethyl acetate (2×20 mL). The aqueous
layer was then acidified with 1M HCl and extracted with
ethyl acetate (2×20 mL). The combined organic layers
were dried over Na SO , filtered and concentrated under
(DCM–ethyl acetate, 1 : 1 R 0.6). Yield 69%. FTIR
f
spectrum, ν, cm–1: 1732 (C=O), 558 (C–Br). 1H NMR
spectrum, δ, ppm: 9.98 s (1H, CHO), 7.53 d (1H, J =
2.0 Hz, CH, C H ), 7.41 d (1H, J = 9.0 Hz, CH, C H ),
2
4
6
5
6
5
reduced pressure. Purification was performed by flash
chromatography to obtain the titled pyroglutamic acid
analogues.
7.21 s (1H, CH, C H ), 4.97 s (2H, CH ), 3.93 s (3H,
6 5 2
OCH ). 13C NMR spectrum, δ , ppm: 19.1 (CH ), 57.1
3
C
2
(OCH ), 113.8 (CH, C H ), 127.4 (C, C H ), 129.0 (CH,
3
6
5
6
5
2
-(But-3-en-1-yl)-5-oxo-1-phenethylpyrrolidine-
C6H5), 134.8 (C, C6H5), 140.0 (CH, C6H5), 157.1 (C,
C6H5), 188.8 (C=O).
2
8
-carboxylic acid (28). Colorless viscous oil, yield
5%. FTIR spectrum, ν, cm : 3456 (O–H), 3024 (C–H,
–
1
3
-[(1H-Pyrazol-1-yl)methyl]-4-methoxybenz-
C H ), 2920 (C–H), 2848 (C–H), 1691 (C=O), 1450
6
5
aldehyde(32).Amixtureof3-(bromomethyl)-4-methoxy-
benzaldehyde (31) (0.45 g, 2.0 mmol), 1H-pyrazole
(0.13 g, 2.0 mmol) and NaH (0.14 g, 6.0 mmol) in
dioxane (40 mL) was stirred for 15 min and then heated
at 90°C for 72 h. Upon completion of the reaction,
the resulting mixture was cooled down, poured into
1
(C–H). H NMR spectrum, δ, ppm: 7.60–7. 13 m (5H,
CH, C H ), 5.92–5.82 m (1H, CH), 5.16–5.06 m (2H,
6
5
CH ), 3.40–3.28 m (2H, CH ), 2.85 t (2H, J = 8.6 Hz,
2
2
CH ), 2.69 t (2H J = 5.8 Hz, CH ), 2.43–2.19 m (4H,
2
2
1
3
2
CH ), 2.07–1.99 m (2H, CH ). C NMR spectrum, δ ,
2 2 C
ppm: 26.8 (CH ), 30.0 (CH ), 32.6 (CH ), 32.9 (CH ),
2
2
2
2
H O (100 mL) and extracted with DCM (4×30 mL).
2
3
4.5 (CH ), 45.3 (CH ), 70.1 (C), 115.2 (CH ), 125.8
2 2 2
The separated organic layers were dried over MgSO4,
filtered and evaporated. The obtained crude product was
purified by flash chromatography (petroleum ether–
(
CH, C H ), 127.5 (CH, C H ), 128.6 (CH, C H ),
6 5 6 5 6 5
1
39.1 (CH), 139.4 (C, C H ), 168.6 (C=O), 180.1
6 5
+
+
(C=O). HRMS (ESI ): 288.1594 [M + H] , calculated
acetone, 2 : 1, R 0.8) to afford 32 as yellow crystals.
f
for C H NO : 288.1594.
–1
17
21
3
Yield 56%, mp 76–77°C. FTIR spectrum, ν, cm : 1684
(C=O), 1259 (C–H). H NMR spectrum, δ, ppm: 9.83
1
5-Oxo-2-(pent-4-en-1-yl)-1-phenethylpyrrolidine-
2
-carboxylic acid (29). Colorless viscous oil, yield 80%.
s (1H, CHO), 7.86 d (1H, J = 8.0 Hz, CH, C H ), 7.58
6
5
–
1
FTIR spectrum, ν, cm : 3452 (O–H), 3026 (C–H, C H ),
d (1H, J = 3.0 Hz, CH, C H ), 7.48 d (1H, J = 2.0 Hz,
6
5
6 5
2
933 (C–H), 2845 (C–H), 1689 (C=O), 1459 (C–H).
C N H ), 7.32 d (1H, J = 2.0 Hz, CH, C H ), 7.26 s (1H,
3 2 3 6 5
1
H NMR spectrum, δ, ppm: 7.25–7. 16 m (5H, CH,
C H ), 5.90–5.86 m (1H, CH), 5.18–5.09 m (2H, CH ),
CH, C H ), 6.31 t (1H, J = 4.5 Hz, C N H ), 5.39 s (2H,
6 5 3 2 3
1
3
CH ), 3.97 s (3H, OCH ). C NMR spectrum, δ , ppm:
2 3 C
6
5
2
3
2
2
2
.47–3.32 m (2H, CH ), 2.88 t (2H, J = 5.9 Hz, CH ),
50.0 (CH ), 56.7 (OCH ), 105.8 (CH, C N H ), 111.6
(CH, C H ), 127.2 (CH, C H ), 129.1 (CH, C N H ),
6 5 6 5 3 2 3
2
2
2 3 3 2 3
.61 t (2H, J = 5.4 Hz, CH ), 2.47–2.20 m (4H, 2CH ),
2
3
2
1
.10–1.98 m (4H, 2CH ). C NMR spectrum, δ , ppm:
129.7 (C, C H ), 131.1 (CH, C H ), 133.2 (C, C H ),
2
C
6 5 6 5 6 5
6.8 (CH ), 28.2 (CH ), 30.7 (CH ), 32.8 (CH ), 33.0
161.8 (C, C H ), 139.5 (CH, C N H ), 191.6 (C=O).
6 5 3 2 3
2
2
2
2
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 12 2019

APPLICATION OF THE CLEAVABLE ISOCYANIDE IN EFFICIENT APPROACH
2569
(
E)-3-{3-[(1H-Pyrazol-1-yl)methyl]-4-meth-
(1H, J = 8.5 Hz, 4.1 Hz, CH, C N H ), 8.11 d (2H,
3 2 3
1
3
oxyphenyl}-1-phenylprop-2-en-1-one (33). To a solu-
tion of aldehyde 32 (0.21 g, 1.0 mmol) and acetophenone
J = 7.5 Hz, CH, C H ). C NMR spectrum, δ , ppm:
6 5 C
35.2 (CH ), 49.8 (OCH ), 53.3 (OCH ), 55.8 (OCH ),
2
3
3
3
(
(
0.13 g, 1.0 mmol) dissolved in MeOH (15 mL), ZrCl4
23.3 mg, 10 mol %) was added. The mixture was stirred
103.3 (C), 105.2 (CH, C N H ), 111.4 (CH), 119.7 (CH,
3 2 3
C H ), 125.7 (CH, C H ), 126.9 (CH, C H ), 127.7 (C,
6
5
6
5
6
5
at room temperature for 3 h. Upon completion of the
reaction (TLC monitoring), the solvent was evaporated
under reduced pressure. The residue was diluted with
C H ), 128.3 (CH, C H ),128.7 (CH, C N H ), 129.6
6 5 6 5 3 2 3
(CH, C H ), 130.2 (C, C H ), 130.8 (C, C H ), 131.2
6
5
6
5
6
5
(CH, Ar), 132.9 (CH), 133.4 (C, C H ), 137.7 (C), 138.7
6
5
H O (20 mL) and extracted with ethyl acetate (4×20 mL).
(CH, C N H ), 143.7 (C, C H ), 158.9 (C, C H ), 188.9
(C=O). HRMS (ESI ): 548.2156 [M + Na] , calculated
2
3 2 3 6 5 6 5
+
+
The combined organic layers were dried over Na SO ,
2
4
filtered and evaporated. The crude product was purified
by flash chromatography (ethyl acetate– petroleum
for C H N O Na: 548.2155.
3
1
31
3
5
CONCLUSIONS
ether, 3 : 1 R 0.7) to give chalcone 33 as white solid.
f
–
1
Yield 77%, mp 93-94ºC. FTIR spectrum, ν, cm : 1611
C=O), 1524 (C=C), 1328 (C–N). H NMR spectrum, δ,
Two efficient methods of synthesys of new pyroglu-
tamic acid analogues involving the Ugi–post-condensa-
tion and the Michael addition reaction have been devel-
oped. These methodologies demonstrate the utility of
1
(
ppm: 7.99 d.d (1H, J = 5.5 Hz, 2.5 Hz, CH), 7.71 d (1H,
J = 13.0 Hz, CH), 7.58–7. 55 m (3H, CH, C H ), 7.51 t
6
5
(
2H, J = 3.9 Hz, CH, C H ), 7.48 t (1H, J = 3.9 Hz, CH,
6 5
1-(2,2-dimethoxyethyl)-2-isocyanobenzene as an efficient
C H ), 6.92 t (1H, J = 8.5 Hz, CH, C N H ), 6.30 t (1H,
6
5
3
2
3
approach to the study of itʼs applicability in pyroglutamic
acid analogues synthesis. Subsequent tests of the poten-
tial biological activity of these compounds are ongoing.
It is anticipated that the convertible isocyanide possess
a potential for interesting applications in construction of
bioactive molecules for drug discovery.
J = 3.0 Hz, CH, C N H ), 5.37 s (2H, CH ), 3.91 s (3H,
3
2
3
2
13
OCH ). C NMR spectrum, δ , ppm: 50.3 (CH ), 56.3
3
C
2
(
OCH ), 105.6 (CH, C N H ), 111.9 (CH, C H ), 120.2
3 3 2 3 6 5
(
CH), 126.2 (CH, C H ), 127.4 (CH, C H ), 128.7 (C,
6
5
6
5
C H ), 128.8 (CH, C H ), 129.2 (C, C H ), 130.7 (CH,
6
5
6
5
6
5
C H ), 131.3 (CH, C N H ), 133.4 (CH, C H ), 138.2
6
5
3
2
3
6
5
(
C, C H ), 139.2 (CH, C N H ), 144.2 (CH), 159.4 (C,
ACKNOWLEDGMENTS
6
5
3
2
3
+
+
C H ), 189.4 (C=O). HRMS (ESI ): 319.1441 [M + H] ,
calculated for C H N O : 319.1439.
6
5
Authors are thankful to the Sheffield University, UK for
performing 1H, 13C NMR, FTIR, and HRMS spectra. Authors
20
19
2
2
3
-{3-[(1H-Pyrazol-1-yl)methyl]-4-methoxy-
are also thankful to the Ministry of Higher Education and Scien-
phenyl}-1-[2-(2,2-dimethoxyethyl)phenyl]-5-
hydroxy-5-phenyl-1H-pyrrol-2(5H)-one (34). A mix-
ture of chalcone 33 (0.31 g, 1.0 mmol) with isocyanide
tific Research (Iraq) for providing infrastructures to this work.
CONFLICT OF INTEREST
No conflict of interest was declared by the authors.
REFERENCES
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5 (0.19 g, 1.0 mmol) in MeOH (10 mL) was stirred at
room temperature for 24 h. After consuming the starting
materials (TLC monitoring), the resulting mixture
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4
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f
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3
3
3
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3
C H ), 7.76–7. 13 m (14H, CH, C H + OH), 7.88 d.d
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