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PROGRESS IN
HETEROCYCLIC
CHEMISTRY
VOLUME
29
Edited by
GORDON W. GRIBBLE
Department of Chemistry, Dartmouth College
Hanover, New Hampshire, USA
JOHN A. JOULE
The School of Chemistry, The University of Manchester
Manchester, UK
Elsevier
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The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom
50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States
This book and the individual contributions contained in it are protected under copyright
by the Publisher (other than as may be noted herein).
Notices
Knowledge and best practice in this field are constantly changing. As new research and
experience broaden our understanding, changes in research methods, professional
practices, or medical treatment may become necessary.
Practitioners and researchers must always rely on their own experience and knowledge
in evaluating and using any information, methods, compounds, or experiments described
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and the safety of others, including parties for whom they have a professional responsibility.
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editors, assume any liability for any injury and/or damage to persons or property as a
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any methods, products, instructions, or ideas contained in the material herein.
ISBN: 978-0-08-102310-5
ISSN: 0959-6380
Steven-Alan G. Abel
University of Tasmania, Hobart, TAS, Australia
R. Alan Aitken
University of St. Andrews, St. Andrews, United Kingdom
K. Alison Rinderspacher
Columbia University, New York, NY, United States
Clémence Allain
PPSM, ENS Cachan, CNRS, Université Paris-Saclay, Cachan, France
Josefa Anaya
Universidad de Salamanca, Salamanca, Spain
Pierre Audebert
PPSM, ENS Cachan, CNRS, Université Paris-Saclay, Cachan, France
Jeanese C. Badenock
University of the West Indies, Cave Hill, Barbados
Edward R. Biehl
Southern Methodist University, Dallas, TX, United States
Alex C. Bissember
University of Tasmania, Hobart, TAS, Australia
Sourav Chakraborty
The University of Akron, Akron, OH, United States
Gavin Chit Tsui
The Chinese University of Hong Kong, Shatin, China
Gilles Clavier
PPSM, ENS Cachan, CNRS, Université Paris-Saclay, Cachan, France
Franca M. Cordero
Università degli Studi di Firenze, Florence, Italy
Donatella Giomi
Università degli Studi di Firenze, Florence, Italy
Christopher Hyland
University of Wollongong, Wollongong, NSW, Australia
Zhihai Ke
The Chinese University of Hong Kong, Shatin, China
Tara L.S. Kishbaugh
Eastern Mennonite University, Harrisonburg,VA, United States
xi
xii Contributors
Luisa Lascialfari
Brachi Testing Services, Prato, Italy
Katherine Lehman
Eastern Mennonite University, Harrisonburg,VA, United States
Justin M. Lopchuk
H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, United States;
University of South Florida, Tampa, FL, United States
Vakhid A. Mamedov
A.E. Arbuzov Institute of Organic and Physical Chemistry, Kazan Scientific Center of the
Russian Academy of Sciences, Kazan, Russian Federation
Adam G. Meyer
CSIRO Manufacturing, Clayton,VIC, Australia
George R. Newkome
The University of Akron, Akron, OH, United States
Albert Padwa
Emory University, Atlanta, GA, United States
Xiao-Shui Peng
The Chinese University of Hong Kong, Shatin, China; The Chinese University of Hong
Kong, Shenzhen, China
Ramón M. Sánchez
Universidad de Salamanca, Salamanca, Spain
Clementina M.M. Santos
Polytechnic Institute of Bragança, Bragança, Portugal
Artur M.S. Silva
University of Aveiro, Aveiro, Portugal
Jason A. Smith
University of Tasmania, Hobart, TAS, Australia
Charlotte C. Williams
CSIRO Manufacturing, Parkville,VIC, Australia
Yong-Jin Wu
Bristol Myers Squibb Research and Development, Wallingford, CT, United States
Larry Yet
University of South Alabama, Mobile, AL, United States
Ying-Yeung Yeung
The Chinese University of Hong Kong, Shatin, China
Farzad Zamani
University of Wollongong, Wollongong, NSW, Australia
Nataliya A. Zhukova
A.E. Arbuzov Institute of Organic and Physical Chemistry, Kazan Scientific Center of the
Russian Academy of Sciences, Kazan, Russian Federation
FOREWORD
This is the 29th annual volume of Progress in Heterocyclic Chemistry and cov-
ers the literature published during 2016 on the important heterocyclic ring
systems. References are incorporated into the text using the journal codes
adopted by Comprehensive Heterocyclic Chemistry and Advances in Heterocyclic
Chemistry, and are listed in full at the end of each chapter.
This volume opens with two specialized reviews, not restricted to work
published in 2016: “Recent Advances in the Synthesis of Benzimidazol-
2-ones via Rearrangements,” written by Vakhid Mamedov and Nataliya
Zhukova of the Arbuzov Institute of Organic and Physical Chemistry, Kazan
Scientific Centre of the Russian Academy of Sciences. The second review,
“Use of Rhodium Carbenoid Intermediates for Dipolar Cycloaddition
Chemistry,” is by Albert Padwa of Emory University, who is a leading figure
in this important area of heterocyclic synthesis.
The remaining chapters examine the 2016 literature on the common
heterocycles in order of increasing ring size and the number of heteroatoms
present. The index is not fully comprehensive but the contents pages list all
the subheadings of the chapters, which allow ease of access to specific topics
for readers.
We are delighted to welcome some new contributors to this volume
and we continue to be indebted to the veteran cadre of authors for their
expert and conscientious coverage. We also acknowledge the important
contributions made by our colleagues at Elsevier Science in supervising and
assisting the publication of this volume and for preparing the index.
We hope that our readers find this series to be a useful guide to the most
recent developments in heterocyclic chemistry. As always, we encourage
suggestions for improvements, ideas for review topics, and inquiries from
interested potential authors.
Gordon W. Gribble
John A. Joule
xiii
EDITORIAL ADVISORY BOARD MEMBERS
PROGRESS IN HETEROCYCLIC CHEMISTRY
2016-2017
xv
CHAPTER 1
1.1 INTRODUCTION
Benzimidazol-2-ones (1,3-dihydro-2H-benzimidazol-2-ones) are impor-
tant heterocycles, with an embedded cyclic urea scaffold, widely distributed
in a variety of pharmacological compounds, such as calcitonin gene-related
peptide receptor antagonists (1) (08BMCL6122), p53-Mdm antagonists (2)
(13BMC3982), cannabinoid receptor 2 antagonists (3) (08BMCL3310),
opioid receptor-like 1 agonists (4) (07BMC1828, 08BMC2829), nonnucle-
oside HIV-1 RT inhibitors (5) (10BMC1702), d-amino acid oxidase inhib-
itors (6) (12ACSMCL839), respiratory syncytial virus fusion inhibitors (7)
(06BMCL1115), as well as Mycobacterium tuberculosis enzyme inhibitors (8)
(10BMC896), p38 MAP kinase inhibitors (9) (06BMCL6316), and antibac-
terial agents (10) (10DPC178) (Fig. 1). Benzimidazol-2-one carboxylic
acids and oxazolidinediones are potential therapeutic agents of selective
peroxisome proliferator-activated receptor γ modulators (11JMC8541), and
can be used to treat Type 2 diabetes mellitus (11) (11JMC8541) (Fig. 1).
Furthermore, benzimidazol-2-one derivatives play important roles as pro-
gesterone receptor antagonists (12, 13) (05BMCL3600, 11SQER775), as a
selective vasopressin 1a receptor antagonist (14) (06OPRD1227), in the
selective inhibition of farnesyltransferase (15) (05BMCL2918), and the acti-
vation of K+ channels (16) (96BMCL1641, 03PM885) (Fig. 1).
Benzimidazol-2-one derivatives have been used for over 30 years as pig-
ments with a broad range of hues in watercolor painting and electrophoto-
graphic developer toner because of their durability and light resistance
(90DP57, 94DP59, 97JE621, 02JMS(T)89, 13DP358).
Figure 1
Recent Advances in the Synthesis of Benzimidazol-2-ones via Rearrangements 3
Two typical methods are usually applied for the synthesis of N-substituted
1,3-dihydrobenzimidazol-2-ones. The first method is the selective alkyla-
tion or arylation of nitrogen atoms in 1,3-dihydrobenzimidazol-2-ones
(05BMCL3600, 06BMCL6165, 07BMCL895).The second method involves
the nucleophilic substitution of fluorine atoms in 2-fluoronitrobenzenes
with amines and subsequent reductive cyclization with components to sup-
ply the carbonyl group, e.g., carbonyldiimidazole (01T981, 05BMCL2918,
06BMCL6316, 12BMCL5134, 14BMC4298). The first method often
requires a strategy for the protection of NH groups, and the second is prob-
lematic because of the limitations of the substituted derivatives of 2-fluoro-
nitrobenzenes. In addition, there are other approaches for obtaining
unsymmetrical 1,3-dihydrobenzimidazol-2-ones, e.g., reactions proceeding
with rearrangements of various heterocyclic systems. Surprisingly, such
methods have not been previously reviewed. Some subsections concern-
ing benzimidazolones in reviews on quinoxalines (79MI1, 16MI1,
16RSCA42132) or benzimidazoles (97MI1, 11RCR397) do not generalize
all the means of synthesizing 1,3-dihydrobenzimidazol-2-ones, and do not
allow one to make predictions about possible new methods. Herein, we aim
to fill in this blank.
1.2 REARRANGEMENT OF BENZODIAZEPINE(DI)ONES
1.2.1 Synthesis of Benzimidazol-2-ones From
Benzodiazepinones
In the presence of traces of acid the product of the interaction of 1,2-diami-
nobenzene (1,2-DAB) 17a with ethyl acetoacetate 18 at room temperature
is ethyl β-o-aminoanilincrotonate 19 (Scheme 1A) (1896B1497, 42JCS303),
while the addition of 1,2-DAB 17a to the ester 18 in boiling xylene con-
taining pyridine leads to o-aminoacetoanilide 20 (Scheme 1B) (40G648).
According to Sexton (42JCS303), adding the ester to the 1,2-DAB 17a in
boiling xylene under neutral conditions gives 4,7-dihydro-5-methyl-1H-
2,3-benzo-1,4-diazepin-7-one 21 (or its tautomeric form) with a melting
point (mp) of 121°C (Scheme 1C), yet if the ester 18 is previously kept over
potassium carbonate or if ethanolic potassium hydroxide solution is added
to the reaction mixture, the product is the isomeric 2-acetonylbenzimid-
azole 22 with an mp of 148°C (Scheme 1D).
Trying to clarify the structure of the proposed diazepine 21 (mp 121°C),
Davoll (60JCS308) revealed that the compound when exposed to phospho-
ryl chloride in the presence of dimethylaniline gave a chlorinated product,
4 Progress in Heterocyclic Chemistry
&
'
Scheme 1
Scheme 2
Scheme 3
Scheme 4
from 1,2-DAB and ketene (57CB825), and was shown by its physicochemical
characteristics to be identical to the product of the counter synthesis.
On reduction, the compound with the mp 121°C also absorbed 1 mol
equivalent of hydrogen to give a product resembling the starting material in
its ultraviolet absorption spectrum and solubility in alkali, but differing in
not being hydrolyzed to benzimidazol-2-one 27 and acetone (Scheme 3)
by dilute acid. The assumption that the product of the hydrogenation of
compound with the mp 121°C is 1-isopropylbenzimidazol-2-one 26, not
diazepine 25, was confirmed with the counter synthesis of the latter from
2-isopropylaminoaniline 28 and urea 29 (Scheme 3) (60HCA1298).
Thus the reaction products of 1,2-DAB 17a with ethyl acetoacetate 18
have been shown to have structures different from those previously assigned
by Sexton (42JCS303). The product with the mp 148°С is benzodiazepine
derivative 21, and the product with the mp 121°С is 1-isopropenylbenz-
imidazol-2-one 30 (60JCS308, 60HCA1298), i.e., not 2-acetonylbenzimid-
azole 22 (42JCS303) (Scheme 4).
As shown in Scheme 5, the formation of compound 30 in the reaction
of 1,2-DAB 17a with ethyl acetoacetate 18 under the conditions studied
occurs through the intermediate formation of the semiaminal derivative A,
the stabilization of which takes place not with the elimination of a molecule
6 Progress in Heterocyclic Chemistry
Scheme 5
Scheme 6
Scheme 7
of ethanol or water, but with the C-2dC-3 bond breakage leading to car-
bamate B. Further intramolecular amidation is completed with the forma-
tion of benzimidazolone system 30.
Although in the literature (68TL4811, 88TL195) the thermal rear-
rangement of dihydrobenzodiazepinone 21 is presented as a [1,3]-sigma-
tropic change (Scheme 6), under the investigated conditions we cannot
exclude a mechanism involving the C-2dC-3 bond breakage as in the
previous case. However, apparently, in this version of the reaction there
will occur the intermediate formation of the more reactive isocyanate C
(Scheme 7) (intramolecular cyclization of isocyanates with the formation
of amide functions is well known) (65T2191, 70JHC807, 86CJC577,
92T6335).
Depending on reaction conditions, dihydrobenzodiazepinone 21,
2-methylbenzimidazole 31, and vinylbenzimidazol-2-one 30 derivatives
can be formed (Table 1).
Table 1
7
aYields are not given.
8 Progress in Heterocyclic Chemistry
Scheme 8
Recent Advances in the Synthesis of Benzimidazol-2-ones via Rearrangements 9
Scheme 9
Scheme 10
1,2-DAB 17a can react not only with ethyl acetoacetate 18 and its acy-
clic derivatives 34, 39 as shown earlier, but also with its carbo- and hetero-
cyclic analogs, such as 2-carbethoxycyclopentanone 43 (60HCA1298),
methyl 4-oxotetrahydrothiophene-3-carboxylate 44 (Scheme 10)
(75MC375), 2-carbethoxycyclohexanone 50, and N-substituted 3-carbe-
thoxy-4-piperidones 51 (Scheme 11) (60HCA1298). In the case of the con-
densation of ester 43 with 1,2-DAB 17a in boiling xylene, along with the
tricyclic derivative 45 (in a yield of 30%), benzimidazolone derivative 46 (in
a 25% yield) (Scheme 10A) was also produced (60HCA1298). When diaz-
epinone 45 was heated in 2-ethoxyethanol in the presence of sodium 2-eth-
oxyethanolate (60JCS308) the process followed a Davoll rearrangement to
form 1-cyclopentenyl-1H-benzimidazol-2(3H)-one 46 (60HCA1298).
Additionally, it should be noted that the condensation of β-ketoester 44
with 1,2-DAB 17a in boiling xylene proceeds with the formation of a
10 Progress in Heterocyclic Chemistry
&
Scheme 11
Scheme 12
Scheme 13
Scheme 14
Scheme 15
Recent Advances in the Synthesis of Benzimidazol-2-ones via Rearrangements 13
Scheme 16
Language: English
By HENRY SLESAR
Illustrated by ENGLE
"Now kill her," said the voice. "And you can go free."
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