Chemistry of Cyclic Imides: An Overview On The Past, Present and Future

1955 Send Orders for Reprints to reprints@benthamscience.
ae
Current Organic Chemistry, 2016, 20, 1955-2001
REVIEW ARTICLE
ISSN: 1385-2728
eISSN: 1875-5348
Chemistry of Cyclic Imides: An Overview on the Past, Present and Future Impact
Factor:
1.949
BENTHAM
SCIENCE
Kankanala Kavithaa, Koduru Sri Shanthi Praveenaa, Edupuganti Veera Venkat Shivaji Ramaraoa, Nandula
Yadagiri Sreenivasa Murthyb and Sarbani Pala,*
a
MNR Degree & PG College, Kukatpally, Hyderabad-500085, T.S., India; bDepartment of Chemistry, School of Engineering, Anurag
Group of Institutions, Ranga Reddy District-501301, India
Abstract: Cyclic imides are commonly encountered structural motifs in natural and syn-
thetic molecules with remarkable pharmacological properties. They are also used widely for
further functionalization through various chemical transformations. Currently, renewed focus
has been devoted worldwide on this important class of compounds for their potential new
applications especially in the area of medicinal / pharmaceutical chemistry as well as in drug
discovery. Consequently, their syntheses have attracted considerable interest. Various inno-
ARTICLE HISTORY
vative methodologies have recently been developed in order to access and functionalize this
class of compounds. For example, the combination of classical as well as modern reactions
Received: December 10, 2015
Revised: April 27, 2016 allowed synthetic chemists to perform the straight forward and direct synthesis of diversity
Current Organic Chemistry
Accepted: May 26, 2016 based library of compounds, often in 1-2 steps. The present report will cover the relevant and
DOI: recent advances in the field of occurrences, synthesis and chemical reactions of cyclic imides mainly from 1980
10.2174/1385272820666160530145
014
to the end of 2015.
Keywords: Cyclic imides, natural product, synthesis, reactions.
1. INTRODUCTION synthesize the complex molecular framework intelligently which

would not been readily accessible. Probably cyclic imides are one
The cyclic imide is an aza analogue of cyclic anhydride consist-
of the most attractive systems because of their wide range of
ing of two acyl groups bound to the nitrogen and the two carbonyl
reactions they can participate. Many biologically active compounds
carbons are connected by a carbon chain. In the recent years cyclic
contain cyclic imide. A brief list of those compounds is presented in
imides have enhanced the armamentarium of organic, medicinal
the following figure (Fig. 1) [5-10].
and polymer chemists in coping with various challenges [1-4].
Novel derivatives have been designed, developed and utilized to
Me COOH NMe2
O
O OMe O N O
N
N
N
O
O O
Alnespirone showed antidepressant and anxiolytic effect Alrestatin, Aldose reductase inhibitor NH2
Amonafide for breast cancer
OMe O
O
Et
NH
N OEt
Me H2N
NH O
O N O
O SO2Me
O CH2CH2NMe2 Aminoglutethimide for cushing’s syndrome and metas-
tatic breast cancer
Apremilast for treatment of auto immune and inflammatory disease
Azonafide, screened for anti-tumor activity
*Address correspondence to this author at the MNR Degree & PG College, Kukatpally, Hyderabad-500085, T.S., India; Tel: +91-40-23041488; E-mail: sarbani277@yahoo.com
1875-5348/16 $58.00+.00 © 2016 Bentham Science Publishers

1956 Current Organic Chemistry, 2016, Vol. 20, No. 19 Kavitha et al.
Fig. (1). Contd…
O H O O
O
HN Ph O N Ph N
N
H NH
O
H O O
Antineoplaston A10 for cancer
Palasimide
treatment O O
Binospirone Anxiolytic effect
H O O
O N H
Me N O N
O
N
Et N 4 N N
Me N Ph
Me Et Me O
O
Ethosuximide, Anticonvulsant Julocrotine as antiproliferative
Geprione, antidepressant and anxiolytic
O N O
H
N N NH
NH
N N N SCCl3
4
O H O N O
O O
N
Buspirone Captan
O
Anxiolytic psychotropic drug Pesticide
Elinafide (LU 79553)

Antitumor activity
Br
N
H2N
O O
H
O
N N
N N F
O
O
O
HN O
HN
Lamprolobine
O O
alkaloid
Ranirestat Lenalidomide
Inhibitor of aldose reductase Myelodysplastic syndromes (MDS)
Me O O Me O O
Ph
O NMe2
N Me O N
Me NH
O O
Me O O2N
Methsuximide
O OH
Mitonafide
Anticonvulsant Me
Migrastatin Antitumor
Treatment of cancer
Ph O O
O O
N N O
N N O Me
NH
O O O
O O
NH2
Phensuximide
n Pomalidomide
Anticonvulsant
Kapton Anti-angiogenic
Polyimide sheet
Chemistry of Cyclic Imides Current Organic Chemistry, 2016, Vol. 20, No. 19 1957
Fig. (1). Contd…
O O O N O N
H H H
HN N N N N
O N N N N N
4 4
O H O H H O
Thalidomide Tandospirone Zalospirone
Mainly in cancer and leprocy Anxiolytic, antidepressant selective 5-HT1A partial agonist
O Cl O OH Br
Me
H O
N R N Me
O
Me COOH
O Cl O O N N F
Procymidone, Pesticide Salfredin,
HN O
C1, R= H,
C2, R=CH2 CO2H, O
C3, R=CHMeCO2H
Ranirestat, Inhibitor of aldose reductase
Inhibitor of aldose reductase
Fig. (1). Biologically active compounds containing cyclic imide framework.
2. NATURAL OCCURRENCE and quite fascinating. Many of them have pharmacological

activities which can be explored to get therapeutic benefits (Table
Cyclic imides are found in nature as they are synthesized by
1) [11-43].
living organisms. A variety of cyclic imides were isolated from
natural sources as primary or secondary metabolite. The list is long
Table 1. Naturally occurring cyclic imides.
From Brazilian Ascidian Didemnum granulatum
Granulatimide [11] G-2 checkpoint inhibitor 6-Bromogranulatimide [12] Isogranulatimide A [11, 13]
H H G-2 checkpoint inhibitor
N O N O
O O H
O N O
NH NH
N
N N N N
H Br H
N N
H
Isogranulatimide B [11, 13] Isogranulatimide C [11, 13]

H H
O N O N
O O
N
N N
N N
H N H
From Caribbean ascidian Didemnum conchyliatum
Didemnimide A, B, C, D [14] Didemnimide E [14]

predetor deterrents predetor deterrents
H O H O
N N
O R2 O
H
N N
N N
R1 N N Me
H H
A; R1 =H, R2 =H, B; R1=Br, R2 =H,
C; R1=H, R2=Me,D; R1 =Br,R2 = Me

Table 1. contd…
From Streptomyces sp
Rebeccamycin [15] Indocarbazostatin A, B, C, D [16] antibiotic

topoisomerase inhibitor O
HN
Cl O
O R1
O N N
NH HO
HO O
OH N H
MeO HN
OH O Me
R2OOC
OH
Cl
A, R1 =H, R2 = Et,B, R1 =NH2, R2= Et,
C, R1= H, R2 = Me,D, R1 = NH 2; R2= Me
FromActinomadura melliaura
AT2433-A1, A2, B1, B2 [17]

antitumor antibiotic
Me
O N
O
N
O H N
R1 O O R2
OH
HO
MeO OH
A1, R1= NHMe; R2=Cl, B1, R1= NHMe,; R2 = H

A2,R1= NH2; R2 = Cl. B2 R1 = NH2 ; R2= H
From Bacterium Pseudomonas fluorescens
Moiramide B [18] peptide antibiotic Andrimid [18] peptide antibiotic

Me O Me O
Me Me Me Me
O Ph O O Ph O
NH NH
Me N N Me N N
H H H H
O O O O
From the culture broth of a strain of actinomycetes
BE-13793C (J-104303) [13] Actiphenol [19]

H anti tumor and antifungal
O N O
O
OH O NH
Me
O
N N
H H R
HO OH
Me R = H, Actiphenol
R = OH, Nong-Kang 101-G
From Lissoclinum Voeltzkowi Michaelson
Dichlorolissoclimide [20] cytotoxic labdane derivative

OH
H2C
O
OH
HN Me
Me
O Me
H
Cl
Cl
Table 1. contd…
From Delphinium (larkspurs)
MethylLycAconitine [21] toxic to animals

Treatment of spastic paralyses in man and it has been shown to have insecticidal properties
Et OMe
N
O H
MeO
OMe
O OMe
O HO HO
N
O
Me
From Aspergillus japonicus JV 23
Asperparaline A, B, C [22]
induce paralysis in silkworm (bombyx mori) larvae
Me
N O
N R2
CO H N
R1 H Me Me
O
A, R1 = Me; R2 = Me.B, R1= Me; R2= H.C, R1= H; R2= Me.
From Pleurobranchus albiguttatus and Pleurobranchus forskalii
Chlorolissoclimide [23] Dichlorolissoclimide [23]

cytotoxic bicyclic diterpene alkaloids OH
OH O OH
O Me
OH HN
Me Me
HN H Me
Me O
H Me Cl
O
Cl
Cl
From Aspergillius strain IMI 337664
Ketoaspergillimide [24]
anthelmintic activity
O Me
Me
N O
N
H
Me
O Me
Me H N
From Lissoclinum Sp
Haterumaimide A, E, F, N, P [25] Haterumaimide B, G [25] Haterumaimide C [25]

cytotxic O O H
N
Cl NH
O
O
R1 O
H
Me
Me NH
OH Me O
Me H Me Cl
O Cl Me
R4
R2 CH2
Cl
R3 H
R Me Me
H
A, R1 = Cl, R2 = H, R3 = OAc, R4= OH, Me Me O
E, R1 = Cl, R2=OH, R3= H, R4 = OH, B, R= Cl

F, R1= H, R2= OH, R3 = H, R4 =OH, G, R= H
N, R1 = H,R2 = H, R3= OAc, R4= OH,
P, R1= H, R2=H, R3=OH, R4= H
Table 1. contd…
Haterumaimide D, H [25] Haterumaimide I [25] Haterumaimide J, K [25] Haterumaimide O [25]

O O H O O
N
NH NH NH
O
O O O
OH Me O OH
Me Cl Me Me
Cl Me Me Cl CH2 Cl CH2
R H
Me Me O RO OAc
H H H
Me Me O Me Me Me
D, R= Cl, H, R= H J, R= HK, R= Ac
From Pleurobranchus Sp
Haterumaimide L [26] Haterumaimide M [26] Haterumaimide Q [26]

O O O
Cl
Cl Me H
H Me
NH Me Me NH NH
Me Me
Me Me H
H OH O
Me
H O OH O
OH O CH2
O Me OH
From a specimen of the marine ascidian, Eudistoma Sp., and Maxomycetes
Arcyriaflavin A, B, C, D [27] [28]

H
O N O
R1
R2 N N R3
H H
A, R1 =H, R2 =H, R3 =H, B, R1 =H, R2 = OH, R3 =H, C, R1 =H, R2 =OH, R3 = OH, D, R1 = OH, R2 = H, R3= OH
From Maxomycetes
Arcyriarubin A, B, C [13] Stachybotryactam V [29]

protein kinase inhibitor antagonist of endothelin and display strong immuno suppressant activity
H HO
N HO
O O
Me
Me
Me O
H O
R1 R2
Me NH
N N
H H O
A, R1 =H, R2 =H, B, R1 =H, R2 = OH, C, R1= OH, R2= OH.
From slime mould
Arcyroxepin A, B [30] Arcyriacyanin A [30] Dihydroarcyriacyanin A [30] Arcyroxocin A, B [30]

fungal metabolite protein kinase c inihibitors cytotoxicity against jurkat cells cytotoxicity against jurkat cells
H H H H
N N O N O O N
O O O O O
H
H
R
R NH
NH NH
N O N
N N N H O
H H H H
A, R=H, B, R=OH
A, R=H, B, R=OH
Arcyriaverdin C [30] Dihydroarcyroxocin A [30] Dihydroarcyriarubin B, C [30]

H H exhibit significant inhibition in tcf/-catenin transcriptional activity
N O O N
O O H
OH N O
H H O
HO H H
NH
N O NH N
H O H O HO R
N N
H H
B, R=H, C, R=OH
Table 1. contd…
From prosobranch mollusks, ascidians and sponges
Polycitrin A, B [31, 32]

Br
OH
O
Br
HO
N
Br
O
R
Br
A, R=OH, B, R=OMe
Produced in culture by Streptomyces uncialis
Cladoniamide A, B, C [33] BE-54017 [33]

Me Me
N O N O
O O
OH HO OH
HO
Cl
R1 N N
R2
N N
H
MeO Me OMe
A, R1 =Cl, R2=H, B, R1=Cl, R2 = Cl, C, R1=H, R2= H.
From the pods of Butea monosperma and identified as palasonin-N-phenyl imide
Palasimide [34] Derivatives of rebbecamycin [34]

H O H
H N O
O
O N Ph
H O
H
N N
H
O R1
OH
HO OH
R2O
(R 1=Cl, R 2= Me), (R 1= H, R2 = Me), (R1 =R2 =H)
Hirsutellone A [34] Hirsutellone D [34]

anti mycobacterium tuberculosis (an mic value of 0.78 g/ml)
H O
H O H
O H
Me O
H O H
Me H H NH
O H
H H O
H NH
O Me
Himanimide A, C [35] Himanimide B [35] Himanimide D [35]

cytotoxic activity cytotoxic activity cytotoxic & antibacterial activity
O Me OH O Me
O O
O Me
Me O Me
R N Me OH HO N
Ph HN Ph
O Ph O
A, R= H, C, R=OH O
Table 1. contd…
Isolated from a purple Red Sea tunicate identified as an Eudistoma sp
Segoline A [36] Segoline B [36] Isosegoline A [36]

antiproliferative activity antiproliferative activity antiproliferative activity
O OMe
H
Me O HN
Me O N
N N
Me NH O Me
N
N NH
N Me
O
O
MeO MeO
From Streptomyces griseus
Cycloheximide (naramycin a, hizarocinactidione, actispraykaken, U-4527) [37a]

interferes in protein synthesis and antiproliferative
O O
HO Me
HN
O
Me
From Streptomyces pulveraceus
Epiderstatin (a distinctive glutarimide antibiotic) [37b]

Me
O
NH O NH
Me
O O
From Streptomyces platensis bacteria
Migrastatin [38a] Isomigrastatin [38a]

anticancer activity anticancer activity
HO OMe MeO
O
O
Me
HN O HO
HN Me Me
O O O O
O Me Me
O Me O
Isolated from the fermentation broth and mycelium of Streptomyces platensis subsp. rosaceus
Dorrigocin A [38a] 13-Epi-dorrigocin A [38a]

antiproliferative blocks translation O HO OMe
Me
HO O HN HO
O
Me
HN HO O Me HO
Me O Me
O
O Me HO
O Me
O
Lactimidomycin [38b] Dorrigocin B [38b] NK30424 A/B [38a]

antiproliferative blocks translation antiproliferative blocks translation
O
MeO MeO H3N+ COO-
O O
HN OH O Me Me
HN O HO HN OH O HO S
O O O O OH O O O
3 O OH
Me Me Me Me Me Me
Table 1. contd…
A glutarimide alkaloid from Croton membranaceus

Julocrotine [39]
anti-inflammatory, analgesic and anti-protozoa
Ph
Et O O
N
Me HN O
From the roots of Cordia globifera

Cordiarimides A,B [40]
has potential for cancer chemoprevention
NHCOMe
O N O
R
A, R= -COPh, B, R= -CH(OH)Ph
Glutarimide alkaloids from Croton pullei
Crotonimide A, B [41] antimicrobial

ROCHN O
Ph
N
O
A, R= Et, B, R= iPr
A glutarimide antibiotic actiketal isolated from the culture fluid of the epiderstatin-producing streptomycete, Streptomyces pulveraceus subsp. Epiderstagenes
Actiketal [42]
antibiotic
Me OH
O O
NH
O
Me O
From the Arctic actinomycete Streptomyces nitrosporeus

Nitrosporeusine A [43a] Nitrosporeusine B [43a]
Antiviral against the H1N1 virus in MDCK cells Antiviral activities against the H1N1 virus in MDCK cells
H H
HO O N HO O N
O O
S H S H
O OH O OH
From the Sesbania drummondii

Sesbanimide [43b]
potent antitumor alkaloids
O
O CH2
HO
HO
HN
Me
O
O O
3. SYNTHESIS by 1,8-diazabicyclo[5.4.0]undec-7ene (DBU) (Scheme 1). An in-

3.1. From Single Component tramolecular photochemical [2+2] cycloaddition strategy was ap-
plied to synthesize cyclobutane fused cyclic imides [45].
The cyclic imide derivatives are conveniently prepared by fol-
O
lowing general procedures: O
3 DBU, O2 atm Ar
3.1.1. By Cyclization Ar Ar1 NR
N
3,4-Diaryl substituted maleimides were synthesized by V. R. MeCN
O R Ar1
Pattabiraman et al. [44] via eco-friendly oxidative cyclization of O
phenacyl amides in the presence of atmospheric oxygen, facilitated Scheme 1. Preparation of maleimides from phenacyl amides.
HO COOH
SiO2 OH SOCl2 SOCl2
SiO2 O COOH SiO2 O COCl
SiO2 Cl
reflux/3h DMF/CH2Cl2
Silica gel SBBA SBBC
O Cl O OH
Ar O
NH Ar O
N
..
O CH2Cl2 H
N Ar +
+
reflux O
30-55 min SiO2 O O
O O O
O O
SiO2 SiO2
HO
Scheme 2. Cyclodehydration of N-arylsuccinimic acids.

EtOSCS
O O
O
Lauroyl peroxide MeO N
N R R
O 1,2-DCE/MeOH,heat
O O
Scheme 3. Synthesis of spirocyclic imide by ipso-type radical cyclization.
Moghadam et al. [46] performed intramolecular dehydration 3.1.2. By Ring Expansion

reaction to synthesise N-aryl succinimides by refluxingN-
You [50] and Alcaide [51] have independently synthesized suc-
arylsuccinimic acids and recyclable dehydrating agent silica bound
benzoyl chloride (SBBC) in dry dichloromethane.0.8 gm of SBBC cinimide derivatives at room temperature in good yield via ring
was used for 1 mmol of the substrate to get good yield. SBBC was opening and expansion of readily accessible 4-formyl--lactams to
prepared by following a three step strategy from silica gel powder. Breslow intermediate [52] in the presence of highly efficient and
At the end of the reaction, the by product silica bound benzoic acid readily available 20 mol % NHC (N-Heterocyclic carbenes) as a
(SBBA) was efficiently converted into SBBC and reused (Scheme catalyst in DCM under mild condition (Scheme 6).
2).
Spirocyclic structures having succinimide moiety were synthe- N N
Mes Mes
sised by an ipso-type radical cyclisation either on a 2-substituted
furan or a suitably substituted pyrrole followed by oxidation.
Ph DBU
(Scheme 3) [47].
Nathan et al. [48] successfully accomplished the synthesis of Ph CHO
maleimides from maleidiamides (Scheme 4). O O
N
NNHC N N
Mes Mes
O O R .. O R
N AcONa,
Ac2O
NPh + NH
rt
NHPh
Mes
O O +
N O Mes
Scheme 4. Cyclisation of maleidiamide. Ph N OH
N
Cyclic imides were synthesized by Barn et al. by applying cy- Ph
BRESLOW INTERMEDIATE
Mes O N
clization followed by cleavage strategy. They optimized the cleav-
age conditions and synthesized different succinimides and N Mes N
phthalimides. The methodology was then applied to synthesize a R Mes R O
new class of -opioid receptor ligand (Scheme 5) [49]. N OH
O Ph
O NHR2 +
O R N
HOAc / toluene
NR2 Mes O
O R N
R1
R1 O R
Scheme 5. Synthesis of cyclic imides using polypeptide resin. Scheme 6. Conversion of 4-formyl--lactams to succinimides using NHC.
3.1.3a. By Oxidation of Lactams Copper (I) catalyzed oxidation of cyclic amines to the cyclic
A rapid synthesis of cyclic imides from lactams was reported imides has been developed (Scheme 10) [57].
using peracetic acid (MeCO3H) and manganese (II) chloride in O
ethyl acetate and under microwave irradiation in good yields
CuCl, 10 mol%, TBHP
(Scheme 7) [53]. Ar NR Ar NR
MeCO3H / MnCl2 CH2Cl2, 50°C
(CH2)n (CH2)n
AcOEt / AcOH O
O O O
N Microwave Irradiation N Scheme 10. Copper catalyzed oxidation of arene-fused cyclic amines.
H H
90 W, 5 min.
3.1.4. By Radical Fragmentation of Carbinolamides
n = 1,2,3
A radical fragmentation sequence has been used for the prepa-
Scheme 7. Oxidation of lactams to cyclic imides using peracetic acid and ration of cyclic imides. Treatment of the carbinolamides with diace-
MnCl2 .
toxyiodobenzene gave the imides in low yield (Scheme 11) [58].
The oxidation of -caprolactam [54] in CCl4 was performed.
The major product azepane-2,7-dione, was formed with a yield of 3.2. From Two Components
more than 90% and can be a potential intermediate during the syn- 3.2.1. From Cyclic Acid Anhydrides
thesis of commercially important antibiotics (Scheme 8).
The most important synthesis of cyclic imides includes conden-
O O
sation of cyclic acid anhydrides with primary amines under various
NH
conditions followed by concomitant dehydration as presented in the
NH
O3 / CCl4 following sections.
O
3.2.1.1. Synthesis via Amic Acids
N-Alkyl maleimides and citraconimides were synthesized by
Scheme 8. Oxidation of lactams to cyclic imides by ozone. the cyclization of N-alkyl maleamic and citraconamic acids pre-
3.1.3b. By Oxidation of Cyclic Amines pared via the reaction of different amines with maleic and citra-
conic anhydrides (Scheme 12) [59a-c]. Polyamides eg Kapton
Five and six membered cyclic imides were synthesized by en-
polyamide sheet (Fig. 1) can be synthesized by cyclodehydration of
docyclic oxidation of corresponding cyclic amines using ruthenium
amic acids. These polyamides are important for their heat
oxide and sodium periodate in ethyl acetate whereas seven mem-
resistance, toughness and electric insulation.
bered ring underwent both endo and exocyclic oxidation under the
same condition (Scheme 9) [55, 56]. 3.2.1.2. From Cyclic Acid Anhydrides and Amines
O Cyclic imides are synthesized from acid anhydrides with substi-
R tuted amines using Lewis acids (ZnBr2/ZnCl2), hexamethyldisi-
N n(H2C)
RuO2/ aq NaIO4 lazane (HMDS) and Et3N [60], pyrolytic [61], diphenyl-2-oxo-3-
NR
oxazolinylaphosponate (DPPOX) [62], pyridine [63] acetic acid or
(CH2)n EtOAc DMF [64], water [65], N,N'-carbonyldiimidazole (CDI) as a con-
O densing agent [66]. Solid phase synthesis of a series of cyclic
Scheme 9. Conversion of cyclic amines to cyclic imides using ruthenium imides using DMAP in DMF on polystyrene resin [67] and
oxide-sodium periodate as oxidant. DABCO [68] were reported (Scheme 13). A facile green synthesis
O Me O Me O Me O Me
HN H PhI(OAc)2 HN HN HN
HO O H O H O H
•
Ph Ph Ph Ph
I2, CH2Cl2
H H • H H
H H I
Scheme 11. Radical cyclization of carbinol amides in the presence of diacetoxyiodobenzene.
O O
et
N O
N
O O O e
O O sh
O + RNH2
(Et)2O
NHR
(MeCO)2O
NR
ide O
n
m
lyi
COOH NaOCOMe O
N
No
O O
100°C, 1h
P O
O n
Scheme 12. Cyclodehydration of amic acid and its application to polyamide synthesis.
[61] [62] [63]

H2, 10% Pd-C Et2O, Ac2O, NaOAc Pyridine
MeOH, 3 days or Et3N, DPPOx 6h reflux
[60]
[64]
HMDS, Lewis acid O O HCON(Me)2
1-4 h reflux, reflux
O + RNH2 N-R
dry benzene, Argon
[65]
[69] O O
H2O, reflux
PTSA
Solid phase [68] [67] [66] 2h
K2CO3/TBAB/ DABCO CDI
OH
alkylating agent
Solid phase CH2Cl2, 0 -45°C
DMAP, DMF, AcOH
Scheme 13. Synthesis of cyclic imides from cyclic anhydrides and amines.
O
NHSO2Me
O
O
NHSO2Me NHSO2Me
O O
O
AcOH, NaOAc O N O
reflux, 10-20 min
NO2 NH2
Nimesulide
Scheme 14. Synthesis of cyclic imides from a NSAID as well as COX-2 inhibitor nimesulide.
RNH2,
O O TaCl5,SiO2 [73] O
H2O [74]
NH4Cl, DMAP [70], [72]
NH O
NR
or NH4OAc [70]
O or NH2OH.HCl, DMAP[71] O O
NH2OMe-HCl [75]
N OMe
O
Scheme 15. Synthesis of cyclic imides under microwave irradiation.
of N-substituted imides was reported by P. K. Dubey and his co- [71]. A number of cyclic imides were synthesized from cyclic acid
workers [69]. anhydrides using ammonium acetate (NH4OAc) [72], a mixture of
K. Kavitha et al. have reported a simple and rapid synthesis ammonium chloride (NH4Cl) and 4-N,N-dimethylaminopyridine
[70] of novel substituted cyclic imides (Scheme 14) that were de- (DMAP) [72, 73] or hydroxyl amine hydrochloride NH2OH. HCl
signed from a well known NSAID, nimesulide. The aromatic amine and DMAP [74], TaCl5-silica gel [75] under microwave irradiation.
prepared from nimesulide was reacted with a variety of cyclic acid A clean, green and rapid synthesis was reported in water using
microwave irradiation by Polshettiwar and Verma (Scheme 15)
anhydrides and sodium acetate to afford the desired products within
[76].
few minutes. Few synthesized compounds showed anti-
inflammatory activities when tested in rats. Imidoyl chlorides, obtained from secondary acetamides and ox-
alyl chloride were reacted with propylene glycol to produce the
3.2.1.3. Using Microwave amine hydrochloride salts. These salts were reacted with phthalic
The first microwave synthesis of 1-methoxypyrrolidine-2,5- anhydride in pyridine-toluene to produce cyclic imides (Scheme 16)
dione was reported by Butcher and his co-workers. (Scheme 15) [77].
HO
1) 2 eq. OH
O 1.2 eq. pyridine Cl
1.1 eq. (COCl)2 0°C Me
R R R NPhth
N Me N
H THF, 0°C, 15 min H 2) 2 eq. phthalic anhydride
3 eq. pyridine, toluene,
reflux, 12h
Scheme 16. In situ synthesis of cyclic imides from phthalic anhydride.
O Cyclic imides were obtained by dehydrative condensation of

CO2H CF3CONH2 diacid and aminoacids [79] or amines [80] at high temperature
R R NH (Scheme 18). Werner and co-workers [81] reported the synthesis of
CO2H EDCCl, HOBt 4-nitro-N-aryl substituted cyclic imides from diacids using poly
O phosporic acid (PPA). Cyclic imides were also obtained using
DCC, DMAP in the presence of DCM [82]. Di acid chlorides were
Scheme 17. Synthesis of unsubstituted cyclic imides from dicarboxylic
acids. treated with lithium nitride to [83] afford cyclic imides (Scheme
18).
3.2.2. From Dicarboxylic Acids or Acid Chlorides
A series of N-substituted cyclic imides [84, 85] were synthe-
Trifluoroacetamide was reacted with diacids in the presence
of N-ethyl-N-dimethyl-aminopropylcarbodiimide (EDCCI) and sized by irradiating various diacids with different amines using
1-hydroxybenzotriazole (HOBt) to afford cyclic imides of different microwave (Scheme 19). Anticancer and anti-inflammatory activi-
ring size providing a single step asymmetric synthesis of thalido- ties of these compounds were tested.
mide (Scheme 17) [78].
[80] [81] [82]
210 °C PPA, 80 °C DCC,DMAP,

O CH2Cl2
O
R R'NH2
[79] R N-R' [83]
250 °C O
R= OH / Cl O DME, Li3N
Scheme 18. Synthesis of cyclic imides from dicarboxylic acids or diacid chlorides.
COOH O
R=
N COOH
NR
N CH2
N
O
N COOH O
N CH2
N
N COOH
NR
N
600W
RNH2 O CH2
COOH S
2-5min N
O
N COOH N
H N (CH2)2
NR
N
H
O
COOH O
O CH2
COOH NR
O
Scheme 19. Synthesis of cyclic imides from dicarboxylic acids under microwave irradiation.
RuH2(PPh3)4 (5 mol%)
+ Br` O
R N N (5 mol%)
R3 i-Pr i-Pr R
OH R2
+ R2 NH2 N
OH R3
R1 NaH (20 mol%), MeCN (5 mol%) R1
toluene, reflux, 24 h, -4H O
2
Scheme 20. Succinimide derivatives from diols.
O O
Ru3(CO)12 (5 mol%)
N CO (10 atm) N
H
N H2O (2 eq.)
ethylene (7 atm) O N
toluene,160 °C, 24 h
Scheme 21. Ru-catalyzed carbonylation of aromatic amides to produce N-substituted phthalimide.
Pd(OAc)2 (10 mol%) O O

O CO (1 atm)
R Ar R
R AgOAc (2 eq.) N
NHAr NAr Reported by Yu et al
TEMPO (2 eq.) PdLn JACS, 2010
H KH2PO4 (2 eq.) Pd0Ln O
n-hexane,130 °C, O
18 h
O
NHCOPh
CO / PdL4 Reported by Perri et al
NPh
DMAc, DBU Patent no 4,933,467, 1990
I
O
3
Scheme 22. Synthesis of succinimides by palladium-catalyzed carbonylation of C(sp )-H bond.
R2
O R
O N
O
BF3.Et2O
R NC + R1 O R1
N THF, reflux
N R2
H
Scheme 23. Synthesis of cyclic imides via cascade reaction.
3.2.3. From Diols TEMPO was used for reoxidation of Pd (0) to Pd (II). Perry et al.
Simple diols and primary amines were condensed successfully performed carbonylation on o-iodo-N-arylbenzamide by using
in a single atom economical and operatively simple step using an tetrakis(tri-phenylphosphine)palladium as a catalyst, dimethy-
in situ generated ruthenium catalytic system for synthesis of cyclic lacetamide as a polar aprotic solvent and DBU as a base (Scheme
imides. The methodology developed by Muthaiah et al. [86] is very 22) [89].
useful for the syntheses of important building blocks in natural 3.2.5. From Isocyanides and Enediones
products and drugs (Scheme 20).
A unique cascade cycloaddition reaction of alkyl isocyanide
3.2.4. From Amides and methyleneindolinone has been reported by Li et al., which rep-
Chatani and co-workers reported synthesis of phthalimides resented a novel transformation involving the ring-opening of
from N-benzoylpyridin-2-ylethylamine derivatives involving direct- methyleneindolinone and simultaneous formation of two new het-
ing group assisted C-H activation and carbonylation approach under erocyclic rings. (Scheme 23) [90].
high pressure [87] (Scheme 21).
3.2.6. From Diesters
Yu et al. reported Pd(OAc)2-catalyzed -C(sp3)-H carbonyla-
tion of N-arylamides using CO at room temperature and pressure Shi Li and his co-workers synthesised polycyclic imides from
(STP) in the presence of KH2PO4, an oxidant AgOAc and an effec- 2,3-bis(alkoxycarbonyl)arenes (Scheme 24) [91]. The products
tive co-oxidant TEMPO (2,2,6,6-tetramethylpiperidinyloxy) [88]. were dependent on substituents at 1,4-positions.
R R O
CO2Me LiAlH4 , AlCl3
NR1
CO2Me R1NH2
R R O
Scheme 24. Synthesis of cyclic imides from 2,3-bis(alkoxycarbonyl)arenes.

O
CO2Me R1 R1
R2
MeCN/H2O/Na2CO3 N R2
+
ClH.H2N R3 R3
CO2Su rt, 3-6 h.
O
Scheme 25. N-phthaloylation using MSB.
O
EtO
1mol. NH2R
N R
O NaCN, H2O, THF O CN

1. H2O, 140°C O
2 .180°C, 1.5h
Cl3C OEt rt, 1-4h. HO OEt O
0.5 mol. H2N EtO O
( )n NH2 OEt
N
( )n N
O
O
O O O
CCl3 OH R
N
NaCN, H2O, THF NH2R
CN
O O 1. H2O, 140°C O O
rt, 1-4h.
2 .180°C, 1.5h
Scheme 26. Synthesis of cyclic imides from -cyano acid.
[94] Fe(CO)5, NaBH4 O

R
R
MeCOOH,CuCl2.2H2O
+ R2NH2 NR2
[95] CO, Fe Cat
R1
R1 [96] Fe3(CO)12 [Fe] (10 mol%)
R2= alkyl or H O
CO, THF, 120 °C
Scheme 27. Iron-catalyzed carbonylative synthesis of succinimides.
R O
Rh4(CO)12 (2 mol%)
R
P(OEt)3 (8 mol%)
+ H2N Py N
Toluene,CO (3 bar) Py
R
R 100 °C
O
Scheme 28. Synthesis of maleimide via carbonylative cyclization.
J. Richard Casimir and his co-workers used methyl 2- 3.3. Using Three Components
((succinimidooxy)carbonyl) benzoate (MSB), a new, highly effec- 3.3.1. From Alkynes, Amines and Metal Carbonyls
tive and readily available reagent for N-phthaloylation which is
Alkyne-iron carbonyl complexes reacted with amine or ammo-
simple, racemization-free and gives excellent results with acids,
nia to give cyclic imides. (Scheme 27) [94-96].
alcohols, dipeptides, carboxamides, and esters having amino group
at the alpha position. (Scheme 25) [92]. A chelation assisted transformation for the synthesis of N-
substituted maleimides was designed by N. Chatani and his co-
3.2.7. From -cyano Acids workers. A MCR was performed by mixing alkyne, carbon monox-
The betacyano acids have been found to be useful precursors ide and substituted methyl amine in the presence of Rh4(CO)12 /
for the preparation of various cyclic imides (Scheme 26) [93]. P(OEt)3 (Scheme 28) [97].
O
0.033 mmol Ru3(CO)12 R1
CO (1 atm)
R1 R2 R N C O N R
+
mesitylene
R2
1 mmol 3 mmol 130°C, 3-42 h
O
Scheme 29. Intermolecular ruthenium-catalyzed synthesis of maleimides.
O
R2 R1
R1 TsN3 R1 TsN
CO2R H
C N
CuI Ts [2+2] O R2
H
CO2R
Cs2CO3
O NHTs
Ts
N TfOH or TsOH R1
R2 O
-ROH O
O
R1
OR R2
Scheme 30. Copper(I) catalyzed MCR for the synthesis of substituted maleimides.
H
R5 IrH5(PiPr3)2 O N O
R1
+ R3
CN R2
NC R2 H2O -NH3 R5 R1
R4
R3 R4
Scheme 31. Iridium-catalyzed synthesis of glutarimides from nitrile, cyanoolefin and water.
O Pd(OAc)2 (5 mol%) O
CO (1 atm)
OMe dppp (10 mol%)
+ RNH2 N R
Cs2CO3 (2 eq.)
I
toluene
O
95 °C, 24 h
Cs2CO3 -MeOH
O O
[Pd] RNH2
OMe OMe
CO PdI NHR
O O
Scheme 32. Aminocarbonylation of o-halobenzoates leading to phthalimide derivatives.
3.3.2. From Isocyanates, Alkynes and Carbon Monoxide catalyst and base respectively for the synthesis of maleimides
Intermolecular ruthenium-catalyzed [2 + 2 + 1] cycloaddition of (Scheme 30) [99].
isocyanates, alkynes, and carbon monoxide proceeded efficiently in 3.3.4. From Olefin, Azides and Water
mesitylene at 130 °C to generate a wide range of polysubstituted Murahashi and co-workers have synthesized glutarimide deriva-
maleimides in good yields (Scheme 29) [98]. tives using an iridium polyhydride-complex [IrH5(PiPr3)2] catalyzed
three-component reaction of a cyanoolefin, a nitrile and water
3.3.3. From Alkynes, Azides and Oxobutynoates
(Scheme 31) [100].
Ma et al. performed a multi component reaction (3CR) of sul-
3.3.5. By Aminocarbonylation of o-halobenzoates
fonyl azides, terminal alkynes, and aromatic 2-oxobut-3-ynoates
catalyzed by copper (I)- to give functionalized 2-iminooxetanes, Larock and Worlikar developed a simple procedure involving
which underwent further smooth rearrangement to the functional- the aminocarbonylation of simple o-halobenzoates to generate sub-
ized maleimide derivatives by trifluoromethanesulphonic acid cata- stituted phthalimides having a wide range of functional groups in
lysed ring expansion under appropriate reaction conditions. The good yields using palladium(II)acetate as a catalyst, 1,3-
copper (I) iodide (CuI) and cesium carbonate (Cs2CO3) were the bis(diphenylphosphino)propane (DPPP) as a ligand, and Cs2CO3 as
O O Me CO2Et
+
CN
Me Et EtO Et CN
HCN
Me Et
HO2C CO2H NC CO2Et
NH3
Me H+
Me
O O Et Et CN
N
H
Scheme 33. Synthesis of ethosuximide.
Hydrolysis
Michael addition Reduction
Photochemical Cyclicimide
imide Cycloaddition
reaction
Cyclic
Cross coupling MCR

Alkylation & acylation
Fig. (2). The involvement of cyclic imides in various chemical reactions.
[106] [107]
2 eq. R X, 2 eq. KOH R X, KF
[bmim]BF4 40 or 80°C, 2-5 h ionic liquid
O O
[104] [108]
X R K2CO3 R X, NaI, 1.1 eq. Cs2CO3
NH NR
2-Butanone DMF, MS 4 Å MW
51 h reflux (100-200 W)70°C, 10-60 min
O O
[110]
KF-Al2O3, Me
O
Scheme 34. N-Alkylation of aromatic cyclic imides using alkyl halides.
a base (Scheme 32) [101]. Alper et al. also performed Pd-catalyzed 4.1. Alkylation
double carbonylation of o-dihaloarenes with amines for the synthe- 4.1.1. N-Alkylation
sis of N-substituted phthalimides.
4.1.1.1. Using Alkyl Halides
3.3.6. Using Four Components The sodium or potassium salt of cyclicimide was N-alkylated
3-Ethyl-3-methypyrrolidine-2,5-dione (Ethosuximide) was syn- with a primary alkyl halide to give the corresponding N-alkyl de-
thesized according to the following Scheme (Scheme 33) [102]. rivative [103]. A practical, efficient and selective N-alkylation of
cyclic imides with alkyl halides was accomplished using K2CO3
4. CHEMICAL REACTIONS during synthesis of tandosporine analogues by Kossakowski et al.
Cyclic imides have found vast applications in a range of chemi- using 33 % excess of alkyl halide in butanone [104] and during the
cal reactions including cycloaddition, MCR, cross coupling, photo- synthesis of stemoamide by Wang et al. [105], using potassium
chemical reactions in addition to several other classical reactions as hydroxide in ionic liquids [106] or potassium fluoride [107],
summarized in Figure 2. Cs2CO3 as the base, in anhydrous DMF [108] using PT catalysts
TMS O Me
TMS
1) K2CO3 (2 eq.)
H
succinimide (2 eq.) O
TBSO OEt
2) Lindlar Catalyst/ H2 TBSO H H N
3) NaBH4, EtOH O
N
Br
O Stemoamide
Scheme 35. N-Alkylation of succinimide during the synthesis of stemoamide.
O O O
BrCH2CO2Et
-OMe
KOH NH
NH N CH2CO2Et
X X X OMe
Y Y Y
O O O O
X=N, Y=CH or X=CH, Y=N
Scheme 36. Rearrangement during N-alkylation.

H2C
O
i) 5-bromopent-1-ene, O H
NaH, DMF, r.t. TFA,CH2Cl2
NH
ii) 5% Grubbs II, N
Me3Si N
4 eq, allylSiMe3, OH
O H
CH2Cl2, reflux O
iii) NaBH4, EtOH
O3,MeOH/CH2Cl2
then NaBH4
OH OH
H H
N N
LiAlH4,THF
O
Tashromine Reflux
Scheme 37. N-Alkylation of succinimide during total synthesis of Tashiromine.
O O
O
1.2 eq. DBU O
Ar + Br N N R= H, Ph, alkyl
1.2 eq. MeCN, rt, 12 h Ar
R
O R O
Scheme 38. N-Alkylation of succinimide using NBS and DBU.
TBAB (tetrabutylammonium bromide) and TBATFB (tetrabuty- During the total synthesis of naturally occurring indolizidine al-
lammonium tetrafluoroborate) [109], KF-Alumina in 2-methyltetra- kaloid tashiromine using cross metathesis approach by Marsden and
hydrofuran [110]. The use of microwave irradiation offered re- his co workers, the key precursor was obtained from N- alkylation
markable advantages than conventional heating (Scheme 34) [108]. of succinimide (Scheme 37) [113].
During the synthesis of stemoamide, an alkaloid, isolated from 4.1.1.2. From NBS or NX
stemonaceae species [111], Wang et al. used N-alkylation of suc- In a one-pot cascade transformation of ketones into -
cinimide (Scheme 35) [105]. imidoketones, N-bromosuccinimide (NBS) was used as a source of
N-Potassium salts of quinolinimide or cinchomeronimide re- electrophilic bromine and nucleophilic nitrogen sources, whereas
acted with ethyl bromoacetate to produce N-substituted glycine the base, diazabicyclo[5.4.1]undec-7-ene (DBU) was used to acti-
esters which underwent rearrangement on treatment with sodium vate NBS (Scheme 38) [114].
methoxide to methyl 5,6,7,8-tetrahydro-5,8-dioxo-1,6-naphthyri- 3-Furancarbaldehyde was allowed to react with succinimide
dine-7-carboxylate or methyl 1,2,3,4-tetrahydro-1,4-dioxo-2,6- donor NBS in chloroform and N,N-dimethylformamide under
naphthyridine-3-carboxylate (Scheme 36) [112]. mild metal free conditions. The product was used to synthesize
O
O
CHO
Ar
CHO O N O
O O Br + Br
N Br O
DMF, r.t O
O BODIPY
X C-N Coupling Ar = N
CHO N N
B
X = Cl, Br X = Cl, NO REACTION F F O
Scheme 39. Reaction of NBS with 3-furan / thiophenecarbaldehyde.
fluorescent dye BODIPY (boron-dipyrromethene). Importantly, OR

NCS did not react with 3-furancarbaldehyde whereas NBS did not O O
undergo the same reaction with 3-thiophene carbaldehyde (Scheme H2N NH
39) [115]. NH NR
SN2 Reaction
4.1.1.3. From Mercury and Silver Salts
Schwartz and Lemer [116] have synthesized N-substituted cy- O O
clic imides from silver and mercury salts of maleimide and alkyl
bromides (Scheme 40). Scheme 42. N-alkylation using O-alkylisoureas.
O O
4.1.1.6. Asymmetric Alkylation (Enantioselective N- alkylation)
Pd-Catalyzed Asymmetric Allylic Alkylation: Nitrogen Nucleo-
NX + RBr NR philes
The Trost group at Stanford University developed the quick
O O atom economical catalytic process using diaminocyclohexyl chiral
X = HgCl or Ag (DACH-PHENYL, DACH-NAPTHYL, DACH-PYRIDYL) ligands
(Fig. 3) in asymmetric allylic alkylation (AAA), to synthesize wide
Scheme 40. Cyclic imides from silver and mercury salts.
range of chiral products in few steps. Reactions were high yielding
4.1.1.4. Using Alcohol (Mitsunobu Condition) with outstanding levels of enantioselectivity (Scheme 43) [121-
N-Alkylation of maleimide and phthalimide with alcohol using 125].
triphenyl phosphine (Ph3P), diethylazodicarboxylate (DEAD) or Gálvez and his co workers synthesized enantiomerically pure
diisopropylazidodicarboxylate (DIAD) was reported by Walker core compound for the total synthesis of (-)-securinine and others of
[117] and Daandapani et al. [118]. Sen et al. also [119] established the Securinega alkaloids by applying the enantioselective coupling
a very convenient two step method for the conversion of allylic of racemic butadiene monoepoxide with glutaric anhydride
alcohols to allylic amines (Scheme 41). (Scheme 44) [126].
4.1.1.5. N-Alkylation of Imides with O-alkylisourea Under Neu- Synthesis of chiral -aryl-,-unsaturated amino alcohols was
tral Conditions performed via a Pd-catalyzed asymmetric allylic amination of 4-
N-alkylation of imides in the presence of O-alkylisoureas has aryl-1,3-dioxolan-2-one using planar chiral 1,2-disubstituted fer-
been found to proceed via SN2 mechanism in neutral condition rocene-based phosphinooxazolines as ligands. Under the optimized
(Scheme 42) [120]. reaction conditions, a series of substrates were examined and the
O
ROH,Ph3P
DEAD/ DIAD
NR Walker et al.
O ROH O THF
-78 °C, N2
FDEAD, FTPP O
Dandapani et al. NR NH
THF, rt, 3h O
R1OH,Ph3P MeNH2
O O
NR1 R1NH2
DIAD
EtOH
O THF, r.t.,4h
F13C6 N O O
FDEAD= O N C6F13
O Sen et al
R1OH =
C6F17
FTPP= OH
Ph2P
Scheme 41. Preparation of cyclic imides under Mitsunobu conditions.

O O
O O
NH HN
NH HN
Ar Ar
Ar Ar
S,S Enatiomer R,R Enantiomer
PPh2
Ar =
PPh2 N
Fig. (3). Chiral catalysts used for asymmetric allylic alkylation.
Intermediate to ethambutol, vigabatrin, bulgecinie,

broussonetine G and DMDP
O O
N
HO
98 %, 96 % ee [121-122]
DACH-naphthyl
H (1.2 mol %)
O Na2CO3, CH2Cl2
O OAc
H
Pd2(dba)3.CHCl3
O OH
( )n
(2.5 mol %)
O O NH O O
N Pd2(dba)3.CHCl3 (R,R)-DACH-phenyl (7.5 mol %) N
HO OH (2.5 mol %) THAB, CH2Cl2
O n= 1,2 or 3
( )n
Yield 87%, ee 82% [125]
O (R,R)-DACH-naphthyl
O
84-95 %, 94-98 % ee
Intermediate to polyoxamic acid (3-15 mol %)
O [123]
Na2CO3, CH2Cl2
O O
N
HO
71-74 %, >99 % ee
[124]
Scheme 43. Rapid and atom economical enantioselective N-alkylation using chiral catalyst.
O
O
O
vinologous Intramolecular
Mannich reaction RCM alkylation
O N O Pd cat O N O N
H
HO
(-)-Securinine
99% ee
Scheme 44. Enantioselective coupling of butadiene monoepoxide with glutarimide.

O
O
O [Pd(3-C3H5)Cl]2 / L i-Pr
N
+ NK Fe PPh2
Ar O O O
O THF, 20 °C N
O OH
Ar
Scheme 45. Enantioselective synthesis of -aryl-, -unsaturated aminoalcohol.
O
O Me O
+ NH O Me O
R O Me Me N
O CH2 H+ O R
N O
O
R O Me
O Me O O R +
+ Me
R O Me O
Me
Scheme 46. N-Acylation by fusion.
products were obtained in good to excellent yields (Scheme 45) reaction proceeded well with excellent yield and high ee. This new
[127]. approach to asymmetric succinimides was used to synthesize im-
portant structural motifs in natural products and pharmaceuticals
N-Acylation of cyclic imides was developed by Rothmann and
his coworkers. They performed brief fusion of cyclic imides and (Scheme 49) [131].
esters in the presence of trace amount of p- toluenesulphonic acid at O O
150-175 ºC (Scheme 46) [128]. (aS)-Ir/BiphPHOX
R (1-0.05 mol%) R
4.1.2. C-Alkylation/ Acylation R' N R' N
H2 (1-20 bar)
4.1.2.1. Alkylation Using Alkyl Halides CH2Cl2, rt
O O
The alpha functionalization of N-alkyl cyclic imides proceeded
through in situ generation of carbanion using strong bases followed Scheme 49. Enantioselective C-alkylation through catalytic hydrogenation
by reaction with alkyl halides (Scheme 47) [129]. by chiral iridium catalyst.
Me 2eq. NaH Me R Metal catalysed asymmetric allylic alkylation reactions have

Ph
2eq. RX or RX2 Ph R been extensively studied (Scheme 50) [132]. B. M. Stoltz and his
co-workers [133] described the highly enantioselective palladium
O O reflux,THF O O
N 12-36 hr N catalysed decarboxylative allylic alkylation and showed very effi-
Me ciently how this can be applied into the de novo synthesis of natural
Me
products [134].
Scheme 47. -Functionalization of N-methylsuccinimides.
4.1.2.3. C-acylation
4.1.2.2. Enantioselective C- alkylation
The alpha acylation of N-methyl succinimides proceeded
Pd-Catalyzed asymmetric allylic alkylation was used to convert through in situ generation of carbanion using sodium hydride fol-
succinimide to maleimide (Scheme 48) [130]. The asymmetric lowed by the reaction with esters under reflux (Scheme 51) [128].
enantioselective alkylation was achieved due to the use of chiral
4.1.2.4. Hydroxyalkylation
catalyst.
Indirect alkylation by iridium-catalyzed asymmetric hydrogena- Hydroxyalkylation of cyclic imides was done using oxiranes
tion of exocyclic double bond was reported by Liu and Zhang. This (ethylene and propylene oxide) in the presence of triethyl amine in
PMB
N PMB
O O
O N HO
OBz
O O
PhO2S O
PhO2S
O
HN
APC (5 mol %) O OH
OBz (S,S)-DACH-phenyl (15 mol %) O HO
NaH, CH2Cl2
OBz L-showdomycin
Scheme 48. Enantioselective allylic alkylation of succinimide.

O O O
BrCH2CO2Et
-OMe
KOH NH
NH N CH2CO2Et
X X X OMe
Y Y Y
O O O O
X=N, Y=CH or X=CH, Y=N
Scheme 50. Palladium catalyzed asymmetric allylic alkylation of glutarimides.
O imides. This enzyme catalyzes the first step of cyclic imide metabo-
Ph
3eq. NaH R Ph lism resulting in the production of monoamidated dicarboxylates.
Me These monoamidated dicarboxylates are deamidated by an amidase
1eq. RCOOEt Me
O O enzyme to yield dicarboxylates (Scheme 53) [137-139].
N reflux, THF O O
N Cyclic imide metabolism has been applied to the production of
Me pyruvate through fumarate intermediate [140]. The carbonyl carbon
Me
of an unsymmetrical succinimide derivative underwent nucleophilic
Scheme 51. Alpha acylation. attack by water and a hydroxyl anion to give aspartate and aspartic
acid. (Scheme 54) [141].
aprotic solvent [135]. Reaction with formaldehyde under conven-
tional and microwave gave N-hydroxymethyl product [136] Cyclic imides can undergo methanolysis and aminolysis result-
(Scheme 52). ing in the imide ring opening to form amidoester and diamide re-
spectively (Scheme 55) [142].
4.2. Hydrolysis and Solvolysis
4.3. Reduction
Cyclic imides can be hydrolyzed by a number of enzymes. Imi-
dase is an enzyme which specifically hydrolyzes the simple cyclic Reduction of cyclic imides has been carried out using following
imides viz succinimide, glutarimide, and sulfur-containing cyclic methods or reagents.
O O R1 O R1
OH OH
CH2O O
N NH N
O O O
Scheme 52. Hydroxyalkylation using oxiranes.

O
H2O NH3
COOH COOH
H2O
NH NH2
Imidase Amidase COOH
O O
O
COOH COOH
imidase amidase
NH NH2
COOH
O O
Succinate
dehydrogenase
Malic
O enzyme OH Fumarase
HOOC HOOC
HOOC
COOH COOH
Me
Scheme 53. Enzyme catalyzed hydrolysis of cyclic imides.
O
O
NH2 O H2O H2O
Me
Me N Me + OH HO2C N
HO2C N H
H H2N NH2
O
Scheme 54. Hydrolysis of unsymmetrical cyclic imides under neutral and alkaline medium.
N N N
O
CONHCH2R1 CO2Me
N R1CH2NH2 N MeOH N
NR
N N N
CONHR CONHR
O
N N N
Scheme 55. Ring opening of cyclic imides during solvolysis.
4.3.1. Catalytic Hydrogenation ylene diamine, triethylamine (0.01 equivalents up to and including
5 equivalents) (Scheme 57) [144].
Hydrogenolysis of cyclic imides produced hydroxyl amides in
the presence of ethyl acetate or ethanol as solvent at room tempera- O
ture and atmospheric pressure over 10 % palladium on carbon cata- LiAlH4
lyst in high yield (Scheme 56) [143]. NR NR
or
O OH NaAlH4 &
O Additives
cat
N R NHR Scheme 57. Reduction of cyclic imides to cyclic bases.
H2
O O 4.3.3. Reduction Using NaBH4
Scheme 56. Catalytic hydrogenolysis of cyclic imides to amido alcohols. One of the carbonyl groups of succinimides and glutarimides
can be chemoselectively reduced by sodium borohydride in the
4.3.2. Reduction Using LiAlH4 and NaAlH4
presence of HCl yielding -carbinol-lactams. Unsymmetrical cyclic
Cyclic imides are reduced to cyclic bases (heterocyclic com- imides undergo reduction with high degree of regioselectivity. The
pounds) by LiAlH4 or by NaAlH4 in the presence of additives eg carbonyl group adjacent to the most substituted C- atom being pref-
LiCl, HCl, LiBr, AlCl3, TiCl4, AlBr3, TiBr4, LiBH(R)3, NaBH 3 erentially reduced (Scheme 58) [145].
(anilide), THF-BH3, LiAlH(OMe)3, LiAlH(O-t-Bu)3, NaAlH 2 Reduction of imides of diphenic acid with NaBH4 has been car-
(OC2H4OCH3), AlH3, ethers such as methyl t-butyl ether, di- ried out by V. A. Yanovskiy and his co workers (Scheme 59). It
methoxyethane, glymes; alcohols such as methanol, ethanol, iso- was shown that the nature of substituent at nitrogen atom influences
propanol, t-butanol, ethereal alcohols and/or their corresponding yields and composition of the reaction products. The nature of alco-
metal alkoxides; primary and/or secondary amines and their corre- hol used influences weakly the reaction products ratio [146].
sponding metal amides and tertiary amines such as tetramethyleth-
O OH
NaBH4
N N R
R
EtOH, HCl
Adjacent to more O
substituted C-atom O
R1 O
O R1 OH
R1 R2
R2
NaBH4 + N R
R2 N N R
R
EtOH, HCl
OH
O
O
MAJOR MINOR
Scheme 58. Regio selective monoreduction to hydroxylactams.
O OH
NR 2eq NaBH4, MeOH O NH2

+
25 °C, 20-25 min
O O O
Scheme 59. Reduction of cyclic imides of diphenic acid with NaBH4.

5 eq.NaBH4 OH MeCO2H ( 18 eq)

NHR H2N- R
O 2-PrOH / H2O (6:1) 80oC, 2 h
rt, 24 h
O
N R
ORI
O NaBH4
N R
RIOH, HCl
O
Scheme 60. Reduction of cyclic imides to alkoxylactams and amidoalcohols.
B2H6, THF, 80 °C
S 1.5h S
O O
75%
N N
H H
Scheme 61. Reduction of cyclic imides by diborane.
O O 4.3.4. Reduction Using Red Aluminium

Red-Al-toluene Instead of LiAlH4, the soluble reducing agent sodium bis (2-
N Me N Me methoxy ethoxy)aluminium hydride (red-Al) can also be used for
100°C the reduction of imides. N-methyl succinimides on treatment with
O red-Al in boiling toluene afforded the product in 92% yield
(Scheme 62) [152].
Scheme 62. Reduction of cyclic imides to lactams.
4.3.5. Reduction Using Samarium Iodide
It was known from the work of Toja et al. [147] and Neipp Using Sml2 at 20 °C, one of the carbonyl groups of N-
et al. [148, 149] that succinimide and glutarimide could be reduced phenylphthalimide was reduced to a CHOH or CH2 group. The
by sodium borohydride in the presence of hydrogen chloride in product depends on the amount of the reagents used and the se-
ethanol to form corresponding alkoxy compound. Phthalimides quence of their introduction into the reaction vessel (Scheme 63)
were reduced to primary amines very efficiently using NaBH4 / 2- [153].
propanol and then polar protic acetic acid. Phthalimides of -amino
4.3.6. Reduction Using DIBAL-H
acids were smoothly deprotected with no measurable loss of optical
activity (Scheme 60) [150]. DIBAL-H in toluene at low temperature reduced substituted
succinimides to hydroxy lactams. Sterically unhindered CO under-
F. Fried and his co workers reduced the two carbonyl groups of
went regioselective reduction which was opposite to regioselective
cyclic imides by diborane in THF solvent (Scheme 61) [151].
reduction done by sodium boro hydride (Scheme 64) [154]. Re-
O O
O
Sml2 excess Sml2
N Ph N Ph
N Ph
20 °C
OH O
Scheme 63. Reduction of cyclic imides by SmI2.
R1 O R1 OH
O
R1 R2 R2
DIBAL-H
R2 N R
N R N R
Toluene, +
-70 to 0°C
OH O
O
Away from more
substituted C-atom MAJOR MINOR
Br HO
O O HO O NMe
N N Br
tBu DIBAL tBu
MeN O
CH2Cl2 MeO
Amathaspiramide A
OMe OMe
Scheme 64. Regioselectivity in reduction of succinimides by DIBAL-H.
cently this reduction has successfully been utilized by K. Chiyoda 4.3.9. Reduction Using CBS Reagent
and his co-workers to synthesise amathaspiramides [155]. Stereoselective reduction of imides using chiral oxazaborolidine
followed by ethanolysis of the hydroxylactams, produced ethoxy-
4.3.7. Reduction Using PMHS and TBAF
lactams in 68-94% e.e. [158]. This Enantioselective reduction
Monoreductions of imides can be achieved with selective re- methodology was applied on meso-imides to the synthesis of (+)-
ducing agent polymethylhydrosiloxane (PMHS) and catalyst tetra- deoxybiotin (Scheme 67) [159].
n-butylammonium fluoride (TBAF) (Scheme 65) [156]. Oba et al. investigated asymmetric synthesis of (3S,4S) and
(3R,4R) series of 3,4-dihydroxyglutamic acids. The main reaction
O O in this synthesis was asymmetric reduction of meso imide derived
TBAF / PMHS from meso-tartaric acid (Scheme 68) [160].
N R N R A variety of N-alkylated imides produced -acetoxy lactams in
rt high yields (75-100%). Despite few limitations, this reductive ace-
O tylation strategy offered rapid entry into N-acylimium ions for use
in Mannich reactions (Scheme 69) [161].
Scheme 65. Reduction of cyclic imides by TBAF / PMHS. R1 R2 1. LiEt3BH (1.1 eq.) R1 R2
4.3.8. Asymmetric Hydrogenation CH2Cl2, -78 °C, 15 min
The active dihydride catalyst trans-[Ru((R)-BINAP)(H)2((R,R)- O O 2. Ac2O (1.3 eq.) O OAc

N N
dpen)] was developed by Bergens research group for the enantiose- -78 to 23 °C, 20 h
lective desymmetrization of meso cyclic imides via mono hydro- R R
genation (Scheme 66) [157]. Scheme 69. -Acetoxylactams from imides.
Me
H Ph
O H O
H THF, 0°C, 50 atm H2
Ph2 H2
P O Ph KOtBu
N
N Ph N Ph
Ru +
P H N Ph H
H2 H O OH
Ph2
Scheme 66. Enantioselective desymmetrisation of succinamides.

R R R R R R
BH3.THF H+
O O H Ph O OH O OEt
N N EtOH N
R1 Ph R1 R1
N
O
B
H
H
H B
N O O
TBDMSO R R
R R
HN NH
Me Ph Ph
O OH
O O N
N
BH3.THF S
R1
R1
(+)-Deoxybiotin
Scheme 67. Enantioselective reduction using CBS reagent.
OH OH
HO2C CO2H HO2C CO2H

AcO OAc
OH NH2 OH NH2
O O
OH N OH
HO2C CO2H PMB HO2C CO2H
PMB = p-methoxybenzyl
OH NH2 OH NH2
Scheme 68. Enantioselective reduction of meso cyclic imides.
O OH
+2e
N Me N Me
[bmim][PF6], phenol
O O
Scheme 70. Electrochemical reduction in ionic liquid.
4.3.10. Electrochemical Reduction 4.4. Cycloaddition

Electrochemical synthesis was carried out in ionic liquid, 4.4.1. Diels Alder Reactions & Retro Diels Alder Reactions
1-butyl-3-methylimidazolium hexafluorophosphate [bmim][PF6].
Cycloaddition reactions mainly Diels Alder reactions are
The reduction of N-methylphthalimide was investigated at glassy
among the most important tools in organic synthesis. An important
carbon electrodes. Cyclic voltammetric experiments indicate that
virtue of this reaction is its stereospecificity. The stereochemical
the imide is reduced in two single-electron reductions. In the pres-
integrity is preserved throughout the course of the reaction. Thus
ence of phenol, the reduction of the imide takes place at a more
with outstanding stereochemical predictability of Diels Alder reac-
anodic potential and occurs in a single two-electron step. Exhaus-
tion, and other related reactions these methods can be used with
tive electrolysis of N-methylphthalimide was carried out in an elec-
remarkable ease during target directed studies in organic syntheses
trochemical cell at a glassy carbon cathode in the presence of phe-
of natural products and biologically active substances (Table 2)
nol when 3-hydroxy-2-methyl-isoindolin-1-one was isolated as the
[163-189].
product (Scheme 70) [162].
Table 2. Examples of Diels Alder adducts.
S. No Product S. No Product
Ph
O O O N
B O
H O
1[163-165] 2 [166]
NR
R
Me
H O
Me O Ph
Ph
O N
O N
Me Me
O O B O
3[167] 4[167] Me O
B
Me
O
Me OMe
OSET
R3
O N
O O
R1 R2
R2
5[168, 169] N R 6[170]
B OH
O
R1
R1
Ar Ar
N N
O O O O
O
AcO
NH S S
7[171] 8[172]
Me
OAc O S NH S NH
76% ee
O O
NR2 O
O O
NC
9[173] N R1 10[174] N R
R
O R1 O
Table 2. contd…
O O Ph
Ph
Me N
N
O O
O H
O COOEt
O O
+
O O Ph
N O O
N Ph
O
Me N
11[175] 12[176]
EtOOC N Me
O
N
O O
O
O O + O
O O O Ph
O O n
Ph
Me N
N
O
COOEt
R1 O R1 R O
N N NH
13[177] NR + 14[178] NR1
N HN N
R1 O O
R1 Me
O
OPh
O
N NHSO2Me
15[179] N 16[180]
O
H t-Bu
O
O O Me OR
H H O
Ph N Ph N
N Ph
17[181] 18[182]
H H
O O
X X Me O
X = OH, Me, OMe R = Me; Me 2S
O O
HO Ph
H Ph N N
N
O
N
N O O
19[183] N 20[184]
O O
N O
Ph
R1
O Me
H
O O R2 O
O
NR X N
21[185] 22[186]
R 3N NR3
NR
H O NH
TMSO Me CH
O O 2 OP O
h
Table 2. contd…
O2
S EWG H O
HN O
N
2 N O NPh
23[187] N 24[188]
Me2N O P
Ph H O
Ph
EWG Me Me
O
25[189] H
O NH NPh
O
CCl3
O R1
R RDA cleavage
Asymmetric
carbonyl to produce chiral R1 R
NR1 NR1
transformation unsaturated lactam
DA reaction
R OR O O NR1
+
O
R1
N O R OR R OR
O R = Me, Bn
R1= Ph
Scheme 71. Retro Diels Alder reaction of maleimide.
MeAlCl2, H
toluene, rt
H
H
O O
[2+2] Ene reaction
O
H N N
N
Me O Me O
O Me
Scheme 72. Cycloaddition reaction.
C8H17 C8H17
Me Me
C8H17 C8H17
Me Me
Me Me
O N O + Me Me
O +
Ar
AcO AcO O H
200°C H
Benzene N Ar AcO N Ar AcO O
H H
N
O O O Ar
Scheme 73. Ene reaction and Diels Alder reaction.
The retro-Diels-Alder reaction (RDA) is widely used for the Thermolysis of N-substituted maleimide with 7-dehydrochol-
synthesis of novel scaffolds. The ability to carry out the RDA reac- esteryl acetate in benzene solution at 200 ºC produced mixtures of
tion on cyclic imides under ambient conditions has made it quite cycloadducts. The major products were obtained by ene addition
attractive (Scheme 71) [190]. where as the minor product was -endo Diels Alder adduct
(Scheme 73) [192].
4.4.2. Ene Reaction
The ene reaction of enyne 1,2-dicyclohexenyl acetylene and di- The terminal olefin and the maleimide underwent the dehydro-
enophile N-methylmaleimide was increased dramatically using genative Diels Alder reaction with wide range of substituents and
microwave irradiation (Scheme 72) [191]. appeared as stereoselective. Substituents on olefin taken were ace-
O O H R
H R'
(CH2SOBn)2
R + N R'' R'' N
Pd(OAc)2
H Dehydrogenative R'
Diels Alder reaction O H
O
Scheme 74. Diels Alder reaction between terminal alkene and maleimides.
O O O
R H3BO3 O H3BO3
NH
N (10% mol) O (10% mol)
+ N R
NH PEG-400, 90°C PEG-400, 90°C O
O NH
N2, 3-8 h N2,1h
R1 R1 O N
R = H, Ph, Bn, CH2Ar O R
R1= H, COMe CH3CN, rt, 3h, N2
NH
N
O Ph
Scheme 75. Unexpected intramolecular cyclization between furfurylamine with maleimide.

O
O
NH NBn
H3BO3
+ H3BO3
O
O
O N
Bn
OH
O NBn
(HO)2B H
O Bn O
N O
H
NH O B
HO
O H B OH
OH
O
OH
OH
O
NBn O NH2
H2N O
O
B
HO
OH
Fig. (4). Possible mechanism for intramolecular cyclization.
tate, silyl group, phthalimide protected amines, benzyl ethers, am- An unusual intramolecular cyclization was observed during the
ides, acetals and enones whereas malemide substrate had both elec- reaction of furfurylamine with maleimides (Scheme 75) [195]. The
tron rich and electron deficient groups (Scheme 74) [193, 194]. plausible mechanism is presented in Figure 4.
O
Me OMe O
Me
O O
N H h
O +
N H
solid
O O
OMe O
Acetonitrile
O
O O
Me OMe
NH O O Me
MeO O + N H
N H
O
O
O O
OMe O O
Me
Scheme 76. 2+ 2 Cycloaddition.
4.4.3. [2+ 2] Cycloaddition 4.4.4. 1,3-Dipolar Cycloaddition

Thermodynamically favourable photo induced union of two 4.4.4.1. As Dipolarophile
double bonds to give a strained four membered ring is a powerful
The [2+3] cycloaddition of 1,3-dipole to an alkene type 1,3-
method in organic process. The stereochemical potential of this
dipolarophilies ideally suited for the region and stereocontrolled
photocycloaddition is evident from the fact that suitably substituted
synthesis of exceedingly complex fused polycyclic systems with
cyclobutane ring can host upto four contiguous asymmetric carbon
many asymmetric centres. This cycloaddition contributes signifi-
centres. Photo irradiation of lactone and maleimide produced highly
cantly and occupies a prominent position in organic synthesis.
stereoselective 2+2 cycloadduct (Scheme 76) [196].
Various examples [197] are listed in Table 3 [198-208].
Table 3. Compounds obtained from [2+3] cycloaddition.
3[200]
1[198] 2[199]
R2 O
CN N
Ph X
O N
O N N O
Ar N O
R2 N
R1
N O
Ar1 CO2Me
Ar2 N O N
H N
R1
4[201]
5[202] 6[203]
O
O OMe OMe O
O X H
H O O
N O
+ H
NR O H
H N N
O NR R
O H Me NH2
O O
O O
exo endo
9 [204]
7 [203] 8 [203]
R
O
O O N
O O O
O
H N N
N O
H NH2 O EtO
O O P N
EtO H
Table 2. contd…
10 [205]
11 [205]
O H
N R2
O R1 R4
R1
O O
R3 N N 12[206]
N
O R3 N Ph
R4
O N
R2 O O O
R5 O O R1
CO2R Ph
R2 R3 N N O CO2Et
N N R4 R1 N
H
R1 O H
O
O O
N O R2
R
13[207]
O
O
HN CO2Et OH
CO2Me 15 [208]
N
O O CO2Me Me
O Me O
or NH
NH
X
O 14 [207] N S
O
O
or R1 O
O X=NMe
O X=O
NH
CH2
O
CH2 O N
N
O O
O Rh2(S-TCPTTL)4
N CO2R
N2 CF3C6H5, 60oC N
O
Me Me
CO2R
endo
Scheme 77. Chiral substituted phthalimide catalysed 1,3-dipolar cyclo addition.
n
n Zn OH
Br
O N
O O +
N PbBr2
R1
R1
Scheme 78. Zinc mediated and PbBr2 catalyzed Barbier type allylation of cyclic imides.
4.4.4.2. As Catalyst 4.5. Addition on Carbonyl Group of Cyclic Imide

The intramolecular cycloaddition of indolyl-substituted 2- Allylations of N-benzyl and N-methyl cyclic imides using allyl
diazo-5-imido-3-ketoesters based carbonyl ylides in the presence of bromide were performed effectively under mild Barbier type condi-
chiral catalyst dirhodium(II) tetrakis[N-tetrachlorophthaloyl-(S)- tions in the presence of zinc metal and catalytic amount of PbBr2
tert-leucinate], Rh2(S-TCPTTL)4, provided cycloadducts in moder- (Scheme 78) [210].
ate yields and enantioselectivities of up to 66% ee as well as with SmI2-mediated couplings between a variety of organic halides
perfect endo diastereoselectivity (Scheme 77) [209]. and cyclic imides have been performed by S. Farcas and his co-
1. n-heptyl iodide n-C6H13

O HO n-C7H15
SmI2, NiI2, THF,
20°C, 10 min
N Me N Me N Me
2. A) HCl (0.1 M) or
or O O
O
B) HCl (0.5 M)
Method A Method B
Scheme 79. Barbier type alkylation of cyclic imides.

O
TBSO SmI2, Fe(DBM)3 TBSO H
HO
THF, 0°C, 2h
N N
4 I N
TBSO TBSO
O O HO
Scheme 80. Synthesis of (+)-Lentiginosine.
O
O NH
SmI2, H2O H
O N Me
Me O
THF, -78°C +
O Me Me
NH O Me
Me Me N Me
SmI2 O
O Me Me
N + Me
NH
H3O+ Me H2C
O +
H O O
N Me
Me O
O
Me H
O Me SmI2, H2O
N Me
Me NH
THF, -78°C Me + O
O Me
O
Me
HN Me
Me
Me
Scheme 81. SmI2 mediated reductive cross-coupling reaction.
workers in the presence of catalytic amount of NiI2 to get either isoindole-1,3(2H)-dione with 100% yield and 64% ee []D+1020(c
hydroxylactams from N-methylsuccinimide and N-methylphthal- 0.05, CHCl3) (Scheme 82) [215].
imide or -ketoamides from N-methylglutarimide. In the latter
Ph Ph O
case, ring opening occurs during hydrolysis (Scheme 79) [211]. O
Imide-alkene coupling reactions constitute a small yet signifi- light
Ph
cant and growing subset of the vast field of SmI2mediated car- N Me N Me
bonyl-alkene couplings introduced by Inanaga and Molander in mid Ph
1980s. Reductive couplings with imides were first investigated in Ph Ph O
O
1996 by Ha, who presented an SmI2-promoted intramolecular Bar- Ph
bier-type reaction of N-(haloalkyl)imides to produce nitrogen-fused Scheme 82. Photoirradiation of substituted succinimide.
polycyclic amides. The extent and regiochemistry of dehydration of
the resulting hydroxylactams to the corresponding enamides was 4.7. Cross Coupling Reactions
observed to be highly dependent on ring size and substituents. This
method was later applied to the synthesis of natural alkaloid (+)- The synthesis of N-aryl cyclic imides using aryl boronic ester
Lentiginosine from N-(Iodoalkyl)succinimide (Scheme 80) [212]. promoted by copper(II)acetate and TEA or pyridine was reported
by Erin et al. [216] and H. M. Hügel et al. [217] separately
A novel application of N-acyl succinimides as acyl transfer rea-
(Scheme 83).
gents in the SmI2-mediated reductive cross-coupling reactions
(RCCRs) between electron-deficient olefins N-tert butylacrylamide Palladium-catalyzed cross coupling reactions of indium or-
and N-acyl succinimides was done by R. H. Tanning and his co ganometallics with halomaleimides was used to synthesize unsym-
workers which provided an entry into some novel enediamide metrical 3,4-disubstituted maleimides. Various alkyl, aryl, het-
(Scheme 81) [213, 214]. eroaryl and alkynyl 3,4-disubstituted maleimides have been pre-
pared in good yields and with high selectivity by Bouissane. L.
4.6. Photochemical Reaction et al. (Scheme 84) [218].
Photoirradiation of the substrate by 100-W high-pressure Hg- A one pot primary aminomethylation of aryl halides, triflates,
lamp gave (+)-2-methyl-4,4,9-triphenyl-3a,4-dihydro-1H-benzo[f] mesylates and tosylates involving Suzuki-Miyaura cross coupling
RO OR
B H
O N O Cu(OAc)2, TEA/pyridine
+
O N O
CH2Cl2, O2, 4Ao MS
Scheme 83. N-arylation of imides with boronic acids.

R 5 mol% Pd(PPh3)4 R
0.5 eq. or Pd(DPEPHOS)Cl2 N
O N O O
O
+ R''3In R = Me (X = Br, Pd(DPEPHOS)Cl2)
THF, reflux, 5-8 h Bn (X = Cl, Pd(PPh3)4)
R' X R' R''
Scheme 84. Palladium catalyzed cross coupling reactions of indium organometallics.
5 Mol %
Pd(OAc)2 or Pd(dba)2
12 mol% SPhos NH2-(CH2)2-NH2
Ar X + NaF3B NPhth
Na2CO3 PrOH/ dioxane/ H2O Ar NH2
dioxane / H2O reflux, 24 h
X= Cl, Br, OTf
reflux, 15-48 h
Scheme 85. One pot primary aminomethylation.
Br S
Br
n Coupling-polymerizations
Coupling-polymerizations
O n
HO OH O O O
N N
O R R HO OH N
B B O R
B S
HO OH DBrRMI B
poly(RMI-alt-Ph) HO OH poly(RMI-alt-TP)
Coupling-polymerizations I
I
O O
N
R
n
poly(RMI-co-Ph)
Scheme 86. Suzuki Miyura cross coupling to synthesize polymer.
with sodium phthalimidomethyltrifluoroborate followed by deami- 4.9. Multicomponent reactions (MCR) (Diversity Oriented Syn-
dation with ethylenediamine was accomplished [219] (Scheme 85). thesis)
Electrooptic materials conjugated polymers are important for Multicomponent reactions are highly atom, time, pot and step
their electrical conductivity, non linear optics and electrolumines- economic reactions as they allow for more bond-forming events per
cence properties. They can be synthesized by using Suzuki-Miyara synthetic operation, and convert simple starting materials to com-
cross coupling polymerization strategy using Pd or Ni catalyst with plex natural and synthetic molecules. Few examples involving cy-
different substituted aryl boronic acid (Scheme 86) [220]. clic imides as one of the reactive components are described in the
following table (Table 5) [237-241].
4.8. Michael Reaction (Conjugate Addition)
4.10. Others
The Michael reaction is the addition of nucleophile (mostly a
4.10.1. Flash Vacuum Pyrolysis
carbanion) or Michael donor to an ,-unsaturated carbonyl com-
pound (Michael acceptor). The following are the examples of 1,4- Flash vacuum pyrolysis (FVP) has been applied to synthesize
conjugate addition of variety of Michael donors to cyclic imides the novel 7-oxa-norbornadiene-2,3-dicarboxylic imide [242-244]
(Table 4) [221-236]. (Scheme 87).
Table 4. Michael reaction of maleimides.
S. No Michael Acceptor Michael Donor Product
O
MeS
1[221] Maleimide Thiol NMe
H
O N
protein
O
OH
H SH OH N
OH S
2[2] N OH H H
O RO N N
HO O RO protein
OH O
HO OH O
N O
O O R
R
O R N
N
+ X
X N
N N H
H O
3[222] X-NH2 O
R = H, X=Bn
O
R = Me, X=Bn
R = H, Me, t-Bu
R = t-Bu, X=Bn
R = t-Bu, X=CH(CH3)Ph
O
O
N
4[223] N Ph NH
N Ph
O
O
NH2
O R
NH O O
O
5[224] N R MeS Ph Ph O
R = Me, Et N
O MeS
R1
NH2
O
O
NH2 O
O
6[224] N R Me
Me O
O N
H
HS
NH O
O
HS Me
NH O Me O
7[224] N R
Me O
Me O
O N
Ph O
HN Ph
O O
Me Me
O O O
HO Me
NH O O O
8[224] N R
Me Me N + O
Me O
O O N
Ph
OH
12% 74%
Table 4. contd…
R1
O HN
O
R Me
R1
O HN O
9[225] N Me
R Me N
O
O
Me
O OH O
O
10[226] N R H R1 N R
R
S
O SH
O
O
O
N R
OHC
11[227] N R
R1 R2 O
O
N
O Me
N N
Me O
12[228] N Ph
N
H N
O Ph
O
O O
R R
13[229]
N Ar PhSH N Ar
PhS
O O
O O
R R
14[229] N Ar PhH N Ar
R = H or Me
Ph Ar = Ph or p-MePh
O O or p-MeOPh
O
O R
R H
N N Ar
15 [229, 230] N Ar
N
O
O
O
R1 = O
N R1
N R Ph Me
Me N
16[231] N R
O Me
N O
R = -Ph, -CH2 Ph
Me
O Ar R
N
H
17 [232] NH Ar N
R O
N
O H O
Table 4. contd…
O O
HN
18[233] NH N,N-dialkylhydroxylamines
O NH
N
O
O
OC CO N R N OC CO
19[234] N Fe R
N N Fe
H
O
O
NHSO2Me
NHSO2Me
OPh
OPh
20[235] ArNH2
N
N O O
O O
NHAr
NHSO2Me
NHSO2Me
OPh
OPh
21[235] ArCONHNH2
N
N O O
O O
NHNHCOAr
NHSO2Me
NHSO2Me
OPh
OPh
22[235] PhNHNH2
N
N O O
O O
NHAr
O
R1OC
N R4
23[236a] Maleimides 1,3-dicarbonyl compounds

O
R1, R2 = Me, Ph, OR
R3 = H, alkyl
R4 = H, alkyl, aryl
O Et O Et O O
N Ph O Ph N
24[236b]
O O O
Table 5. MCR involving cyclic imides.
S. No Reactions
1[237] Me
O N
O O
I NH2 H
Pd2(dba)3, tfp H
+ H2C C CH2 + MeO2C + N Me H
CO2Me CO2Me
Cs2CO3, PhMe,
CHO CO2Me
O
CH2
2[238] O R1 NH
COOR O
CH2Cl2 N
+
2 R1 N C- + + NH N CO2R
reflux, 48 h
COOR CO2R
O O
3[239]
O O O
R2NH2
N R2
H 30 mol % O NaBH(OAc)3 NH
N R N R N R
O H CH2Cl2
CHCl3
O R1 O R1 O
H
R1
H O H O
N N
R KOtBu R
N R2 N R2
O MeOH O
R1 R1
4[240] Ts H Ts H
O N O N O
Ts H2C PPh3, methyl acrylate
Ar N + Ar R +
R + NHPhth Ar R
MeCN, 270C, 4-48 h
NPhth
NPhth
erythro threo
5[241] O
NO2
R2
{Pd2} Catalyst NHBz
N OAc
R1 O
+ Ac2O + M(OAc)n + R1
R2
O
Bz NH
O O O O
H
FVP O FVP
O NR +
3750C NR 4300C
O O
NR O H
O - O
R = CH2CH2OMe
Scheme 87. Flash vaccum pyrolysis.

Ph Ph
O Ph O
O O
Ph Me Ph N
N FVP
Ph O + N Me
N O N COOEt
O
O
COOEt COOEt O N
Me
Scheme 88. FVP by using RDA strategy.
Some flash vacuum pyrolysis (FVP) experiments were con- 4.10.2. Complex Formation
ducted to explore the preparation of the novel aza-izobenzofuran A variety of cyclic imides with imido protons were allowed to
(aza-IBF) system. Retro Diels Alder (RDA) methodology was cho- react with Hg(II) to obtain imide-Hg-imide complexes through an
sen since there were many examples of its successful use in the imido proton-metal exchange process. The reaction was reversible
preparation of various IBFs (Scheme 88) [245]. and proceeded quickly at moderate to high pH (Scheme 89) [246].
O O O O
NH Hg2+ N Hg N + 2H+
+ + HN
O O O O
Scheme 89. Cyclic imide-mercury complex.
Tetracene dicarboxylic imide disulfide (TIDS) and Pt(PPh3)3 O O

were allowed to react to obtain a platinum complex (Fig. 5) [247].
N Ar Nucleophile N Ar
THF, 55°C R
O O HO
S
Ar= heterocycles
hex N [Pt]
S Scheme 91. Nucleophilic addition of cyclic imides.
O 4.10.4. Cascade Reaction
Chemical and electrocatalytic cascade cyclization of Guareschi
imides converded them to the 2,4-dioxo-3-azabicyclo[3.1.0]hexane
scaffold (Scheme 93) [250] following a one-pot, simple and effi-
Fig. (5). Platinum complex of tetracene imide disulfide (TIDS).
cient method.
4.10.3. Cyclic Imides as Nucleophiles R1 R2
R1 R2
Pankaj Chauhan and his co workers have reported an asymmet- NC CN EtONa,Br2,EtOH NC CN
ric Morita-Baylis-Hillman (MBH) reaction involving maleimides as or
nucleophiles and readily available chiral -isocupreidine (-ICPD)
electrolysis,NaBr in O N O
as catalyst (Scheme 90). A series of chiral 3-substituted-3- O N O
MeOH
hydroxyoxindole derivatives were synthesized in high yield and up R R
to >99 % ee under mild reaction conditions [1].
Scheme 93. Cascade reaction of Guareschi imides.
Cyclic imides undergo nucleophilic addition at one of their
amidic carbonyl carbon in the presence of a number of nucleophiles 4.10.5. Allylic Addition
(Scheme 91) [248]. An allylic addition of N-aryl alkylidene succinimides to N-
The synthesis of an intermediate for the aldose reductase inhibi- carbamoyl imines was developed using bicyclic guanidines as pro-
tor rainrestat AS-3201, catalyzed by a lanthanum complex (Scheme moters [251]. -Addition followed by a 1,3-proton shift led to the
92) was achieved by the addition of 3-substituted succinimide as a amine derivatives as the only product formed. Importantly, -
nulceophile [249]. addition was not observed (Scheme 94) in this case.
OH
Et
O
O
O O N
R1 N R3
N H HO
O + N R2 R1
N ICPD O
O
R O N
R
Scheme 90. MBH reaction between maleimides and isatins.
Me Me
OH O OH O
H
O N
N EtO2C NH
Boc H
O
NH N
+ O
N BocN
EtO2C
O Boc La(OiPr)3, N,N-DMA AcOEt NHBoc
or CHCl3, 0oC
Scheme 92. Synthesis of an intermediate for rainrestat AS-3201.

N
O But tBu
O
O
H2C N N Me
H
N R + O N H N R
Et N
CHCl3, rt Et3CO
Et Et Ar
O O
O Ar
Scheme 94. Addition of N-aryl alkylidene-succinimides.

O H OTBS OH
HO OH TBSO
N MPM OTBS OH
HOOC COOH N N
TBSO
O O (1S, 2S, 8aS)-1,2-dihydroxy
indolizidine alkaloid,
Letiginosine.
Scheme 95. Synthesis of lentiginosine from substituted succinimide.

O O
O
Base
R1 O- Phthalyl R1
MeCN/ H2O Amidase O-
N H + H2N
or N R1 O-
R2 R2
0.2 M buffer
O (pH 8.0) O R2 O
Scheme 96. Phthalimide as a protecting group.
Wang and co-workers reported a reaction based on the addition employed as a clever tactic and of course provided elegant and
of lactones to N-Boc aldimines catalyzed by bifunctional rosin- exceedingly efficient solutions (Table 6) [256-276].
derived amine thiourea catalysts [252]. Synthesis of a trans-
dihydroxy indolizidine alkaloid, lentiginosine was accomplished 6. CONCLUSION
using deoxygenation of the quaternary -hydroxy lactam prepared
In conclusion, we have made an attempt to highlight some of
from a chiral C2-imide (Scheme 95) [253, 254].
the attractive features of cyclic imide chemistry and elegant contri-
butions made to this area of research. We have covered occur
4.10.6. Deprotection
rences, method of preparation, chemical reactions and medicinal
Phthalyl amidase enzyme selectively deprotected phthalimido application of cyclic imides reported mainly during the time from
groups under very mild aqueous conditions in a one-pot reaction to 1980 to the end of 2013. Various interesting synthetic strategies
produce phthalic acid and the free amine (Scheme 96) [255]. used for the construction of this ring system along with the remark-
able reactivities displayed by the resulting compounds are pre-
5. APPLICATION IN SYNTHESIS OF HETEROCYCLES sented. It is evident from the previous sections that the development
of a novel reaction or a new catalyst can modify the synthetic strat-
It is important at this juncture to discuss an important applica-
egy considerably and can enhance the access to the diversity based
tion in the state of the art for synthesizing heterocycles. The use of
derivatives of cyclic imide. Indeed, intense research in this area
cyclic imides for the construction of heterocyclic compounds was
Table 6. Synthesis of various heterocycles from cyclic imides.
S. No Heterocycles S. No Heterocycles
EtO2C
NH H H
N
S N CONHR1
1[256] 2[257] N NMe
R
N
R2 H
O
Me O
N Me N
O
3[258] 4[259] R
N X
Me Ph
O X=OH/ H
Table 6. contd…
Me O
O
Me
N R3
H N R4
5[260] 6[165] N
O
H OH O
H N
R1 R2
R2
R1
Me Me
N N O
N
7[261] 8[262]
N N N
R3
Me
O
O
O
OH OH
Me H
9[263] 10[264] N
n=2 TMSO
n N n
n N MeO2C
O
O
HO OH
N
11[265] 12[264]
N N
OTMS
MeO2C
O O
O O O
OTMS OTMS
N N
13[264] OTMS 14[266]
+ OTMS
OTMS N
OTMS H
CO2Me CO2Me HO2C
H
N N
Ar
OH
15[267] 16[268] N
N N
n Cl OH
N
X N
H
R R
NC CN R
O N O
H2N NH2
O O
17[268] N 18[269]
O Me
N N
Ph
Cl
Me
Me
H O
O H
N OCOMe
19[270] OH 20[270]
O
N
COOMe Me
N O
Me
Me
O HO
H
AcO HO
H
21[270] 22[270] H
N
N N (±)-Epilupinine
O CO2Me
Table 6. contd…
O X Et
N
23[271] N R 24[272] N
Y Et
O
N O
O TBDMS
O
R Me
N
Me HN
25[273] 26[274]
N O
O H
HO N
P N
NaO H
O O COOH
O
N
H
O
HN
H H
27[275] 28[276]
H
N O
H
H H
N O N O
O
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Chemistry of Cyclic Imides: An Overview On The Past, Present and Future

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Chemistry of Cyclic Imides: An Overview On The Past, Present and Future

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1955 Send Orders for Reprints to reprints@benthamscience.

Current Organic Chemistry, 2016, 20, 1955-2001

Keywords: Cyclic imides, natural product, synthesis, reactions.

1. INTRODUCTION synthesize the complex molecular framework intelligently which

Amonafide for breast cancer

1875-5348/16 $58.00+.00 © 2016 Bentham Science Publishers

Fig. (1). Contd…

Binospirone Anxiolytic effect

Elinafide (LU 79553)

Fig. (1). Contd…

Fig. (1). Biologically active compounds containing cyclic imide framework.

2. NATURAL OCCURRENCE and quite fascinating. Many of them have pharmacological

Table 1. Naturally occurring cyclic imides.

From Brazilian Ascidian Didemnum granulatum

Isogranulatimide B [11, 13] Isogranulatimide C [11, 13]

From Caribbean ascidian Didemnum conchyliatum

Didemnimide A, B, C, D [14] Didemnimide E [14]

A; R1 =H, R2 =H, B; R1=Br, R2 =H,

C; R1=H, R2=Me,D; R1 =Br,R2 = Me

Rebeccamycin [15] Indocarbazostatin A, B, C, D [16] antibiotic

AT2433-A1, A2, B1, B2 [17]

A1, R1= NHMe; R2=Cl, B1, R1= NHMe,; R2 = H

From Bacterium Pseudomonas fluorescens

Moiramide B [18] peptide antibiotic Andrimid [18] peptide antibiotic

From the culture broth of a strain of actinomycetes

BE-13793C (J-104303) [13] Actiphenol [19]

From Lissoclinum Voeltzkowi Michaelson

Dichlorolissoclimide [20] cytotoxic labdane derivative

From Delphinium (larkspurs)

MethylLycAconitine [21] toxic to animals

From Aspergillus japonicus JV 23

From Pleurobranchus albiguttatus and Pleurobranchus forskalii

Chlorolissoclimide [23] Dichlorolissoclimide [23]

From Aspergillius strain IMI 337664

Haterumaimide A, E, F, N, P [25] Haterumaimide B, G [25] Haterumaimide C [25]

E, R1 = Cl, R2=OH, R3= H, R4 = OH, B, R= Cl

Haterumaimide D, H [25] Haterumaimide I [25] Haterumaimide J, K [25] Haterumaimide O [25]

Haterumaimide L [26] Haterumaimide M [26] Haterumaimide Q [26]

From a specimen of the marine ascidian, Eudistoma Sp., and Maxomycetes

Arcyriaflavin A, B, C, D [27] [28]

Arcyriarubin A, B, C [13] Stachybotryactam V [29]

From slime mould

Arcyroxepin A, B [30] Arcyriacyanin A [30] Dihydroarcyriacyanin A [30] Arcyroxocin A, B [30]

Arcyriaverdin C [30] Dihydroarcyroxocin A [30] Dihydroarcyriarubin B, C [30]

From prosobranch mollusks, ascidians and sponges

Polycitrin A, B [31, 32]

Produced in culture by Streptomyces uncialis

Cladoniamide A, B, C [33] BE-54017 [33]

From the pods of Butea monosperma and identified as palasonin-N-phenyl imide

Palasimide [34] Derivatives of rebbecamycin [34]

Hirsutellone A [34] Hirsutellone D [34]

Himanimide A, C [35] Himanimide B [35] Himanimide D [35]

Isolated from a purple Red Sea tunicate identified as an Eudistoma sp

Segoline A [36] Segoline B [36] Isosegoline A [36]

From Streptomyces griseus

Cycloheximide (naramycin a, hizarocinactidione, actispraykaken, U-4527) [37a]

From Streptomyces pulveraceus

Epiderstatin (a distinctive glutarimide antibiotic) [37b]

From Streptomyces platensis bacteria

Migrastatin [38a] Isomigrastatin [38a]

Dorrigocin A [38a] 13-Epi-dorrigocin A [38a]

Lactimidomycin [38b] Dorrigocin B [38b] NK30424 A/B [38a]

A glutarimide alkaloid from Croton membranaceus