Реакції розширення циклу, які супроводжуються розривом C-N зв’язку, в синтезі циклів середнього розміру та макроциклів
The literature review discusses and systematizes synthetic approaches to medium-sized cycles and macrocycles based on ring expansion reactions of bi- or polycyclic systems via C-N bond cleavage. Ring expansion reactions of bicyclic ammonium salts proceed via thermal decomposition or the action of st...
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Journal of Organic and Pharmaceutical Chemistry| _version_ | 1874364481911390208 |
|---|---|
| author | Lysenko, Viacheslav Nazarenko, Kostiantyn Kostyuk, Oleksandr |
| author_facet | Lysenko, Viacheslav Nazarenko, Kostiantyn Kostyuk, Oleksandr |
| author_institution_txt_mv | [
{
"author": "Viacheslav Lysenko",
"institution": "Institute of Organic Chemistry of the National Academy of Sciences of Ukraine",
"orcid": ""
},
{
"author": "Kostiantyn Nazarenko",
"institution": "Institute of Organic Chemistry of the National Academy of Sciences of Ukraine",
"orcid": ""
},
{
"author": "Oleksandr Kostyuk",
"institution": "Institute of Organic Chemistry of the National Academy of Sciences of Ukraine",
"orcid": "0009-0009-0997-3590"
}
] |
| author_orcid_str_mv | 0009-0009-0997-3590 |
| author_sort | Lysenko, Viacheslav |
| baseUrl_str | https://ophcj.nuph.edu.ua/oai |
| collection | OJS |
| container_end_page | 40 |
| container_issue | 2 |
| container_start_page | 26 |
| container_title | Журнал органічної та фармацевтичної хімії |
| container_volume | 22 |
| datestamp_date | 2026-08-23T16:14:17Z |
| description | The literature review discusses and systematizes synthetic approaches to medium-sized cycles and macrocycles based on ring expansion reactions of bi- or polycyclic systems via C-N bond cleavage. Ring expansion reactions of bicyclic ammonium salts proceed via thermal decomposition or the action of strong bases. Bi- or polycyclic systems containing a common amine group can be reduced with strong reducing reagents, e.g. lithium aluminum hydride. Ammonium derivatives are much more prone to nucleophilic attack and quite often are used as starting materials for the synthesis of medium-sized cycles. Bicyclic systems containing a common aminal or amidine group are used for the synthesis of medium-sized rings and macrocycles via cleavage of the endocyclic C-N bond. Various methods of their activation and reduction are discussed in the review. |
| doi_str_mv | 10.24959/ophcj.24.312453 |
| first_indexed | 2025-07-23T04:43:31Z |
| format | Article |
| fulltext |
ISSN 2308-8303 (Print) / 2518-1548 (Online) 26
Review Article
http://ophcj.nuph.edu.ua
UDC 547.8:54.057
V. Lysenko, K. Nazarenko, O. Kostyuk
Institute of Organic Chemistry of the National Academy of Sciences of Ukraine,
5 Academician Kukhar str., 02098 Kyїv 02660, Ukraine
Ring Expansion Reactions via C-N Bond Cleavage in the
Synthesis of Medium-sized Cycles and Macrocycles
Abstract
The literature review discusses and systematizes synthetic approaches to medium-sized cycles and macrocycles based on
ring expansion reactions of bi- or polycyclic systems via C-N bond cleavage. Ring expansion reactions of bicyclic ammonium
salts proceed via thermal decomposition or the action of strong bases. Bi- or polycyclic systems containing a common amine
group can be reduced with strong reducing reagents, e.g. lithium aluminum hydride. Ammonium derivatives are much more
prone to nucleophilic attack and quite often are used as starting materials for the synthesis of medium-sized cycles. Bicyclic
systems containing a common aminal or amidine group are used for the synthesis of medium-sized rings and macrocycles via
cleavage of the endocyclic C-N bond. Various methods of their activation and reduction are discussed in the review.
Keywords: cleavage; ring expansion; aminal; amidines; medium-sized cycles; macrocycles
В. Лисенко, К. Назаренко, А. Костюк
Інститут органічної хімії Національної академії наук України,
вул. Академіка Кухаря, 5, м. Київ, 02660, Україна
Реакції розширення циклу, які супроводжуються розривом C-N зв’язку, в синтезі циклів
середнього розміру та макроциклів
Анотація
В огляді літератури описано та систематизовано синтетичні підходи до одержання циклів середнього розміру та ма-
кроциклів, які засновані на реакціях розширення циклу бі- або поліциклічних систем, що супроводжуються розривом
C-N зв’язку. Реакції розширення циклу біциклічних солей амонію протікають шляхом їх термічного розкладання або
дії на них сильних основ. Бі- або поліциклічні системи, що містять спільну аміногрупу, можна відновити сильними
реагентами, як-от літій алюмогідрид. Похідні амонію значно більш схильні до нуклеофільної атаки, і їх досить часто
використовують як вихідні матеріали для синтезу циклів середнього розміру. Біциклічні системи, що містять спільну
групу аміналю або амідину, використовують для синтезу циклів середнього розміру та макроциклів шляхом розриву
ендоциклічного зв’язку C-N. В огляді наведено різні способи їх активації та методи розщеплення.
Ключові слова: розщеплення; розширення кільця; аміналі; амідини; середні цикли; макроцикли
Citation: Lysenko, V.; Nazarenko, K.; Kostyuk, A. Ring Expansion Reactions via C-N Bond Cleavage in the Synthesis of Medium-sized Cycles
and Macrocycles. Journal of Organic and Pharmaceutical Chemistry 2024, 22 (2), 26 – 40.
https://doi.org/10.24959/ophcj.24.312453
Received: 17 June 2024; Revised: 1 September 2024; Accepted: 3 September 2024
Copyright© 2024, V. Lysenko, K. Nazarenko, A. Kostyuk. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0).
Funding: The authors received no specific funding for this work.
Conflict of interests: The authors have no conflict of interests to declare.
ISSN 2308-8303 (Print) / 2518-1548 (Online) 27
Journal of Organic and Pharmaceutical Chemistry 2024, 22 (2)
■ Introduction
Cyclic systems containing medium rings
(i.e., 8 – 12 membered cycles) are important
structural components of various natural mole-
cules, as well as biologically active compounds.
However, despite their presence in many impor-
tant natural products, medium-sized rings are
underrepresented in marketed drugs and drug
development programs, mainly due to a lack of
synthetic methods. While synthetic approaches
to 5-, 6-, and 7-membered rings are typically ba-
sed on cyclization and cycloaddition reactions,
these strategies are often ineffective for medium-
sized rings due to negative entropic factors and
transannular interactions. The kinetic and ther-
modynamic barriers associated with their synthe-
sis are generally higher than for rings of other
sizes, that is, they are large enough for the cy-
clization of a linear precursor to occur with sig-
nificant loss of entropy, yet still small enough to
experience destabilizing transannular interac-
tions and strain [1]. Therefore, relatively fewer
methods based on conventional cyclization or cyc-
loaddition reactions are used to prepare medium-
sized rings from acyclic precursors. Nevertheless,
some elegant cycloaddition and annulation ap-
proaches have proven to be useful for the synthe-
sis of these structures, particularly metal-cataly-
zed intramolecular cyclization [2 – 5], metathesis
reactions [6], and click chemistry [7]. However,
a more effective strategy is the ring expansion
method, which allows for avoiding negative ef-
fects associated with the cyclization of medium-
sized and macrocycle derivatives [8]. The sim-
plest class of ring expansion reactions is based
on the cleavage of an endocyclic bond in a fused
bi- or polycyclic system. There are two mechani-
stically related approaches underlying this stra-
tegy for constructing medium-sized cycles and mac-
rocycles. One of them is the successive ring expan-
sion methodology (SuRE-approach), which has
been widely used in the synthesis of medium- and
macrocyclic lactams, lactones, and ketones [9] in
the 1970s (Scheme 1). This approach is based on
the sequential introduction of linear fragments
into existing cyclic systems 1, forming a condensed
bicyclic system 3 in situ. Further fragmentation
leads to the ring expansion affording monocyclic
compounds with larger ring sizes 4.
Another approach mechanistically linked to
the SuRE-method involves cleavage of an endo-
cyclic bond in condensed bi- or polycyclic systems 3
previously synthesized (Scheme 1). This approach
is more efficient for generating medium-sized
cycles and macrocycles, but it requires the start-
ing substrates, which synthesis is not always a
trivial task.
Since synthetic methods based on the SuRE-
approach have been extensively analyzed in re-
cently published reviews [8, 10], this literature
review discusses and systematizes approaches
to the synthesis of derivatives of medium-sized
cycles and macrocycles based on ring expansion
reactions of bi- or polycyclic systems with the
C-N bond cleavage.
■ C-N bond cleavage in bicyclic amines
In the synthesis of medium-sized cycles and
macrocycles, reactions involving the cleavage of
C-N bonds are frequently used. This approach
Y
X
H
H
Y
X
X
Y
XH
YL
1 2
3
4
Scheme 1. The strategy for constructing medium-sized cycles and macrocycles
ISSN 2308-8303 (Print) / 2518-1548 (Online) 28
Журнал органічної та фармацевтичної хімії 2024, 22 (2)
requires the prior activation of starting mate-
rials 5 via the acylation or nitrogen atom qua-
ternization. The subsequent fragmentation of
activated substrates and the formation of mono-
cyclic compounds 6 can occur via the reductive
cleavage or the action of nucleophilic reagents
(Scheme 2).
The historically first example of the C-N
cleavage in the synthesis of a medium-sized cy-
cle is the work by Clemo in 1932 where ammo-
nium salt 7 was used to prepare a 10-membered
derivative 8 via the Hofmann elimination in the
presence of Ag2O (Scheme 3) [11]. However, the
cleavage of the C-N bond occurs non-selectively,
with piperidine derivative 9 being a side pro-
duct [12].
The presence of a benzyl substituent adjacent
to the carbon atom makes the elimination pro-
cess more straightforward (Scheme 4) [13].
This approach has been more extensively
studied using indolizidine derivatives [14, 15]
(Scheme 5). It involves the oxidation of com-
pounds 12 with mercuric acetate and the subse-
quent introduction of a substituent at the carbon
atom by the reaction of iminium salts 13 with or-
ganometallic reagents (2-pycolyl lithium, Grig-
nard reagents, and Reformatsky-type enolate).
The subsequent alkylation of indolizidines 14 with
methyl iodide and treatment of the resulting am-
monium salts 15 with bases, such as sodium eth-
oxide, sodium amide, or n-butyl lithium, leads to
the ring expansion product – 1-azacyclononane 17.
The authors assumed that the C-N bond cleavage
occurred via the β-elimination with the forma-
tion of carbanion 16 as an intermediate. In the
presence of a carboxyl group (R2 = CO2Et), the for-
mation of regioisomer 18 is observed, resulting
from the isomerization of compound 17 into the
thermodynamically more stable endocyclic olefin.
The authors [15] emphasize that the cleavage
of the C-N bond can also occur via the β-elimi-
nation induced by the thermal decarboxylation
of betaine 19 (Scheme 6). According to this mo-
dification, derivative 20 with an exocyclic dou-
ble bond was formed, which could not be ob-
tained by the treatment of salts 15 with sodium
ethylate.
N
C
N C-N bond cleavage
5 6
C
Y
X
Scheme 2. The C-N bond cleavage in bicyclic amines
N
Ag2O, H2O
180 200– oC
N
Me Me
+
N
Me
I
7 8 9
Scheme 3. The Hofmann elimination in the synthesis
of 10-membered derivative
N
Me
Ph
base
2 5 h– N
Me
Ph
10, 84 %
I
1
Scheme 4. The synthesis of 8-membered cycle 11
N
R1
N
R1
Nu =
ZnCH2CO2Et, 2-picolyllihtium
base = NaNH2/NH3 EtONa/EtOHor
R1 = H, Et
R2 = Ph, Allyl, 2-Py, CO 2Et
Nu
HR2
N
R1HR2
Me
base
N
R1R2
Me
N
R1
R2
Me
13 14 15
16 17
N
R1
12
Hg(OAc)2
+
N
R1
R2
Me
18
MeI
Scheme 5. Indolizidine derivatives in the synthesis of medium-sized cycles
ISSN 2308-8303 (Print) / 2518-1548 (Online) 29
Journal of Organic and Pharmaceutical Chemistry 2024, 22 (2)
Thus, ring expansion reactions in bicyclic am-
monium salts 15 to form unsaturated derivati-
ves can occur via the thermal decomposition or
the action of strong bases.
It is worth mentioning a series of studies de-
voted to the synthesis of nitrogen-containing he-
terocycles with medium-sized ring 22 via the
cleavage of C-N bonds in quarternary salts of indo-
lizidine and quinolizidine 21 (Scheme 7) [14 – 18].
It was demonstrated that the endocyclic C-N bond
could be easily cleaved under reductive conditions
(methods A – C) and upon the action of a nucleo-
philic Grignard reagent (method D).
An original approach to the synthesis of 9-in-
dolizidines suitable for their further transforma-
tion into 1-azacyclononanes via the cleavage of
the C-N bond was demonstrated [16]. Nitrile 23
was used as the starting compound, wherein the
CN-group can be easily substituted with a vinyl
or acetylenyl residue upon treatment with the
corresponding Grignard reagents, forming indo-
lizidines 24 and 25 (with the yields of 94 % and
96 %, respectively) (Scheme 8). The reaction of
N-alkylated derivative 25 with lithium aluminum
hydride leads to the formation of a mixture of
regioisomers 26 and 27 in ratios depending on
the solvent and concentration of the reactants.
Meanwhile, the reaction product of the acetyle-
ne derivative 24 with lithium aluminum hydride
in THF or ether is allene 28 with the yield of 96 %.
A similar approach based on the activation
of bicyclic systems with a nitrogen atom via the
N-alkylation has also been successfully applied
to derivatives of benzoindolizidines and benzo-
quinolizidines 29 (Scheme 9) [19 – 21]. The qua-
ternary ammonium salts 30 underwent reduc-
tive cleavage with metallic lithium in liquid am-
monia (Emde-Birch reaction). In this case, the
yield of 10-membered cyclic derivatives 31 (n = 1)
was nearly quantitative due to the selective
cleavage of the C-N bond [20, 21]. At the same
time, the formation of 9-membered derivatives 31
(n = 0) occurred selectively only in the presence of an
activating phenyl substituent (R3 = Ph, X = bond).
This result is explained [19] by forming a more
stable benzhydryl carbanion under the Emde-
Birch reaction conditions.
Another example of the successful implemen-
tation of the above-mentioned approach is the
N
O
O
Me
200 oC
neat
N
Me
H
H
19, 63 % 20
Scheme 6. The thermal decarboxylation of betaine 19
N
X
Y
R
N
X
Y
R
2/NH3 EtONaor
Method B: LiAlH4
Method C: Li/NH3
Method D: Grignard reagent
X = bond, CH2
R = Me, Bn
Y = C2H3, Ph, COMe
21 22
Scheme 7. The C-N bond cleavage in quaternary salts of indolizidine and quinolizidine derivatives
N
CN
23
24, 94 %
NN
MgBrMgBr
25, 96 %
1. MeI
2. LiAlH4
N
C
Me
N
R1
N
R1
Me
1. R1Hal
2. LiAlH4
+
28, 96 % 26 27
R1 = Me, Bn
Scheme 8 Quaternary salts in the ring expansion reaction
N
X
Me
N
X
R1
R2
R3
I
R3
R1
R2
HN
X
R3
R1
R2
MeI
CHCl3, rt
Li
NH3, ROH
-33 oC
X = (CH2)n
n = 0, 1, 2
R1, R2, R3 =
29 30 31
Scheme 9. The Emde-Birch reaction in the synthesis of medium-sized cycles
ISSN 2308-8303 (Print) / 2518-1548 (Online) 30
Журнал органічної та фармацевтичної хімії 2024, 22 (2)
synthesis of 9- and 10-membered derivatives of
pyrrole 34 [22]. The treatment of salts 33 with
metallic sodium in liquid ammonia leads to the
cleavage of the endocyclic C-N bond affording the
target medium-sized heterocycles 34 (Scheme 10).
The application of the Emde-Birch reaction
for the synthesis of bicyclic structures with me-
dium-sized rings is also known (Scheme 11).
1-Azabicyclo[4.4.4]tetradec-5-ene 36 was obtained
by cleaving the endocyclic C-N bond in 35 with
sodium in liquid ammonia in the presence of tert-
butanol in the yield of 58 % [23]. Another example
is the synthesis of manxine (1-azabicyclo[3.3.3]
undecane) 38 by cleaving azapropellane 37 [24].
In the above-mentioned examples the activa-
tion of endocyclic C-N bonds in bicyclic com-
pounds was achieved via the quaternization of
the nitrogen atom, and the resulting quaternary
ammonium salts were used as starting materials
in the ring expansion reactions. However, there
are other methods for cleaving the C-N bond
where a sequential action of an electrophile (on
the nitrogen atom) and a nucleophile (on the car-
bon atom) occurs (Scheme 12) [25 – 43]. This ap-
proach is illustrated by a ring expansion of well-
known derivatives of tetrahydro-β-carboline 39.
The cleavage of the endocyclic C-N bond is often
a key step in the synthesis of various alkaloids
featuring an indole fragment. It is worth noting
that in all cases the derivatives of tetrahydro-β-
carboline 39 are initially treated with alkylating
(RX, BrCN) or acylating (RCO2Cl, (RСO)2O) re-
agents to increase the electrophilicity of the start-
ing compounds.
Electrophiles and nucleophiles that could be
used for this synthetic approach are presented
in Table 1. The main feature of this method is
the use of a wide range of reagents. It allows for
synthesizing functionalized derivatives of medium-
sized rings 40, which can be used as building
blocks for constructing biologically active com-
pounds.
The ability of the C-N bond in derivatives of
tetrahydro-β-carboline 39 for cleavage can be ex-
plained by an additional stabilization provided
by the indole fragment 43 formed in the first step
of quaternary salt 42 (Scheme 13) [33]. It is known
that the C-N bond cleavage in bi- and polycyclic
compounds induced by cyanogen bromide is a well-
known approach for the synthesis of medium-
sized cycles and macrocycles and is a modifica-
tion of the von Braun reaction.
N
Me N
X
MeI, K2CO3
acetone, 16 h, rt
N
Me N
X
Me I
NH3, EtOH
-78 oC to rt, 19 h
N
Me N
X
Me
32 33, 47 48 %– 34, 49 56 %–
X = (CH2)n
n = 1, 2
Na
Scheme 10. The ring expansion reaction of fused pyrrole derivatives
N
N
BF4
Na, NH3
N
N
Na, NH3
35, 58 % 37, 60 %
BrtBuOH
3836
Scheme 11. The synthesis of bicyclic structures via the C-N bond cleavage
N
H
N
X
E, Nu
N
H
N
X
Nu
X = (CH2)n
n = 0, 1, 2
39 40
E
Scheme 12. The ring expansion of tetrahydro-β-carboline derivatives
Table 1. The type of electrophile and nucleophile in the ring
expansion of tetrahydro-β-carboline derivatives
No. Electrophile, Е Nucleophile, Nu Reference
1 RCO2Cl H- [25 – 27]
2 RCO2Cl ROH, RNH2 [28 – 32]
3 BrCN ROH, H2O [33 – 36]
4 (RСO)2O RCOO- [37, 38]
5 RX Li or Na, NH3 [39 – 41]
6 RX CN- [134, 135]
ISSN 2308-8303 (Print) / 2518-1548 (Online) 31
Journal of Organic and Pharmaceutical Chemistry 2024, 22 (2)
Another example is a ring expansion reaction
under the action of ethyl chloroformate/lithium
aluminum hydride (Scheme 14) [17]. The reac-
tion produces a mixture of N-methylamines 47 – 48
in the ratio of 40:60. The formation of diene 48
is explained by the elimination of hydrogen from
an intermediate carbamate or quaternary salt.
The authors did not determine the exact posi-
tion of the endocyclic double bond.
The cleavage of C-N bonds in heterocyclic salts
is possible not only under conditions of the reduc-
tive cleavage, but also under the action of nucleo-
philic reagents. Bremner and Winzenberg disco-
vered a photosolvolysis reaction of benzoindoli-
zidines and benzoquinolizidines, as well as their
oxo-analogs (Scheme 15) [44 – 46]. They demon-
strated that the synthesis of 9- and 10-membered
heterocyclic systems 50 could be achieved by the
ultraviolet irradiation of alcohol or water solu-
tions of salts 49. It is worth noting that the course
of the reaction and the yield critically depends
on the structure of the starting material.
For example, the irradiation of quaternary
salt 51 leads to the formation of the cleavage pro-
duct with a much better yield (49 %) compared to
salt 52 (2 %). It is noteworthy that the starting
salt 52 was recovered unchanged after the reac-
tion (82 %). The authors suggest that the reason
for such different reactivity of quaternary salts
51-52 under conditions of the photosolvolysis
reaction is the stability of intermediate carboca-
tions 53 – 54 (Figure 1). In the case of cation 54,
there is a more effective overlap between the va-
cant p-orbital of the carbon atom and the lone
pair of the nitrogen atom compared to carboca-
tion 53, which likely results in the formation of
the starting salt in the reaction mixture.
■ The C-N bond cleavage in bicyclic
amidines and aminals
One method for synthesizing medium-sized
cycles and macrocycles is the cleavage of bicyclic
systems containing a common aminal or amidi-
ne moiety 55 (Scheme 16). This type of reaction
can serve as a convenient method for obtaining
medium-sized cycles with one or more hetero-
atoms in ring 56. The cleavage of the C-N bond
can occur under the action of nucleophiles. It is
known that aminals are unstable in the absence
of an electron-withdrawing substituent in the
α-position and easily undergo hydrolysis in the
presence of acid. Another approach to the break-
ing of the C-N bond is the reductive cleavage.
It is worth noting that in the case of amidines,
the reaction proceeds via the formation of inter-
mediate aminal derivatives.
Aminals, which have two nitrogen atoms con-
nected by a sp3-hybridized carbon, are primarily
used for synthesizing medium-sized and macro-
cyclic heterocycles. For example, the treatment
of derivative 58 with hydrochloric acid in diox-
ane leads to the formation of the N-unsubstitut-
ed derivative of 1,5-diazocine 59 (Scheme 17).
N
H
N
CN
N
H
N
CN
MeOH
N
H
N
CN
O
Me
N
H
N
BrCN, MeOH,
Na2CO3
THF, rt, 1 h
41 42, 77 %
HO HO HO HO
43 44
Scheme 13. A modified von Braun reaction in the synthesis of 10-membered cycle
N
N
Me
Me
+
N
Me
45 47, 40 % 48, 60 %
N
O OEt
46
ClCO2Et LiAlH4
19 h 15 h
Scheme 14. The ring cleavage of a carbamate derivative
MeO
MeO
R1
N
Me
h , R� 2OH NMeO
MeO
R1 OR2
I
49 50
Me
R1 = H, D, Me, Ph
R2 = H, Me
Scheme 15. The photosolvolysis of benzoindolizidines and benzoquinolizidines
ISSN 2308-8303 (Print) / 2518-1548 (Online) 32
Журнал органічної та фармацевтичної хімії 2024, 22 (2)
Meanwhile, the hydrogenation of compound 58
using the Adams catalyst allows for obtaining
N-methylated derivative 57 (Scheme 17) [47].
Another example is the cleavage of polynu-
clear aminals with a common sp3-carbon atom.
The sequential treatment with an alkylating agent
and an aqueous acid solution of tricyclic ortho-
amide 60 leads to the formation of 1,4,7-triazona-
ne 62 with the yield of 79 % (Scheme 18) [48 – 51].
A bicyclic quaternary salts of amidines can
also form medium-sized rings when reacted with
other nucleophiles. For example, an approach to
the nitrile derivative 1,4,7-triazacyclononane 65
by the nucleophilic cleavage of the benzylated
quaternary salt of octahydroimidazolo[1,2-a]-
pyrazine 64 with sodium cyanide was developed
(Scheme 19) [52].
Another example involves the cleavage of 1,2-
polymethylene imidazolium salts 66 with potas-
sium cyanide leading to functionalized diazoci-
nes 67 and diazocanes 68 (Scheme 20) [53].
It has been shown that the hydrolytic cleav-
age of bicyclic amidines 69 can occur via two
pathways involving the concurrent cleavage of
two C-N bonds and critically depends on the size
of the saturated cycle (Scheme 21) [54]. For in-
stance, alkaline hydrolysis of derivative 69 (n = 2)
leads to the formation of 11-membered azalac-
tam 71 by cleaving the endocyclic C-N bond.
Conversely, reducing the size of the saturated
cycle (n = 1) results in derivatives 70.
Recently, it has been discovered that the hy-
drolysis of DBU (72) leads to the formation of
caprolactam derivative 73 (Scheme 22). However,
N
Me
MeO
MeO
N
Me
MeO
MeO
53 54
overlap of empty p orbital of
carbocation and lone-pair orbital of N
MeO
MeO
N
51
Me
MeO
MeO
N
Me
52
overlap of empty p orbital of
carbocation and lone-pair orbital of N
Figure 1. The stability of intermediate carbocations in the photosolvolysis reaction
N
N
N
NH
C-N bond cleavage
N
NH
X
Y
55 56
Scheme 16. The C-N bond cleavage in bicyclic amidines
and aminals
R = Cl, H
R
NN
O
Ar
R
NH
HN
O
Ar
R
N
HN
O
Ar
Me
HCl
dioxane/H2O, rt, 0.5 h
H2, PtO2
58 59, 89 %57, 66 %
HOAc, rt, 0.5 h
Scheme 17. The synthesis of 1,5-diazocines
N
N
N
N
Cl
THF, rt, 7 days
N
N
N
N
H
N
N
N
N
OH2O HCl/Hor 2O
60 61 62, 79 %
Scheme 18. The synthesis of 1,4,7-triazonane derivative via the cleavage of a polynuclear aminal
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Journal of Organic and Pharmaceutical Chemistry 2024, 22 (2)
a small amount of 11-membered azalactam 74
was also found in the reaction mixture; it was
confirmed by 1H NMR [55].
It is worth noting that in the hydrolysis of
DBU, the yield of medium ring 76 is significant-
ly higher (60 %) in the presence of an alkylating
agent due to the formation of an intermediate
quaternary salt (Scheme 23). However, the for-
mation of caprolactam derivative 75 is also ob-
served [56].
Much more examples of the reductive cleav-
age of amidines are known in the literature com-
pared to aminals since the synthesis of the lat-
ter is often more difficult. Moreover, amidines
are frequently used as starting materials for ob-
taining aminals. It is important to note that, un-
like the hydrolysis of bicyclic amidines, the re-
ductive cleavage of these compounds (and there-
fore, the formation of medium-sized cycles) is an
irreversible process, and the selectivity of the reac-
tion is not strongly dependent on the size of the
saturated cycle. The reductive cleavage of ami-
nals and amidines is closely interconnected since
this process for amidines occurs via the forma-
tion of an intermediate of bi- or polycyclic struc-
ture with an aminal fragment.
Yamamoto and colleagues demonstrated the
possibility of applying the reductive cleavage
HN
N
N
H
N
N
N
Bn
Bn
Bn
Br
N
N
N
Bn
Bn
Bn N
2CO3
MeCN, 10 oC, 6 h
NaCN
3 days, rt
63 64, 63 % 65
Scheme 19. The nucleophilic cleavage of quaternary salts of octahydroimidazolo[1,2-a]pyrazine
N
N
Me
R1
R2
I
NaBH(OAc)3
N N
Me R1
R2
CN
N N
Me R1
R2
CN
66 67, 74 93 %– 68, 57 88 %–
DMSO/H2O, rt, 18 h
KCN
HOAc, 0.5 h
R1, R2 =
Scheme 20. The synthesis of diazocines and diazocanes
(CH2)n
N
N
2 M KOH
N
O
NH2 N
H
NH
O
+
69
n = 1, 2
70
for n = 1
71
for n = 2
Scheme 21. The hydrolytic cleavage of bicyclic amidines
72 74
N
N MeCN-d3/D2O
27 oC
HN
NH
O
N
O
73
NH2
+
Scheme 22. The hydrolysis of DBU
76, 60 %
N
N
N
N
O
+
DCM/H2O, rt, 48 h
K2CO3 Bn
Bn
72
75, 30 %
+BnCl N
O
N
Bn
Bn
Scheme 23. The hydrolysis of alkylated DBU
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Журнал органічної та фармацевтичної хімії 2024, 22 (2)
reaction of bicyclic derivatives of aminals and ami-
dines 77 using DIBAL-H and proposed a mecha-
nism for this reaction (Scheme 24) [57].
It has been shown that the DIBAL-H induced
cleavage is an effective synthetic approach not only
for the synthesis of medium-sized but also mac-
rocyclic compounds 78 in high yields (Table 2).
Other examples of the reductive cleavage of
bicyclic aminals are provided, for instance, in the
works [58 – 62].
However, for 1,2-fused benzimidazoles, the
reaction outcome largely depends on the size of
the saturated ring (Scheme 25). Thus, for 7- and
8-membered derivatives 79 (n = 3, 4), the main
product of the reaction is diazacycloalkanes 83,
whereas the reduction of 6- and 5-membered de-
rivatives 79 (n = 1, 2) yields approximately the
equimolar mixture of 83 and 84 due to the com-
petitive cleavage of C-N or C=N bonds in inter-
mediate 80. The result obtained could be explained
by steric hindrance in the formation of N,N′-bis-
amides 81 (path 1) in the case of n = 1, 2 [63].
The method developed by Yamamoto is high-
ly effective in the synthesis of medium-sized and
macrocyclic derivatives of diazaheterocycles.
However, the use of a strong reducing agent like
DIBAL-H imposes certain limitations on the
starting compounds with functional groups and
technical difficulties in carrying out the reaction.
The activation of aminals or amidines via the
formation of quaternary salts allows the use of
less hazardous reducing agents, such as lithium
aluminum hydride (LiAlH4), and in many cases,
the reductive cleavage of bicyclic compounds is
achieved using sodium borohydride (NaBH4) in
water or alcohols.
An example of the application of lithium alu-
minum hydride LiAlH4 is the synthesis of bicy-
clic diamines with a medium-ring fragment by
reducing derivatives 85 (Scheme 26) [64 – 66].
It has been shown that the reduction of salts 85
with LiAlH4 in DME at room temperature leads
to the formation of bicyclic [5.4.2], [5.5.2], [5.4.3],
and [5.5.3] diamines 86 in high yields. It is worth
noting that the authors have successfully applied
this strategy for the synthesis of derivatives of
7 – 12-membered rings.
Another example of the LiAlH4 application
is the approach to synthesizing analogs of azac-
rown ethers by cleaving tricyclic ortho-amides,
which was first proposed by Weisman and co-
workers (Scheme 27) [67 – 82]. The reduction of
tricyclic guanidine salts 87 (n = 1, 2) with LiAlH4
in THF leads to the formation of ortho-amides 88
with the yield of 75 %, while derivative 87 (n = 3)
gives a mixture of products due to the reduction
N
N DIBAL-H
NH
NH
(CH2)m
77 78
(CH2)n
(CH2)m+1 (CH2)n
Scheme 24. The reductive cleavage of bicyclic aminals and amidines derivatives
Table 2. Yields of ring cleaved products
m n Ring size of 77 Yield of 78, %
4 2 9 79
5 3 11 96
7 2 12 90
7 3 13 74
11 2 14 92
11 3 15 83
N
N
N
Al
iBuiBu
Al
iBu
iBu
path 1
path 2
DIBAL-H
79
83
84
80
81
82
n = 1, 2, 3, 4
n
N
N n
Al
iBuiBu
N
N
Al
iBu
iBu
AliBu
iBu
n
N
H
H
N
n
N
n
NH2
N
n
Scheme 25. The reductive cleavage of 1,2-fused benzimidazoles
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Journal of Organic and Pharmaceutical Chemistry 2024, 22 (2)
of the C=N and C-N bond, resulting in 88 and 89.
In all cases, the acidic hydrolysis of orthoami-
des 88 and 89 obtained allows the formation of
monocyclic triamines 90 in nearly quantitative
yields [68].
As mentioned above, the C-N bond can also
be cleaved with NaBH4. This method has been
successfully used for the development of synthetic
methods for cyclam derivatives 93 (Scheme 28)
[83 – 87]. It has been demonstrated that the treat-
ment of salts 92 with sodium borohydride NaBH4
in 95 % ethanol at room temperature for 3 to 16 days
leads to the formation of derivatives 93 [84].
Attempts to optimize reaction conditions (increas-
ing temperature, varying solvent volume) resul-
ted in the formation of a large amount of side
products. Additionally, attempting to reduce the
quaternary salt 92 with LiAlH4 in diethyl ether
also leads to a mixture of unidentified com-
pounds. It is worth emphasizing that the inac-
tivated compounds 91 do not react with NaBH4
or LiAlH4 and are isolated unchanged after the
reaction. These compounds can only be reduced
using the Yamamoto method [57].
Two more examples of the facile reduction of
quaternary salts 64 and 66 with NaBH4 include
the synthesis of medium-sized ring derivatives 94
and 96 (Schemes 29, 30) [52, 53].
The presence of electron-withdrawing substi-
tuents near one of the nitrogen atoms (typically
a carbonyl group) in bicyclic amidines or aminals
is itself an activating factor that significantly
N
H
N
(CH2)m Cl
(CH2)m
N
N
DME, rt, 24 h
LiAlH4
n, m = 1, 2
(CH2)n (CH2)n
85 86
Scheme 26. The application of LiAlH4 is the synthesis of bicyclic diamines
N N
N
BF4
LiAlH4
THF, 75 %
HCl
(CH2)n
N N
N
(CH2)n
NH HN
H
N
(CH2)n
+
N HN
N
for n = 3for n = 1, 2
87 88, 89 % 89 90
Scheme 27. The cleavage of tricyclic ortho-amides
N N
N N
R-X N N
N N
R
R
N N
N N
R
R
NaBH4
2X
91, 72 93 %– 93, 88 90 %–
R = Me, Bn
X =MeCN EtOH
−
92
Scheme 28. The synthesis of cyclam derivatives
N
N
N
Bn
Bn
BnNaBH4
EtOH, -10 oC, 12 h
94, 37 %
N
N
N
Bn
Bn
Bn
Br
64
Scheme 29. The reductive cleavage of octahydroimidazolo[1,2-a]pyrazine
NaBH(OAc)3
N N
Me R1
R2
N N
Me R1
R2
95, 77 92 %– 96, 50 86 %–
EtOH, rt, 18 h
H
H
H
H
NaBH4
HOAc, rt, 0.5 h
R1, R2 =N
N
Me
R1
R2
I
66
Scheme 30. The reductive cleavage of 1,2-polymethylene imidazolium salts
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Журнал органічної та фармацевтичної хімії 2024, 22 (2)
facilitates the progress of reductive cleavage reac-
tions. As an example, the cleavage of the inter-
nal C-N bond in an isoindole derivative 97 with-
out prior activation leads to the formation of an
8-membered derivative 98 (Scheme 31) [88, 89].
It has also been demonstrated that the cleav-
age of the C-N bond can occur in derivatives of
1,2-fused pyrimidones. The reaction of the reduc-
tive cleavage of the amidine bond has been suc-
cessfully applied in the synthesis of a wide range
of spermine and spermidine alkaloids [90 – 96].
As an example, the final stage of the synthesis
of (±)-dihydroperiphylline 100 is the treatment
of annulated pyrimidone 99 with 3 equivalents of
sodium cyanoborohydride in acetic acid yielding
the thirteen-membered heterocycle 100 in the
yield 93 % (Scheme 32).
The striking difference in the progress of a si-
milar reductive cleavage for the derivative of pyr-
rolo[1,2-a]pyrimidine 101 should be noted. Under
similar conditions, the yield of the expected 9-mem-
bered azalactam 102 was only 31 % (Scheme 33)
[94]. As side products, bicyclic aminals 103 and
104 were formed in the yields of 18 % and 25 %,
respectively. It is worth mentioning that this is
the only attempt in synthesizing medium-sized
cycles by this method [94].
However, a more detailed study of the reductive
cleavage reaction of derivatives of 1,2-fused pyri-
midines is presented in the work [97]. The authors
demonstrated that the cleavage of the derivative
of pyrrolo[1,2-a]pyrimidine 105 (X = bond) and
the formation of a 9-membered 107 (X = bond)
azalactam was possible only in the presence of
a bulky substituent in position C2 of the heterocy-
clic system (Scheme 34). At the same time, the
use of piperidine, morpholine, and azepane de-
rivatives led to the formation of 10- and 11-mem-
bered azalactams 107 (X = CH2, (CH2)2, O) in the
yields of 53 – 92 %.
N
N
H
O
N
H
NH
LiAlH4
Cl
Cl
Et2
97 98, 55 %
Scheme 31. The reductive cleavage of an isoindole derivative 97
N
N
N
O
O
Ph
Ph
N
H
N
H
N
O
OPh
Ph
NaBH3CN
HOAc, 25 50– oC, 14 h
99
dihydroperiphylline
100, 93 %
Scheme 32. The key step in the synthesis of (±)-dihydroperiphylline
N
N
O
Ph N
H
N
O
Ph N
N
O
Ph
Et
+ +
101
102, 31 % 103, 18 % 104, 25 %
HN
NH
O
PhNaBH3CN
HOAc, 45 oC to rt, 24 h
Scheme 33. The synthesis of 9-membered azalactam via the reductive cleavage of pyrrolo[1,2-a]pyrimidine derivative
N
N
O
R
105
NaBH3CN
HOAc, 24 h
R1
R2
X
R3
N
H
H
NO
R
R2
R1
X
R3
+
R, R1, R2, R3 =
X = bond, CH2, (CH2)2, O
106, 63 95 %–
for X = bond
107, 53 92 %–
for X = CH2 (CH2)2 O
N
H
N
O
R
R1
R2
X
R3
, ,
Scheme 34. The reductive cleavage of 1,2-fused pyrimidines
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Journal of Organic and Pharmaceutical Chemistry 2024, 22 (2)
At the same time, the use of derivatives of
2,3-fused dihydrothiadiazines 108 in the ring ex-
pansion reaction leads to the formation of aza-
sultam derivatives 109 in the yields of 63 – 91 %
[98]. It is worth noting that this reaction depends
little on the size or nature of the ring annulated
to the 1,2,3-thiadiazine core (Scheme 35).
■ Conclusion
There are various approaches to medium-sized
cycles and macrocycles based on reductive cleavage
reaction. Two types of bicyclic or polycyclic sys-
tems are used as starting materials – deriva-
tives that contain amine or ammonium common
fragments and aminal or amidine common frag-
ments. The reductive cleavage proceeds with the
splitting of the endocyclic C-N bond. Various re-
ducing agents are used for the reaction. A com-
mon approach to facilitate the reaction is the qua-
ternization of nitrogen or the introduction of ac-
tivating groups. Despite the availability of nu-
merous methods, further efforts are required to
develop more reliable procedures.
■ References
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S
N
108
NaBH3CN
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HN
S
H
N
X
X = bond, CH2 (CH2)2 (CH2)3 O
O O
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109, 63 91 %–
, , ,
Scheme 35. The reductive cleavage of 2,3-fused dihydrothiadiazines
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Information about the authors:
Viacheslav Lysenko earned a Master’s degree (2019) in Chemical Technologies and Engineering at the National Technical University
of Ukraine “Igor Sikorsky Kyiv Polytechnic Institute” with a thesis “Reductive Cleavage of Polymethylene Dihydropyrimidones and
Polymethylene Dihydrotiadiazine-1,1-dioxides”. He is currently a PhD student in the research group of Dr.Sci., Senior Research Scientist
Nazarenko K. at the Institute of Organic Chemistry of the NAS of Ukraine (Kyiv). The area of scientific interest is the chemistry of
medium-sized cycles and macrocycles and their annulated derivatives. https://orcid.org/0000-0001-5177-7678.
Kostiantyn Nazarenko received a Dr.Sci. degree in 2016 with a thesis “Cyclic Amidines, Enamines, and Derivatives of 2-Chloro-1,4-
benzothiazin-3-one in the Synthesis of Polynuclear Heterocyclic Systems and ω-Heteroarylalkylamines”. His current research lines are
focused on the synthesis of sp3-enriched heteroaromatic systems. He has also served as a Senior Research Scientist at the Institute of
Organic Chemistry of the NAS of Ukraine. https://orcid.org/0000-0002-1037-6381.
Oleksandr Kostyuk (corresponding author) received a Dr.Sci. degree in 2009 with a thesis devoted to the development of the
methodology of regioselective functionalization of methyl substituted tertiary push-pull enamines with activated carbonyl compounds,
their imines, and phosphorus(III) halides. In 2009, prof. Kostyuk was appointed as the Head of the Department of Chemistry of
Organophosphorus Compounds at the Institute of Organic Chemistry of the NAS of Ukraine. https://orcid.org/0000-0002-4326-4968;
e-mail for correspondence: a.kostyuk@yahoo.com.
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| spelling | oai:ojs.journals.uran.ua:article-3124532026-08-23T16:14:17Z Ring Expansion Reactions via C-N Bond Cleavage in the Synthesis of Medium-sized Cycles and Macrocycles Реакції розширення циклу, які супроводжуються розривом C-N зв’язку, в синтезі циклів середнього розміру та макроциклів Lysenko, Viacheslav Nazarenko, Kostiantyn Kostyuk, Oleksandr розщеплення розширення кільця аміналі амідини середні цикли макроцикли cleavage ring expansion aminal amidines medium-sized cycles macrocycles The literature review discusses and systematizes synthetic approaches to medium-sized cycles and macrocycles based on ring expansion reactions of bi- or polycyclic systems via C-N bond cleavage. Ring expansion reactions of bicyclic ammonium salts proceed via thermal decomposition or the action of strong bases. Bi- or polycyclic systems containing a common amine group can be reduced with strong reducing reagents, e.g. lithium aluminum hydride. Ammonium derivatives are much more prone to nucleophilic attack and quite often are used as starting materials for the synthesis of medium-sized cycles. Bicyclic systems containing a common aminal or amidine group are used for the synthesis of medium-sized rings and macrocycles via cleavage of the endocyclic C-N bond. Various methods of their activation and reduction are discussed in the review. В огляді літератури розглянуто та систематизовано синтетичні підходи до одержання циклів середнього розміру та макроциклів, які засновані на реакціях розширення циклу бі- або поліциклічних систем, що супроводжуються розривом C-N зв’язку. Реакції розширення циклу біциклічних солей амонію протікають шляхом їх термічного розкладання або дії на них сильних основ. Бі- або поліциклічні системи, що містять спільну аміногрупу, можна відновити сильними реагентами, як-от літій алюмогідрид. Похідні амонію значно більш схильні до нуклеофільної атаки, і їх досить часто використовують як вихідні матеріали для синтезу циклів середнього розміру. Біциклічні системи, що містять спільну групу аміналю або амідину, використовують для синтезу циклів середнього розміру та макроциклів шляхом розриву ендоциклічного зв’язку C-N. В огляді розглянуто різні способи їх активації та методи розщеплення. National University of Pharmacy 2024-11-08 Article Article application/pdf https://ophcj.nuph.edu.ua/article/view/312453 10.24959/ophcj.24.312453 Journal of Organic and Pharmaceutical Chemistry; Vol. 22 No. 2 (2024); 26-40 Журнал органической и фармацевтической химии; Том 22 № 2 (2024); 26-40 Журнал органічної та фармацевтичної хімії; Том 22 № 2 (2024); 26-40 2518-1548 2308-8303 en https://ophcj.nuph.edu.ua/article/view/312453/304471 Copyright (c) 2024 National University of Pharmacy http://creativecommons.org/licenses/by/4.0 |
| spellingShingle | розщеплення розширення кільця аміналі амідини середні цикли макроцикли Lysenko, Viacheslav Nazarenko, Kostiantyn Kostyuk, Oleksandr Реакції розширення циклу, які супроводжуються розривом C-N зв’язку, в синтезі циклів середнього розміру та макроциклів |
| title | Реакції розширення циклу, які супроводжуються розривом C-N зв’язку, в синтезі циклів середнього розміру та макроциклів |
| title_alt | Ring Expansion Reactions via C-N Bond Cleavage in the Synthesis of Medium-sized Cycles and Macrocycles |
| title_full | Реакції розширення циклу, які супроводжуються розривом C-N зв’язку, в синтезі циклів середнього розміру та макроциклів |
| title_fullStr | Реакції розширення циклу, які супроводжуються розривом C-N зв’язку, в синтезі циклів середнього розміру та макроциклів |
| title_full_unstemmed | Реакції розширення циклу, які супроводжуються розривом C-N зв’язку, в синтезі циклів середнього розміру та макроциклів |
| title_short | Реакції розширення циклу, які супроводжуються розривом C-N зв’язку, в синтезі циклів середнього розміру та макроциклів |
| title_sort | реакції розширення циклу, які супроводжуються розривом c-n зв’язку, в синтезі циклів середнього розміру та макроциклів |
| topic | розщеплення розширення кільця аміналі амідини середні цикли макроцикли |
| topic_facet | розщеплення розширення кільця аміналі амідини середні цикли макроцикли cleavage ring expansion aminal amidines medium-sized cycles macrocycles |
| url | https://ophcj.nuph.edu.ua/article/view/312453 |
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