ABDULRAHMAN AL-SUMAIT UNIVERSITY.

DEPARTMENT NAME: NATURAL SCIENCE DEPARTMENT.

COURSE TITTLE : ORGANIC CHEMISTRY III
COURSE CODE : CH 354
COURSE LECTURER : Mr. SALIM A. SALEH.
MODE OF WORK : GROUP ASSIGNMENT.
ACADEMIC YEAR : THIRD YEAR (2021/2022).
ASSIGNMENT QN : WRITE THE CHEMISTRY OF
HETEROCYCLIC COMPOUND OF 8-
MEMBERED RING
GROUP MEMBERS;
i. FATMA 19/BC/0
ii. ZAINAB 19/PC/0
iii. ALI JUMA HAJI 19/BC/0
iv. MUHAMMAD YUSUPH RASHID 19/BC/071
v. ALI ISSA 19/PC/0
vi. HAMZA NASSIR 19/BC/042
vii. IS-HAQ 19/PC/0

 HETEROCYCLIC COMPOUNDS (8-MEMBERED RING)

  INTRODUCTION

Heterocyclic compounds; are organic compounds that contain a ring structure containing atoms

in addition to carbon, such as sulfur, oxygen or nitrogen, as part of the ring. They may be
either simple aromatic rings or non-aromatic rings.
Shortly we can state that Heterocyclic compounds are cyclic compounds which contains
one/more hetero atoms of other elements along with carbon atoms.
Hetero atoms; are those which contains an atom other than carbon such as nitrogen, sulphur,
phosphorus etc.
Generally,Heterocyclic chemistry is the chemistry branch dealing exclusively with synthesis,
properties and applications of heterocycles especially vital to drug design. Under this section we
will look on the heterocyclic compound of 8 membered ring.

 HETEROCYCLIC COMPOUND WITH 8 MEMBERED RING.

These are organic compounds that contain a ring structure containing seven carbon atom with
one hetero atom either sulfur, oxygen or nitrogen attached between two adjacent carbon atom.
Consider the example below;

Azocane Oxocane Thiocane Azocine Oxocine Thiocine

8-Atom
Ring

 8 MEMBERED RING WITH ONE NITROGEN ATOM AS HETERO ATOM

These are heterocyclic compound with seven carbon and a hydrogen atom connected together in
aring structure.example of this compounds are azocine (unsaturated) and azocane(saturated)
The primary concern of this part is eight-membered azaheterocycles, azocines. Azocines are a
diverse class of compounds, that frequently occur as biologically active compounds as well as
being widely used in synthetic chemistry. Azocines have received more attention because of their
increasing usefulness both as synthetic intermediates and as therapeutic agents

 STRUCTURE AND NOMENCLATURE

Eight-membered rings with one nitrogen atom can be classified broadly into five categories:
unsaturated, partially saturated, fully saturated, bridge-head, and fused ring systems (l)-(5). The
most commonly used systematic nomenclature for eight-membered heterocyclic compounds is
the Hantzsch-Widman system. . According to this system,
  the compound (1) with four noncumulative double bonds is named azocine, with the
prefix "aza" indicating the nitrogen atom,
 followed by the stem "ocine" indicating the ring size and unsaturation. The nitrogen atom
takes the atom number one.
 Partially saturated systems are expressed by the prefixes dihydro-, tetrahydro-,
hexahydro-, and octahydro- with azocine.

For example; (2) is named as 1,8-dihydroazocine. The fully saturated system (3) is named
"azocane" or "perhydroazocine

cyclooctanone (6), octahydroazocine (7), hexahydroazocin-5-one (8)

 SYNTHESIS OF 8 MEMBERED RING WITH ONE NITROGEN ATOM

Synthesis of azocines embraces that of azepines and azonines in the use of general methods like
Beckmann rearrangement, Schmidt reaction, and intramolecular cyclization. Since azocines are a
diverse class of compounds, their preparative methods remain specific and often inefficient.

 Synthesis of azocines

synthesis of azocine/azacyclotetraene was achieved by the only route, photocycloaddition of a

nitrile group into an aromatic ring.
This methodology is successful only if the benzenes have both electrondonor and electron-
acceptor substituents in the para relationship to give azocines para-substituted methoxy
benzonitrile (72) reacted with phenol (71) to yield lactam (75) by initial 1,2-photocycloaddition,
followed by ring opening and tautomerization
  Synthesis of hydroazocines

Generally hydroazocines are prepared via cycloaddition; but depending upon the degree of
unsaturation, the preparation can also be achieved by other routes. Consider the following;

 Hexahydroazocines
i. Intramolecular cyclization of (76) in the presence of NaH gave exo (77) and endo (78)
products.

ii. An unstable enaminone azocine derivative (81) was formed after the desulfurization of
the bicyclic aminal (80), which in turn was synthesized from the Diels-Alder adduct,
dihydrothiopyranone (79).

 Tetrahydroazocines
i. The [2 + 2] cycloaddition of tetrahydropyridine (88) with HC==CCO2Me gave
tetrahydroazocine (90)
 ii. Cycloaddition of fulvene (91) with cyclic imine (92) gave the azocine (93)

 Dihydroazocines

Unsymmetrically substituted ethynes (104) bearing at least one electron-withdrawing group

underwent efficient cycloaddition with l--styryl-l,2-dihydropyridine (105) to provide 3,4-
substituted 1,8-dihydroazocines (106) regioselectively.

 Perhydroazocines

Intramolecular cyclization of suitable starting materials with appropriate reagents afforded per-
hydroazocines. The secondary -styryl (N-methylamino) alkane (107) under- went
intramolecular photochemical addition to yield regioisomeric adducts in which C—N bond
formation had occurred either at the -carbon to give N-substituted azocine (109) or at the -
carbon to give N-substituted azepine (108).
  Synthesis of benzazocines

The benzo-fused azocine derivatives are diverse, hence grouping them together and presenting
strategic synthetic routes becomes rather intricate. A desirable benzazocine can be easily
separated from other products by flash chromatography.
Intramolecular cyclization is one of the common methods used to obtain benzazocines base
catalyzation of N-phthalimido substituted -Ketoester provided benzazocine trione .
Cyclization of hydroxylamine derivative (122) in MeOH with NaBH3CN gave (123).

 REACTIONS OF 8 MEMBERED RING WITH ONE NITROGEN ATOM

 Hydroazocines reactions

Hydroazocine lactams have been shown to also undergo acylation. Via modified Tiemann
rearrangement, cyclic amidoxime O-methanesulfonate has been transformed into cyclic
carbodiimides.

 Perhydroazocines reactions

Perhydroazocines readily undergo nucleophilic substitution to yield N-substituted derivatives. N-

Substitution has been achieved by both acylation and alkylation procedures.
N-Acylation is accomplished by reaction of (3),azocane compound with (i) acyl chloride(ii) 1,1-
carbonyldiimidazole , and (iii) acid anhydrides.
N-Alkylation is accomplished by reaction with the corresponding halides (I, Br, Cl) or

 by Mannich reaction shown below

 The -carbon of the lactam (34) was functionalized to obtain the racemic eight-
membered lactam (39). The racemic mixtures were resolved via its pyroglutamic salts.
 Benzazocines reactions
 Benzazocines can be easily alkylated by alkyl halides and acylated by acid chlorides.
 Benzazonium ylide (52) with sodamide in liquid ammonia solely underwent the Stevens
rearrangement (1-2 migration) rather than the Sommelet-Hauser reaction (2-3 migration)
to afford one carbon ring enlargement product (53).formation of 9-membered ring.

 When the nitrogen atom bears one methyl group and another methyl or ethyl group, (55)
afforded the ring-opened product, enamine (56).

 Thermolysis of 2-methyl hexahydrobenzazocine Noxide (57) afforded the ring-enlarged

product, methylhexahydrooxabenzazonines (58).
  Ring C-alkylation was achieved by exploiting the chiral formamidine leaving group
allylic proton pKa. Subsequent reduction of unsaturation using Rh/C furnished the
benzomorphan( + )-metazocine. The -carbon was functionalized into an amino group
via bromination, phthalimidation, alkylation, or amination to obtain (60) from (59). The
introduced amino group was further reductively alkylated and saponified to give (61).
Various related derivatives were prepared with a number of "R" groups on the aromatic
ring.

 APPLICATION OF 8 MEMBERED RING WITH ONE NITROGEN ATOM

Eight-membered azaheterocycles have found a wide spectrum of applications as summarized

below;

 Azocines

Completely saturated azocines possess numerous applications. N-Acylated derivatives of

perhydroazocines are used as herbicides, as antiarrhythmic agents and they also possess anti-con
vulsant activity.

 Benzazocines

Benzazocines are a biologically important group of compounds because of their diverse

functions. Interestingly, some benzazocines are analgesics and some are antagonists of
analgesics. Benzazocine 1,3-diones possess antiarrhythmic activity . Benz-fused lactams have
been shown to be antagonists of the peptide hormone (cholecystokinin (CCK)), antagonists of
angiotensin converting enzyme and antihypertensives.

mitomycin (antitumor antibiotics)

 Dibenzazocines

Dibenzazocines have found major applications in the area of pharmacology. Dibenz[c.e]azocine

and apogalanthamine analogs have been proven to be adrenergic blocking agents. . Yet other
pharmacological uses such as antihistaminic, antiinflammatory, antiarrhythmic, and
anticholinestrase have been mentioned.
  REFERENCES
i. https://www2.chemistry.msu.edu/faculty/reusch/virttxtjml/heterocy.htm
ii. http://aether.cmi.ua.ac.be/artikels/MB_11731/HET2v9Ch18.pdf