Piperidine-Based Drug Discovery

Ruben Vardanyan
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Piperidine-Based Drug Discovery
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Heterocyclic Drug Discovery Series

Piperidine-Based
Drug Discovery

Ruben Vardanyan
University of Arizona Tucson, AZ, USA
Elsevier
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Contents

1. Introduction
1.1 The Scope of the Material Under Consideration 1
1.2 General Methods of the Synthesis of Piperidine Compounds 5
Nucleophilic Substitution Reactions 6
Intermolecular Michael Reactions 9
Catalyzed Hydroamination Reactions 12
Aza-Diels
Alder Reactions 13
Intramolecular Ene Reactions 18
Ring-Closing Metathesis Reactions 22
Synthesis of Piperidin-4-Ones 23
Nucleophilic Addition Reactions to the Carbonyl Group
of Piperidin-4-Ones 30
Nucleophilic Substitution Reactions Involving α-Carbon
of Piperidin-4-Ones 39
Piperidin-3-Ones 45
Piperidin-2-Ones 49
4-Cyano-4-Phenylpiperidines 56
References 57

2. 1-Substituted Piperidines
2.1 Derivatives of 1-Phenyl-3-(Piperidin-1-yl)Propan-1-ol 83
Trihexyphenidyl 83
Biperiden 84
Pridinol 85
Cycrimine 85
2.2 Derivatives of 1-Phenyl-4-(Piperidin-1-yl)Butan-1-ol 86
Diphenidol 86
Pirmenol 87
2.3 Derivatives of 2-(Piperidin-1-yl)Ethan-1-ol and
3-(Piperidin-1-yl)Propan-1-ol 88
Cloperastine 88
Benproperine 89
Pipazethate 89
Raloxifene 90
Flavoxate 92
Piperocaine 93

v
vi Contents

2.4 Derivatives of 3-(Piperidin-1-yl)Propane-1,2-Diol

and 3-(Piperidin-1-yl)Propane-1,1-Diol 94
Diperodon 94
Pipoxolan 95
2.5 Derivatives of 1-Phenyl-3-(Piperidin-1-yl)Propan-1-One 95
Dyclonine 96
2.6 Derivatives of 2,2-Diphenyl-4-(Piperidin-1-yl)Butanamide 96
Fenpiverinium Bromide 96
References 97

3. 2-Substituted and 1,2-Disubstituted Piperidines

3.1 Methylphenidate 103
3.2 Perhexiline 103
3.3 Pipradrol 104
3.4 Mefloquine 105
3.5 Mepivacaine 106
3.6 Ropivacaine 106
3.7 Bupivacaine and Levobupivacaine 107
3.8 Flecainide 109
3.9 Encainide 110
3.10 Thioridazine 110
3.11 Rimiterol 112
3.12 Lobeline 112
3.13 Argatroban 115
3.14 Ascomycin, Pimecrolimus, Tacrolimus, Sirolimus, Everolimus,
and Temsirolimus 117
References 118

4. 3-Substituted and 1,3-Disubstituted Piperidines

4.1 Methixene 127
4.2 Tipepidine 127
4.3 Timepidium 128
4.4 Tiagabine 129
4.5 Piperidolate 130
4.6 Mepenzolate 131
4.7 Pipenzolate 131
4.8 Benidipine 132
4.9 Paroxetine and Femoxetine 133
4.10 Troxipide 136
4.11 Linagliptin 137
4.12 Tofacitinib 138
References 140
 Contents vii

5. 4-Substituted and 1,4-Disubstituted Piperidines

5.1 4-Piperidinols and Their Derivatives 147
Periciazine 147
Diphenylpyraline 148
Ebastine 149
Bepotastine 150
Lamifiban 150
Eucatropine 151
Propiverine 153
Pentapiperide 153
5.2 4-Phenylpiperidin-4-ols and Their Derivatives 154
Haloperidol 154
Bromperidol 155
Moperone 156
Trifluperidol 157
Penfluridol 158
Loperamide 159
Alpha-Prodine 160
5.3 Derivatives of 4-Phenylpiperidine-4-Carboxylic Acids 163
Pethidine 163
Phenoperidine 165
Diphenoxylate 168
Levocabastine 168
5.4 Derivatives of (4-Phenylpiperidin-4-yl)Ketones 169
Ketobemidone 169
Ketanserin 170
5.5 Derivatives of 4-Phenylpiperidine-4-Carboxamide 172
Metopimazine 172
Pipamazine 172
5.6 Derivatives of Piperidin-4-Amines 173
Indoramin 173
Clebopride 174
Cinitapride 175
Prucalopride 176
Lomitapide 176
Cisapride 178
Astemizole 181
5.7 Derivatives of 4-Anylinopiperidines 181
Fentanyl 182
Carfentanil 184
Remifentanil 187
Sufentanil 188
Alfentanil 189
Lorcainide 190
5.8 Derivatives of 4-(N,N-Disubstituted)-Piperidines 191
Bamipine and Thenalidine 191
Mizolastine 192
viii Contents

Sabeluzole 193
Lubeluzole 194
5.9 Derivatives of 4-(Dialkylamino)Piperidine-4-Carboxamide 195
Pipamperone 195
Piritramide 196
Carpipramine 197
Clocarpramine 197
5.10 Alvimopan 198
References 199

6. Piperidin-4-Ylidene Substituted Tricyclic Compounds

6.1 Cyproheptadine 223
6.2 Azatadine 225
6.3 Loratadine and Desloratadine 225
6.4 Rupatadine 228
6.5 Ketotifen 228
6.6 Pizotifen 229
6.7 Alcaftadine 231
6.8 Ritanserin 232
References 234

7. Piperidine-Based Nonfused Biheterocycles

With C
N and C
C Coupling
7.1 Piperidine-Based Nonfused Biheterocycles With C
N
Coupling 241
Droperidol 242
Benperidol 243
Timiperone 243
Pimozide 245
Zaldaride 246
Domperidone 246
Bezitramide 247
Benzpiperylon and Piperylon 248
7.2 Piperidine-Based Nonfused Biheterocycles
With C
C Coupling 250
Risperidone 250
Paliperidone 252
Iloperidone 253
Naratriptan 254
Sertindole 256
References 257
 Contents ix

8. Piperidine-Based Fused Biheterocycles

8.1 Thienopyridine Derivatives 269
Ticlopidine 270
Clopidogrel 271
Prasugrel 273
8.2 γ-Carbolines 275
Mebhydrolin 275
Gevotroline and Carvotroline 275
8.3 5,6,7,8-Tetrahydropyrido[4,3-c]pyridazines 276
Endralazine 276
Phenindamine 277
References 279

9. Piperidine-Based Spiro-Fused Biheterocycles

9.1 Spiperone 288
Fluspirilene 288
Mosapramine 289
Fenspiride 290
Clospirazine 291
Pazinaclone 292
References 294

10. Classes of Piperidine-Based Drugs

10.1 Piperidine-Based Analgesics 299
4-Phenylpiperidines 300
4-Anilidopiperidines 301
Miscellanous Analgesic Piperidine Derivatives 301
10.2 Piperidine-Based Antipsychotics 303
Butyrophenones 303
Diphenylbutylpiperidines 305
Benzisoxazoles 306
Phenothiazines 306
Dibenzazepines 307
Tetrahydro-γ-Carbolines and 3-(Piperidin-4-yl)-1H-Indoles 307
10.3 Piperidine-Based Antihistamine Drugs 308
Piperidin-4-Ylidene Diaryl[a,d][7]Annulenes 308
4-(Benzhydryloxy)Piperidines 308
Miscellanous Antihistamine Piperidine Derivatives 309
10.4 Piperidine-Based Anticholinergic Drugs 310
Muscarinic Receptor Antagonists 311
10.5 Piperidine-Based Local Anesthetics 313
Aminoamide-Type Local Anesthetics 313
Amino Ester
Type Local Anesthetics 314
x Contents

10.6 Piperidine-Based Antithrombotic Drugs 315

Antiplatelet Drugs 315
Anticoagulant Drugs 316
10.7 Piperidine-Based Antiarrhythmic Drugs 317
10.8 Piperidine-Based Antihypertensive Drugs 318
10.9 Piperidine-Based Drugs for Treating Respiratory System
Diseases 319
Cough Suppressants 319
10.10 Piperidine-Based Antidepressants 320
Selective Serotonin Reuptake Inhibitors 321
Norepinephrine-Dopamine Reuptake Inhibitors 321
10.11 Piperidine-Based Antiparkinsonian Drugs 322
10.12 Piperidine-Based Hypolipidemic and Antihyperlipidemic
Drugs 322
10.13 Piperidine-Based Adrenergic (Sympathomimetic) Drugs 323
10.14 Piperidine-Based Central Nervous System Stimulants 323
10.15 Piperidine-Based Selective Estrogen Receptor Modulators 324
10.16 Piperidine-Based Antianginal Drugs 324
10.17 Piperidine-Based Drugs for Treating Protozoan Infections 325
10.18 Piperidine-Based Antimigraine Drugs 325
10.19 Piperidine-Based Nootropic and Neuroprotective Drugs 325
10.20 Piperidine-Based Antiemetics 326
10.21 Piperidine-Based Antidiarrheal and Prokinetic Drugs 327
Antidiarrheals 327
Prokinetics 328
10.22 Piperidine-Based Gastric Antisecretory Drugs 328
10.23 Piperidine-Based Hypoglycemic Drugs 329
10.24 Piperidine-Based Drugs Used in the Treatment
of Rheumatoid Arthritis 330
10.25 Piperidine-Based Nicotinic Cholinomimetics 330
10.26 Piperidine-Based Immunosuppresant Drugs 330
10.27 Conclusion 331

Index
Trade Names 333

Index
Substance Classes 337
Chapter 1

Introduction
1.1 THE SCOPE OF THE MATERIAL UNDER CONSIDERATION
Heterocyclic compounds constitute the largest and most varied family of
organic chemistry that is gaining enormous importance in chemical and
pharmaceutical industry. Numerous agrochemicals, information storages,
electronics, plastics and optics modifiers and stabilizers, cosmetics additives,
etc., are heterocyclic in nature.
Piperidine and its functionalized derivatives are increasingly popular
building blocks in a vast array of synthetic protocols. The piperidine ring
can be recognized in the structure of many synthetic compounds of practical
interest and in the structure of many alkaloids and other natural or synthetic
compounds with various biological activities known today. Piperidine is
the compound which gives black pepper its spicy taste and gave the name
of the compound in question.
Today it is possible to assert unequivocally that the mainstream of phar-
maceuticals is heterocyclic and the leading heterocycle in the structure of
pharmaceuticals is piperidine, which is the most encountered heterocycle
found in pharmaceutical agents [1].
A search of the chemical and patent literature reveals thousands of refer-
ences to this simple ring system, which is present in the structures of poten-
tial drugs in clinical and preclinical research.
As of October 8, 2015, the day of beginning the work on this monograph,
93,984 references containing the concept “piperidine” were found in
SciFinder
the world’s largest and most reliable collection of chemistry and
related science, which, of course, is not an exhaustive number of publications
on the subject under consideration. By January 10, 2017, the date on which
work on this monograph was completed, that number grew to 97,972, which
constitutes the appearance of roughly 4000 additional publications within a
year and a half. Information about piperidine-containing compounds exists in
publications and patents that do not contain the word piperidine as well as in
other sources of scientific information, which we did not use. For example,
by analyzing the scaffold content of the CAS Registry from more than 24
million organic compounds it has been found that the most frequently occur-
ring references on heterocycles concern piperidine (191.803) [2].

Piperidine-Based Drug Discovery. DOI: http://dx.doi.org/10.1016/B978-0-12-805157-3.00001-6

Copyright © 2017 Elsevier Ltd. All rights reserved. 1
2 Piperidine-Based Drug Discovery

The huge contribution in the development of piperidine-derived series of

drugs belongs to Otto Eisleb, Anton Ebnother, Solomon Snyder, Samuel
McElvain, Ivan Nazarov, Miroslav Protiva, and, of course, the great Dr. Paul
Janssen, the most prolific drug inventor of all time: his team has produced more
than 60 new therapeutics, most of which belong to the piperidine series [3
5].
This book was conceived as an attempt to show the panorama of drugs,
the structure of which contains a piperidine ring, and to show methods for
their synthesis. It is necessary to emphasize here the word “drugs.”
Any attempt to create a more or less complete picture of a biologically
active compound containing a piperidine ring in its structure was doomed to
fail due to the inability to “grasp the immensity” and to show the entire
existing material in reasonable frames.
But even the relatively limited list of piperidine drugs also creates a num-
ber of problems, the first of which is the mode of their classification and,
consequently, the presentation.
One alternative classification is the attempt to build material based on
their pharmacological properties thereby putting them into a traditional order
according to, e.g., a generally accepted narration in pharmacology textbooks,
just as we did in our two previous books [6,7].
However, to put the emphasis on the structure and methods of the synthe-
sis of drugs requires another way of presentation that is more
acceptable from the standpoint of an organic chemist. It was decided that the
order and degree of substitution of the piperidine ring would be the best way
to sort existing piperidine drugs.
So, the collected factual material in general was divided and distributed
into chapters and subchapters according to the following generalization: deri-
vatives of 1-substituted piperidines (such as trihexyphenidyl (Artane)
(1.1.1)); derivatives of 2-substituted piperidines or 1,2-disubstituted piperi-
dines (such as bupivacaine (Marcaine)) (1.1.2)); derivatives of 3-substituted
piperidines and 1,3-substituted piperidines (such as troxipide (Aplace))
(1.1.3)); and tofacitinib (Xeljanz) (1.1.4) (Fig. 1.1).

O
N O O N N
N H
NH N N
OH O
N
O HN
N O N
H
Trihexyphenidyl Bupivacaine Troxipide Tofacitinib
(Artane) 1.1.1 (Marcaine) 1.1.2 (Aplace) 1.1.3 (Xeljanz) 1.1.4

FIGURE 1.1 Construction of subchapters in the book.

More diverse groups are represented by derivatives of 4-substituted and

1,4-disubstituted piperidines
fexofenadine (Allegra) (1.1.4), ebastine
(Evastin) (1.1.5), astemizole (Hismanal) (1.1.6), indoramin (Baratol) (1.1.7),
fentanyl (Sublimaze) (1.1.8), metopimazine (Vogalene) (1.1.9), ketanserin
(Sufrexal) (1.1.10) (Fig. 1.2).
 Introduction Chapter | 1 3

OH
O
OH O
N N
O
HO
Fexofenadine Ebastine
(Allegra) 1.1.4 (Evastin) 1.1.5

O R2 O
O N N
N
N F N HN
N O R1 N
H
F
Ketanserin Astemizole
(Sufrexal) 1.1.10 O (Hismanal) 1.1.6
NH2 O
N
HN
O N
S N N O
O NH
S N

Metopimazine Fentanyl Indoramin

(Vogalene) 1.1.9 (Sublimaze) 1.1.8 (Baratol)1.1.7

FIGURE 1.2 Structures of some of 1,4-disubstituted piperidine-based drugs.

No less common in the market are 1,4,4-trisubstituted piperidines

exemplified by haloperidol (Haldol) (1.1.11), loperamide (Imodium) (1.1.12),
trimeperidine (Promedol) (1.1.13), pethidine (Meperidine) (1.1.14), ketobemidon
(Cliradon) (1.1.15), pipamperone (Dipiperon) (1.1.16), piritramide (Dipidolor)
(1.1.17), alfentanil (Alfenta) (1.1.18), and remifentanil (Ultiva) (1.1.19), which
in turn can be subdivided to alcohols, amines, ketones, amides, etc. Examples of
these compounds are presented on the (Fig. 1.3).

Cl
HO

N
Cl N
HO
O Loperamide
O (Imodium) 1.1.12 O
N N
O
F
Haloperidol Trimeperidine
O (Haldol) 1.1.11 (Promedol) 1.1.13
O
N R2 R3 O
O
N N
O N
O R1
O Remifentanil Pethidine
(Ultiva) 1.1.19 (Meperidine) 1.1.14

O O
N
N NH N
N N O 2 N
N N H 2N O
N N O O N HO
O
Alfentanil N Ketobemidone
(Alfenta) 1.1.18 F (Cliradon) 1.1.15
Piritramide Pipamperone
(Dipidolor) 1.1.17 (Dipiperon) 1.1.16

FIGURE 1.3 Structures of some of 1,4,4-trisubstituted piperidine-based drugs.

4 Piperidine-Based Drug Discovery

Another group of piperidine drugs could be represented as a combination

of a piperidine ring with another heterocycle, and they can be classified as
biheterocyclic compounds where the piperidine ring is not fused with another
heterocycle and, in turn, is subdivided to those where: it is just bonded to
another heterocycle by single C
C bond (such as naratriptan (Amerge)
(1.1.20)); it is bonded to another heterocycle by double CQC bond (such as
ketotifen (Zaditor) (1.1.21)); or by single C
N bond (such as pimozide
(Orap)) (1.1.22). Another group could be represented as derivatives of piperi-
dines fused with another heterocycle at 3,4-positions (such as clopidogrel
(Plavix) (1.1.23)). The third group is described as derivatives of piperidines
with spirofusion with another heterocycle at 4,4-positions (such as spiperone,
(Spiropitan) (1.1.24)) (Fig. 1.4).

O
S
O
HN S N NH
O H O
N

N
N F N
Ketotifen
(Zaditor) 1.1.21
Naratriptan Pimozide
(Amerge) 1.1.20 (Orap) 1.1.22

+ other heterpcycle F
N
R1
NH
N S
O

O N N Cl
O
O
F
Spiperone Clopidogrel
(Spiropitan) 1.1.24 (Plavix) 1.1.23

FIGURE 1.4 Structures of some of drugs represented as a combination of piperidine ring with
another heterocycle.

In this book we have described the synthesis of about 150 piperidine

drugs, but we did not know how to determine their relative importance.
Building a panorama of about 150 drugs, derivatives of piperidine,
we did not know how to determine their relative importance and the rele-
vance of a drug in the entire arsenal of piperidine drugs. The same general
question also relates to the entire list of existing drugs in medicinal
practice. So we had to come up with a way to determine some Comparative
Drug Significance Index (DSI) or Comparative Drug Impact Factor
(CDIF). In our opinion, one of the simplest possible solutions of the
problem could be a determination of a number of publications on the drug
that definitely shows a real interest in the scientific community of the drug.
 Introduction Chapter | 1 5

Of course, this parameter depends on the influence of Pharma at every time

interval, which, of course, also reflects a real significance of a drug.
Therefore, after mentioning the name of a medicine described in this book,
we decided to mention and bring in the number of publications devoted
to it in SciFinder.
It seems that this approach to some extent could reflect the Comparative
DSI.
Perhaps it will be much more correct to determine Comparative DSI as a
sum of certain indicators. For instance, as a sum of some conditional
figures derived from the number of publications divided by one thousand
and sales, divided by one billion, e.g., as:
X Citations Salesð$Þ
5 1
103 109

1.2 GENERAL METHODS OF THE SYNTHESIS OF PIPERIDINE

COMPOUNDS
Piperidine (1.2.1) itself and most of its derivatives are easily produced by
catalytic hydrogenation of the corresponding pyridine (1.2.2) derivatives
over nickel, palladium, or ruthenium catalysts at 170
200 C [8
11]. Other
reducing agents are sodium in ethanol or tin in hydrochloric acid [12].
Pyridine itself was first synthesized from acetylene and hydrogen cyanide
[13,14]. More affordable sources of pyridine are coal tar, light-oil, and
middle-oil fractions. Pyridine has been produced commercially from coal-tar
sources contains only about 0.1% pyridine since the 1920s. Nowadays, most
pyridine is produced synthetically via a number of synthetic processes.
Reaction of acetaldehyde and formaldehyde with ammonia is the most
widely used industrial method for pyridine production (Chichibabin pyridine
synthesis) [14
17]. This thermal cyclocondensation reaction that occurs by
passing on heating aldehydes and ammonia over a contact catalyst such as
alumina is a low-yield process. Besides aldehydes, ammonia gas also reacts
with acetylene or acetonitrile to give pyridine derivatives. The transformation
is regarded as aldol condensations in conjunction with a Michael-type reac-
tion and ring closures with ammonia.
Pyridine can also be prepared from furfuryl alcohol or furfural by passing
a mixture of tetrahydrofurfuryl alcohol, H2, and NH3 over a Ni catalyst at
about 200 C under high pressure [18,19] from glutaric acid, its anhydride or
alkyl glutarates with ammonia, and H2 at high temperatures and under high
pressure in the presence of Ru-C or Co catalysts [20,21]. Pyridine can be
prepared by oxidative dealkylation of alkylated pyridines, which are obtained
as by-products via the synthesis of other pyridines using air over vanadium-,
nickel-, silver- or platinum-based catalysts [22
24] (Fig. 1.5).
6 Piperidine-Based Drug Discovery

H 2 / Ni-Al2O3, or Pd-Al 2O3 Al2O3, 250ºC O

OH or H NH3 + HCHO +
O O H
O NH3, 200–500ºC, <4 atm

H2 / Ni-Al 2O3
N 100–260ºC, 5–50 atm
Pyridine
1.2.2

Sn Na, EtOH
or
O O O O H2, Raney Ni HCl Reflux
or R R or
O O O O O HO OH 250–260ºC N
H
Piperidine
1.2.1

FIGURE 1.5 The major methods for the synthesis of pyridine followed by hydrogenation
piperidine.

The major methods for the synthesis of pyridine derivatives, which in

principle could be hydrogenated to corresponding substituted piperidine com-
pounds include Hantzsch, Bönnemann, Kröhnke, Boger, Gattermann-Skita
pyridine synthesis, and Ciamician-Dennstedt rearrangement which are well
reviewed [25].
Onwards, in this introduction, it was decided to describe briefly the basic
approaches for the synthesis of piperidine compounds, mainly functionalized
piperidines of practical meaning, which can serve as basic starting materials
and are the most ubiquitous heterocyclic building blocks for the synthesis of
piperidine-based drugs. A huge amount of synthetic effort spent on the prep-
aration of these compounds is reviewed [26
56].
A plethora of methodologies are available for the synthesis of piperidine
derivatives and includes nucleophilic substitution reactions, intermolecular
Michael, hydroamination, Diels
Alder reactions, ring-closing, metathesis,
aldol reactions, Dieckmann condensations ene reactions, and others.

Nucleophilic Substitution Reactions

One of the methods of piperidine ring creation is based on the nucleophilic
substitution of two leaving groups in a linear chain that contains the desired
substitution pattern such as halides-, acetyl-, tosyl- or mesyl- groups, even
hydroxyl- groups separated by five carbon atoms.
Several examples of reaction of amines with dihalides (1.2.3) to give
substituted piperidines (1.2.4, 1.2.5) are described [57
59]. The reaction
conditions require a large excess of amine, long-term reflux. Reaction with
volatile amines need to be carried out in a sealed tube. The main difficulty
of this type of cyclization is the correct choice of reaction conditions. Dilute
reaction mixture gives a slow reaction that is too concentrated and thereby
fraught with the intramolecular nucleophilic substitution or polymerization
reaction.
 Introduction Chapter | 1 7

The intramolecular displacement of a halide by a nitrogen nucleophile

followed by deprotection of the functional groups, if necessary, is an analog
and a well-established method for forming piperidine rings.
Phosphonamides (1.2.6) that have a chlorine group on the distance of five
carbon atoms easily form piperidine ring when t-BuOK in dimethylforma-
mide (DMF) is used as a base to give substituted diphenyl(piperidin-1-yl)
phosphine oxides (1.2.7), which, after oxidative cleavage, give substituted
piperidines (1.2.5) [60]. Compounds with N-tosyl or N-nosyl groups disposed
on the distance of five carbon atoms (1.2.8) have been converted into
piperidines (1.2.9) using 4-dimethylaminopyridine (DMAP) to effect
NH-deprotonation and intramolecular iodo- of bromo- substitution. Cleavage
of the N-tosyl group resulted in poor yields of the free amine. However,
deprotection of the N-nosyl compounds was achieved without difficulty.
The N-nosyl group was removed by treatment with thiophenol and K2CO3
in acetonitrile/dimethyl sulfoxide (DMSO) to give substituted piperidines
(1.2.5) [61].
A simple, one-pot preparation of piperidine ring via efficient chlorination
of amino alcohols (1.2.10) with use of SOCl2 in dimethoxyethane was
proposed recently and obviates the need for the N-protection-cyclization-
deprotection sequence commonly employed for this type of transformation
[62] (Fig. 1.6).

R 1 R2 R 1 R2 Deprotection R 1 R2 R 1 R2 R1 R2
RNH2 if necessary O3 t-BuOK
Hal N CH 2Cl2/CH 3OH N DMF Cl HN
Hal N
R H Ph P Ph Ph P Ph
O O
1.2.3 1.2.4 1.2.5 1.2.7 1.2.6

1. MeOH, K2CO3
R 1 R2 R1 R2 2. PhSH, K 2CO3 R1 R2 R1 R2 R1 R2
DMAP MeCN/DMSO NaOH SOCl2
+
Br CH2Cl2 Cl HN Cl + DME HO
HN N H3N Cl- H 2N
O S R3 O S R3 Cl O
O O
1.2.10
1.2.8 1.2.9

FIGURE 1.6 Methods for the synthesis of substituted piperidines by nucleophilic substitution
reactions.

The intramolecular nucleophilic substitution of an alcohol moiety is a

less commonly used method in piperidine derivatives synthesis, but intramo-
lecular substitution of an activated alcohol moiety (tosylate, mesylate, tri-
flate, acetate) is another more common method for the synthesis of
piperidine ring.
The N-tosylamino alcohols (1.2.11) are easily transformed to the
desired piperidines under Mitsunobu conditions (triphenylphosphine (PPh3),
azodicarboxylate (DEAD), tetrahydrofuran (THF)) to give high yields of
1-tosylpiperidines (1.2.12). Reduction of obtained tosylate with sodium bis
8 Piperidine-Based Drug Discovery

(2-methoxyethoxy)aluminumhydride (Red-Al) yields desired piperidines

(1.2.5) [63].
The case of N-Boc-amino alcohols (1.2.13) for the transformation to
piperidine (1.2.5) needs preliminary conversion of the alcohols (1.2.13) into
the triflate (1.2.14) followed by removal of the Boc-protecting group with
HCl, and cylization in dioxane/saturated NaHCO3 solution at 50 C (high
dilution) [64].
Reaction of bis-tosylates [65] and bis-mesylates [66] (1.2.15) which takes
place with large excess of primary amines is also described (Fig. 1.7).

R1 R2 R1 R2
PPh3, DEAD Red-Al
HO THF N THF
HN
Ts Ts R1 R2 R1 R2
RNH2
1.2.11 1.2.12
N (MsO) TsO
TsO
H (MsO)
R1 R2 R1 R2
(CF3SO2)2O 1. HCl / Dioxane
1.2.5 1.2.15
HO Py, CH 2Cl2 TfO 2. NaHCO3
HN HN
Boc Boc H2O/Dioxane

1.2.13 1.2.14

FIGURE 1.7 Methods for the synthesis of substituted piperidines by nucleophilic substitution
reactions.

Among numerous synthetic strategies a rather different approach was

demonstrated implementing reduction of cyclic imines (1.2.17) which can be
prepared in different ways.
One-pot reaction occurred when substituted 5-bromopentanenitrile
(1.2.16) was reacted with Grignard reagent followed with sodium borohy-
dride reduction to give 2,3,4,5-tetrahydropy-ridine derivative
imine
(1.2.17), which was reduced to substituted piperidine (1.2.5) using sodium
borohydride in methanol [67].
Another method implements a highly enantioselective catalytic method
for the hydrosilylation of imines (1.2.17) in the presence of the ethylenebis
(η5-1,2,3,4-tetrahydroindenyl)titanium difluoride precatalyst ((EBTHI)TiF2).
The method was proposed for the preparation of alkaloid (S)-coniine and a
constituent of fire-ant venom (2R,6R)-trans-solenopsin A. For this purpose
chloro ketones (1.2.18) were converted into azido ketones (1.2.19) via solid/
liquid phase-transfer catalysis, followed by aza-Wittig cyclization to give
intermediate (1.2.20), which afforded the desired imines. Obtained imines
underwent catalytic asymmetric reduction of the imine group with phenylsi-
lane in the presence of (EBTHI)TiF2 (which had been activated by treatment
with pyrrolidine and methanol, followed by acidic hydrolysis of the initially
formed aminosilane [68] (Fig. 1.8).
 Introduction Chapter | 1 9

R1 R1 R1 R2
R2MgX NaBH4
Br THF
N N R 2 CH3OH N
Reflux H
1.2.16 1.2.17 1.2.5 1. PhSiH3, THF,
CH3OH, Pyrrolidine,
H2 2. HCl
Pd(OH) 2

CH3OH
NaN3 R1
R1 R1 R1 R1 R2
TBABr Ph3P Benzene Ph3P
Ph3P
Cl Benzene N3 N Reflux THF/H2O N3
O R2 O R 2 Benzene O R2 N R2 MsO

1.2.18 1.2.19 1.2.20 1.2.17 1.2.21

FIGURE 1.8 Methods for the synthesis of substituted piperidines by nucleophilic substitution
reactions.

The Staudinger reaction, which is a very mild azide reduction, makes

it possible to use azides as an NH2-group synthons. This reaction was
employed and for the piperidine ring synthesis. The azide (1.2.21) was
reacted with triphenylphosphine resulting in intermediate iminophosphor-
anes, which in turn, released the free amines in aqueous tetrahydrofuran.
The obtained amines immediately cyclized to imines (1.2.17). Hydrogenation
in the presence of palladium hydroxide in methanol furnished requested
piperidine (1.2.5) [69,70] (Fig. 1.8).

Intermolecular Michael Reactions

Different approaches for construction of functionalized piperidine ring was
demonstrated implementing Michael addition reactions as a key step.
A successful example of highly enantioselective tandem intermolecular
Michael reaction and application of obtained functionalized piperidine
derivative (1.2.27) for the syntheses of several alkaloids.
The synthesis started from N-benzyl-2,2,2-trifluoroacetamide (1.2.22),
which was alkylated with 2-(2-bromoethyl)-1,3-dioxane using sodium
hydride as a base followed by partial hydrolysis dioxolane protecting group
with oxalic acid which resulted aldehyde (1.2.23). Wittig-type reaction of
(1.2.23) with (ethoxycarbonylmethylene)triphenylphosphorane gave (1.2.24),
which, by the hydrolysis of trifluoroacetamide group, resulted in the amine
product (1.2.25). The obtained amine (1.2.25), was used in the first Michael
reaction via treating with methyl vinyl ketone to furnish key compound
(1.2.26).
The last (1.2.26) was then treated with 1 equivalent of (R)-1-pheny-
lethyl-1-amine as a chiral base in THF to give the desired optically
active ethyl 2-((3R,4R)-3-acetyl-1-benzylpiperidin-4-yl)acetate (1.2.27) [71]
(Scheme 1.1).
10 Piperidine-Based Drug Discovery

O
1. COOEt
O O Br CHO
N CF3 NaH, Benzene-DMF O Ph3P=CHCOOEt O K2CO3
H
2. Oxalic acid N CF3 CH2Cl2 N CF3 H2O/EtOH
THF/H2O H

1.2.22 1.2.23 1.2.24

COOEt COOEt COOEt

O O NH2 O
Ph
NH CH2Cl2 N mol. sieves 5 A N

1.2.25 1.2.26 1.2.27

SCHEME 1.1 Synthesis of substituted piperidines implementing Michael addition reactions as

key steps.

A convergent one-pot construction of piperidine framework has been

accomplished through conjugate addition of a N-nucleophile to an electro-
philic olefin followed by intramolecular trapping of the generated enolate by
a built-in α,β-unsaturated acceptor. The well-known versatility of the
nitroethylene and its propensity to polymerization has been overcome by its
generation in situ from 1-benzoyloxy-2-nitroethane. Thus, treatment of equi-
molecular amounts of the latter with 6-(benzylamino)hex-3-en-2-one (1.2.28)
at room temperature led to the direct formation of the desired result (1.2.29)
[41] (Scheme 1.2).

O O O

NO2 NO2 NO2

NH ( O O ) N N
N+ –
Ph O O

1.2.28 1.2.29

SCHEME 1.2 Synthesis of substituted piperidines implementing Michael addition reaction as a

key step.

Enantiopure piperidines were synthesized starting from the 7-oxo-2-

enimide (1.2.30), which on treatment with benzylamine in toluene at 215 C
in presence of MgSO4, give intermediate imine, which then attaches intramo-
lecularly to the conjugate double bond. The obtained product was hydroge-
nated at 1 atm. In presence of Pd/C to afford the piperidine (1.2.31). The
N-benzyl group in (1.2.31) may be readily removed with the concomitant
esterification by hydrogenation under rather forced conditions (3 atm hydro-
gen pressure, 24 hours) to give (1.2.32). Esterification, while retaining the
N-benzyl group, can also been achieved by a reaction with MgClOMe
solution at 0 C to give (1.2.33). (MgClOMe was prepared from MeMgCl in
diethyl ether by reaction with methanol at 0 C (Scheme 1.3).
 Introduction Chapter | 1 11

NH2
H2 - Pd/C O Bn
N HN O
O O O 1 atm N N
O N O N 45 min
O N O O O
O O
Bn EtOAc
Bn Bn

1.2.30 1.2.31
MgClOMe H2 - Pd/C
CH2Cl2 3 atm., 24 h
0 oC EtOH

O O
N OMe N OEt
H

1.2.33 1.2.32

SCHEME 1.3 Synthesis of substituted piperidines implementing Michael addition reaction as a

key step.

Another strategy implementing intramolecular Michael addition, which is

the crucial step of the proposed synthesis, consists of intramolecular cycliza-
tion enone (1.2.34), which takes place smoothly under reflux in benzene in
the presence of BF3  Et2O to give hexafluoroacetone protected 4-oxo-L-pipe-
colic acid (1.2.35). Simultaneous deprotection of the vicinal amino and car-
boxylic functions proceeds under very mild conditions (i-PrOH/H2O) at
room temperature gives 4-oxo-L-pipecolic acid (1.2.36) [72] (Scheme 1.4).

O O O
BF3.OEt 3 i-PrOH/H 2O

HN O Benzene N O r.t. N COOH

reflux H
F3C O F3 C O
CF3 CF3
1.2.34 1.2.35 1.2.36

SCHEME 1.4 Synthesis of substituted piperidines implementing Michael addition reaction as a

key step.

N-substituted O-protected γ-hydroxy-α,β-unsaturated sulfones (1.2.37)

after a complete N-Boc deprotection by treatment with trifluoroacetic acid
(TFA) in dichloromethane afford the corresponding ammonium salts, which,
after isolation, redissolution in THF, cooling at 278 C, and a workup with
an excess of Et3N, gave piperidines (1.2.38a, 1.2.38b). Regardless of the
substitution at nitrogen atom, the cyclizations were complete in less than
30 minutes, giving mixtures of isomeric cis/trans piperidines (1.2.38a,
1.2.38b) [73] (Scheme 1.5).
OR 1 1. TFA, CH2Cl2 OR 1 OR 1
+
NR 2. Et3N, THF N N
Boc SO2Ph –78ºC R SO2Ph R SO2Ph

1.2.37 1.2.38a 1.2.38b

SCHEME 1.5 Synthesis of substituted piperidines implementing Michael addition reaction as a

key step.
12 Piperidine-Based Drug Discovery

Catalyzed Hydroamination Reactions

The employment of hydroaminations to the intramolecular cyclization of
amino olefins to piperidine derivatives is of big synthetic utility and could be
mediated by different catalysts.
For example, N-Boc protected 5-phenylpent-4-en-1-amine (1.2.39) in
dichloromethane in the presence of 2.5% methanol was converted to N-Boc
protected 2-phenyl-3-(phenylselanyl) piperidine (1.2.40) using chiral 2,6-bis
[1-(R)-ethoxyethyl]phenylselenenyl trifluoromethanesulfonate (ArCSeOTf)
prepared in situ to give a diastereoisomeric mixture in a 25:1 ratio. The abso-
lute stereochemistry of the major product was assessed by removal of the
chiral organoselenium moiety by reduction with triphenyltin hydride in
the presence of catalytic amount of azobisisobutyronitrile in refluxing tolu-
ene and comparison of the optical rotation of the resulting product (1.2.41)
with literature data [74] (Scheme 1.6).

0.3 eq. ArCSeOTf ArCSe

(C6H5)3SnH
Ph HN CH2Cl2, –78 oC Ph N AIBN Ph N
Boc Boc Toluene Boc
1.2.39 1.2.40 1.2.41
OTf
OEt Se OEt
; N
ArCSeOTf = AIBN = N
N
N

SCHEME 1.6 Synthesis of substituted piperidines implementing catalyzed hydroamination

reaction.

Another example of intramolecular reaction of amines with double bond of

is lanthanocene-catalyzed, hydroamination. It was shown that the complex
Cp2NdCH(TMS)2 converted 2-substituted 8-nonen-4-amines such as (2R,4S)-
2-((tert-butyldiphenylsilyl)oxy)non-8-en-4-amine (1.2.42) to 2,6-disubsituted
piperidine (1.2.43) with greater than 100:1 selectivity for the formation of the
cis isomer. A short synthesis of pinidinol (1.2.44), an alkaloid isolated from
various pine and spruce species, was carried out this way [75] (Scheme 1.7).
Other examples of this reaction are described in the literature [76,77].

OTBDPS Cp*2NdCH(TMS)2 OTBDPS 1. KOH, MeOH OH

H 2N Benzene, r.t. N 2. HCl N
H 3. KOH H
1.2.42 1.2.43 1.2.44

OTBDPS = O Si ; Cp*2NdCH(TMS)2 = NdCH(TMS)2

SCHEME 1.7 Synthesis of substituted piperidines implementing catalyzed hydroamination

reaction.
 Introduction Chapter | 1 13

Allyl alcohol (1.2.45) was stereoselectively cyclized in the presence of

PdCl2(MeCN)2 to form piperidine (1.2.46a, 1.2.46b) with a cis:trans diaste-
reomeric ratio of 8:1 [78] (Scheme 1.8).

OBn OBn OBn

PdCl2(MeCN)2
+
HN THF N N
Boc Boc Boc
HO
1.2.45 1.2.46a 1.2.46b

SCHEME 1.8 Synthesis of substituted piperidines implementing catalyzed hydroamination

reaction.

There are many other examples of intramolecular hydroaminations reac-

tions with double bond, triple bond, and allenic systems that are well
reviewed in [30,32,34,77].

Aza-Diels
Alder Reactions
The aza-Diels
Alder reaction is an important tool for the preparation of
substituted piperidines, which allows the construction of functionalized
piperidine derivatives with regio-, diastereo- and enantio-selectivity [79].
There could be three ways to carry out these [4 1 2] cycloaddition reactions
for creation of piperidine ring:
The reaction of imines (1.2.47) or iminium salts with carbon dienes is the
most implemented way reported to date.
1-Azadienes (1.2.48) in Diels
Alder reaction are rarely used and because
of low conversion and competitive imine addition often thwarting and has
not proved to be one of the major routes to piperidine synthesis.
2-Azadienes (1.2.49) have been very poorly studied as starting materials
for the synthesis of piperidine derivatives via the Diels
Alder reaction
(Fig. 1.9).

R1
+
N R2
R
1.2.47

R2
R3
R2 R2
+
R1 + R1 R3 R1
N R3 N N
R R
1.2.48 1.2.49

R2
R1 R3
N
R
1.2.50

FIGURE 1.9 Synthesis of substituted piperidines implementing aza-Diels
Alder reactions.

14 Piperidine-Based Drug Discovery

All of obtained intermediate tetrahydropyridine compounds have been

hydrogenated to final piperidine compounds (1.2.50).
For the reaction of imines (1.2.47) with carbon dienes it is necessary to
have electron-poor imine and an electron-rich diene the most implemented
way reported to date.
In general, it has been considered necessary to use of N-acyl and N-tosyl
imines, or imines protected with silylamine groups [80
83]. But benzyli-
mines also have been implemented in this reaction [84,85]. In the cases of
N-acyl and N-tosyl imines (4 1 2) cycloaddition reactions are typically cata-
lyzed by Lewis acids, which vary with the structure of reagents and solvents.
The reaction of benzylimines have to be carried out in DMF, using 1 equiva-
lent of TFA and catalytic amount of water, or in trifluoroethanol containing
catalytic amount of (TFA) and molecular sieves [85].
One of the classical examples of this reaction is the reaction of the diene
(1.2.51) with ethyl 2-(tosylimino)acetate (1.2.52) at room temperature in tol-
uene to give cis-2,6-disubstituted piperidine (1.2.53) [86] (Scheme 1.9).

COOEt ZnCl2
+ O
O N Toluene, r.t. N COOEt
Ts
Ts

1.2.51 1.2.52 1.2.53

SCHEME 1.9 Synthesis of substituted piperidines implementing Diels
Alder reaction of
dienes with imines.

An example of the implementation of imino Diels
Alder reaction with

benzylimines could serve the reaction between the Danishefsky’s diene
(1.3.54) and imine (1.2.55) obtained from benzylamine and (R)-2,3-diisopro-
pylideneglyceraldehyde. The reaction was carded out in acetonitrile with 0.2
eq. of ZnI2 at 240 C with excellent yield but with low stereoselectivity to
give a mixture of diastereomeric enaminones
dihydropyridones (1.2.56a,
1.2.56b) [84] (Scheme 1.10).

O O O
Si Bn ZnI2
N O
+ H + H
O Acetonitrile –40ºC
O N O N O
Bn O Bn O

1.2.54 1.2.55 1.2.56a 1.2.56b

SCHEME 1.10 Synthesis of substituted piperidines implementing Diels
Alder reaction of

dienes with imines.
 Introduction Chapter | 1 15

The reaction between Danishefsky’s diene (1.2.54) and enantiomerically

pure imine (1.2.57) obtained from (R)-2,3-di-O-benzylglyceraldehyde (S)-N-
a-(methylbenzyl)imine was carried out in the same conditions, but using 1.1
eq. ZnI2 give cyclic only a single diastereomer
enaminone (1.2.58). The
double bond was reduced at 278 C with L-Selectride (lithium tri-sec-butyl
(hydrido)borate) to give 4-piperidinone (1.2.59). Keto group in obtained
4-piperidone (1.2.59) was protected by ketalization with ethyleneglycol to give
dioxolane (1.2.60). The obtained compound was N-debenzylated under H2 at 1
atm. in ethanol, for 3 hours at room temperature using 20% Pd(OH)2/C as a
catalyst and then, without separation of intermediate secondary amine, was
acylated with di-tertbutyl dicarbonate in THF in the presence of diisopropy-
lethylamine (DIPEA) giving Boc-derivative (1.2.61). For O-debenzylation the
product (1.2.61) was again hydrogenated at room temperature using the
same catalyst
20% Pd(OH)2/C under H2 at 1 atm. in ethanol, but now for
24 hours, to produce the desired polyfunctionalized piperidine derivative
(1.2.62) [84] (Scheme 1.11).

O O O
Si ZnI2 L-Selectride HO OH
Bn
+ Ph N O
O CH3CN, –40ºC N OBn THF, –78ºC N OBn BF3 . EtO2
O Bn
OBn OBn CHCL3
Ph Ph

1.2.54 1.2.57 1.2.58 1.2.59

O O 1. H 2 - Pd(OH)2/C O O H 2 - Pd(OH)2/C O O
EtOH EtOH
N OBn 2. (Boc)2O N OBn N OH
OBn DIPEA Boc OBn Boc OH
Ph
THF
1.2.60 1.2.61 1.2.62

SCHEME 1.11 Synthesis of substituted piperidines implementing Diels
Alder reaction of

dienes with imines.

Many other examples of the reaction of imines with carbon dienes for
creation of piperidine ring are presented in the literature [87
108].
Examples of 1-azadienes (1.2.48) in Diels
Alder reaction are limited.
It was demonstrated that N-acyl- or N-phenyl-α-cyano-1-azadienes are reac-
tive substrates in the Diels
Alder reaction with a range of dienophiles such as
ethyl vinyl ether, styrene, 1-hexene, and alkyl acrylates, and this process can
provide an efficient method for the preparation of synthetically useful piperidine
derivatives [109
113]. For example, N-acyl- or N-phenyl-2-cyano-1-aza-1,3-
butadienes (1.2.63) undergo efficient Diels
Alder cycloaddition with ethyl acry-
late and vinyl ether giving 1,2,3,4-tetrahydropyridines (1.2.64) and (1.2.65).
The only regioisomer observed for the reaction of both (N-acyl- and N-
phenyl) azadienes (1.2.63) with dienophile that is activated with an electron-
withdrawing group (methyl acrylate) has the carboxyl group β- to the
16 Piperidine-Based Drug Discovery

nitrogen atom, and the only regioisomer observed for the reaction electron-
donating group (vinyl ethers) has the ethoxy- group α- to the nitrogen atom.
The Alder endo rule is fully applicable to the stereochemical pathway in the
reactions of azadienes with mentioned dienofiles [113] (Scheme 1.12).

COOR1 Ph
COOR1 OR2

NC N NC N NC N O
R R R R
2
1.2.64 1.2.63 1.2.65

R = Ac,Ph

SCHEME 1.12 Synthesis of substituted piperidines implementing 1-azadienes in Diels
Alder

reaction.

Another approach to overcome the reluctance of 1-azadienes to undergo

in Diels
Alder reaction was demonstrated with the implementation of the
diene (1.2.66)
an α,β-unsaturated hydrazone derived from methacrolein
and 1,1-dimethylhydrazine. This compound reacted regioselectively with a
variety of dienophiles (acrylonitrile, methylvinylketone, dimethylmaleate,
and dimethylfumarate) to give the corresponding adducts (1.2.67, 1.2.68).
Reductive cleavage of the N
N bond with zinc in acetic acid along with a
simultaneous reduction of the carbon-carbon double bond gave tetrahydro-
pyridines (1.2.69, 1.2.70).
Interestingly, the dimethylamine substituent had reversed the “normal”
regiochemistry of the Diels
Alder reaction [114] (Scheme 1.13).

O
O
O
Zn
N
or O or COOMe Zn COOMe

N X AcOH N X O N O N COOMe AcOH N COOMe

H N N H
O
O O
1.2.69 1.2.67 1.2.66 1.2.68 1.2.70

X = CN, COMe

SCHEME 1.13 Synthesis of substituted piperidines implementing 1-azadienes in Diels
Alder

reaction.

1-Azadiene (1.2.71) derived from α,β-unsaturated aldehyde and Enders’

hydrazines cycloaddition to cyclic dienophiles with high facial selectivities
gave (1.2.72). Esterification followed by the cleavage of the N
N bond
readily affected with zinc in acetic acid with the reduction of the double
bond, which leads to a mixture of epimers at C3 (1.2.73a, 1.2.73b) [115]
(Scheme 1.14).
 Introduction Chapter | 1 17

O MeOH
O O COOMe COOMe
X CH2N2
X +
N Zn, AcOH N COOMe N COOMe
N O H H
OMe
OMe
1.2.71 1.2.72 1.2.73a 1.2.73b

X = O, NPh

SCHEME 1.14 Synthesis of substituted piperidines implementing 1-azadienes in Diels
Alder

reaction.

Reactions of the N-(phenylsulfonyl)- (1.2.74) or N-(methylsulfonyl)-2-

(ethoxycarbonyl)-1-aza-1,3-butadienes with series of vinyl ethers were
found to proceed 6-methoxy-1-(phenylsulfonyl)-1,4,5,6-tetrahydropyridine-2-
carboxylates (1.2.75
1.2.78) with full preservation of the dienophile olefin
geometry in the reaction products [116] (Scheme 1.15).

OR OR or

EtOOC N OR EtOOC N OR
SO2Ph SO2Ph
OR
Ph 1.2.76
1.2.75

EtOOC N
SO2Ph OAc
RO OR 1.2.74 OAc
OCH2Ph or
OR
EtOOC N OR AcO EtOOC N OCH2Ph
SO2Ph SO2Ph
OCH2Ph
1.2.77 1.2.78

SCHEME 1.15 Synthesis of substituted piperidines implementing 1-azadienes in Diels
Alder

reaction.

Another example of hetero Diels
Alder reaction with 1-azadienes was

demonstrated using as a diene the sulfinimine (1.2.79), which, with a variety
of enol ethers, leads to the corresponding tetrahydropyridines (1.2.80a,
1.2.80b) in high yields. The sulfinyl group in the adducts can be removed
with MeLi followed by treatment with AcCl to give corresponding N-acetyl-
tetrahydropyridine (1.2.81) [117] (Scheme 1.16).
Ph Ph Ph 1. MeLi Ph
NC NC NC NC
XR 2. AcCl
+
N N XR N XR N XR
–O S+ – S+ – S+ Ac
p-Tol O p-Tol O p-Tol

1.2.79 1.2.80a 1.2.80 1.2.81

b
XR = OMe, OEt, Ot-Bu, SMe, SPh

SCHEME 1.16 Synthesis of substituted piperidines implementing 1-azadienes in Diels
Alder

reaction.
18 Piperidine-Based Drug Discovery

The few available studies on 2-aza-1,3-dienes have indeed shown that

they are able to undergo Diels
Alder reaction with dienophiles. The utility
dienes such as vinylformimidate (1.2.82) for the synthesis of functionalized
piperidines (1.2.83) and (1.2.84) was demonstrated by their facile reaction
with methyl acrylate and maleic anhydride [118] (Scheme 1.17).

O
O
H
COOMe COOMe O O O O
Si O H
N O N O
O N Si
H H
O
Si
1.2.83 1.2.82 1.2.84

SCHEME 1.17 Synthesis of substituted piperidines implementing 2-azadienes in Diels
Alder

reaction.

Intramolecular Ene Reactions

The ene reaction is defined as the addition of a compound with a multiple
bond (an enophile) to an olefin with an allylic hydrogen (an ene) [119
126].
The ene reaction is mechanistically related to the much better known
Diels
Alder reaction since both reactions proceed through concerted six
electrons cyclic transition states. Initially by intramolecular ene reactions
were classified to three types [125]. Type four reactions, which are a varia-
tion of type one are occasionally observed were added to this classification
system later [126].
There are few examples of implementation of ene reactions for the syn-
thesis of functionalized piperidines.
Zirconium-catalyzed cyclization using Grignard reagent was reported.
Treatment of the N-allylbut-3-en-1-amine (1.2.85) with zirconocene catalyst
(S)-(EBTHI)ZrBINOL gave intermediate zirconacycle (1.2.86) which addi-
tion of n-BuMgCl gave another intermediate (1.2.87) which on reaction with
an electrophile (O2 in this case) followed by quenching with 10% HCl
afforded the piperidine (1.2.88) [127] (Scheme 1.18).

HO HO
ZrCp2 Bu
(S)-(EBTHI)ZrBINOL ZrCp2
BuMgCl, THF 1. O 2
Ph N Ph N Ph N 2. HCl Ph N

1.2.85 1.2.86 1.2.87 1.2.88

(S)-(EBTHI)ZrBINOL = Zr O
O

SCHEME 1.18 Synthesis of substituted piperidines implementing intramolecular ene reaction.

Tetraene (1.2.89) on treatment with Pd(OAc)2 and PPh3 afforded the

piperidine (1.2.90) in 86% yield [128] (Scheme 1.19).
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 When the mother-bird must go
away, to stretch her wings in flight,
or to get food, the father-bird takes
her place. While she is on the nest,
he often brings her something good
to eat. He sits on some branch near
and sings to her. He watches to see
if any snake or squirrel, or other
enemy, is coming near. Then he
often flies down, and scolds, or
pecks at the foe to drive it off.
I am sorry to tell you that the
handsome blue jay is very cruel to
other birds. He often tears up their
nests, breaks their eggs, or kills
their little ones, for the mere sake of
doing it. The eggs of smaller birds,
he carries to his own nestlings for
food. I knew a lady who saw a jay
bring three small eggs to his nest.
He carried them in his bill.
One summer, a pair of woodpeckers
built in a tall flag-pole near my
house. They had cut out a nice
round hole in the pole, and dug a
deep place for a nest. Several times
each day the father-bird took his
turn on the nest, while the mother-
bird went off to a swamp to get food.
It was curious to watch the nest-
cleaning each night. The birds took
THE KING OF THE TREE. up refuse from the nest in their
claws, and flew off some distance
before they dropped it.
When the little birds came from the shell, the old ones were very
busy, going and coming several times each hour, with food.
It was funny to see them at night-fall. The father-bird took his place,
clinging high up on the pole, like a watchman on a tower, to take a
final look, and see if all was right. The mother-bird, at the same time,
put her handsome head out of the hole, and stretched her neck, as if
to take a look from her window before she went to bed.
When the birds were fledged, there was a grand time teaching them
to fly. They were taken to a roof near by, where they sprawled about.
Then they would be coaxed to make a little flight. The parents flew
low and slowly before them. Great was the joy, if one of the little
things flew a few yards. The old birds seemed to think that they had
never before seen quite such nice flying! Then the father-bird stood
proudly before them, to give them a lesson in drumming, that is, in
pecking at wood, to break it up, to find grubs or insects hidden in it.
He seemed to say, “Look at me!” Then he braced his feet and tail,[28]
held his head on one side, and gave a number of swift, strong blows
on my porch roof. He would drum, and then look at the little ones to
imitate him.
Then they flew over the way, and the father seemed to say, “Now for
another lesson in drumming!” At it he went. But that house had a tin
roof. He could not make the splinters fly!
He tried again. It was of no use. Then he looked much surprised. He
eyed the roof, and tried once more. The little birds looked on.
But the father-bird failed again. Instead of a long, deep roll of sound,
there was only a sharp rattle; no chips, no grubs! He seemed much
ashamed. His wings and his tail drooped. Away he flew to the pole,
and sat there very sad. He seemed to be thinking how much better
houses grew when he was young!
The hole of these birds, in the pole, was tinned over after they left.
They returned next year, and cut a hole lower down. That was
covered with tin in the fall. Next spring, they came back, and cut a
hole higher up. They did this for five years.
Finally the pole had to be taken down as dangerous, it was so cut
up.
Woodpeckers are not the only good bird parents. You can see how
kind and careful mother-birds are, if you watch the hens in the farm-
yard. Do you see them lead their little chicks out? They scratch the
earth, and call the chicks to come and pick up food. When a hawk
appears, the hen cries out, and spreads her wings wide, to shelter
her chicks.
When it rains, or when the little ones are tired, or at night, the hen
calls them to rest under her wide, warm wings.
If you watch a pair of robins raising a brood, you will wonder to see
how many times in an hour they go and come, bringing food. When
the little ones are fledged, notice how they are taught to fly. You may,
also, see the father bird giving his little ones a lesson in singing.
When one of the young birds is weaker than the rest, one of the
parents will leave the others, and give all the time to teaching and
helping that weak one.
A bluebird in my garden, lost, by one trouble and another, all her
brood but one. That one the parent birds were teaching to fly. It
rested on the gravel walk, while the old birds sat on the fence, and
called it.
A boy of three years, seeing the young bird, went up close to look at
it. The father bluebird flew close over the child’s head scolding. As
the child got near the young bird, the old bird flew upon the child’s
head and pulled his hair with its beak!
The little boy ran screaming back to me. The young bluebird lifted his
wings, and flew with his parents into a bush. Was not the father
bluebird brave? The child, though only three years old, was many
times bigger than the bird.
I told you how the birds cleaned their nests. Birds are neat creatures.
You notice that their feathers are bright and clean. Have you seen
how much they prune or dress them?
Birds are very fond of a bath. If you set a basin or pan of clean, fresh
water, on the grass, among shrubs or trees, you will see many birds
going to it to take a bath. They splash the water about in fine style.
When the young birds are fledged, they will be brought to your basin
to have a wash.
When birds roll or whirl in dust or sand, it is not that they like dirt;
they are having a sand bath. The sand flirted in and out among their
plumage takes out grease and little insects and dirt. Then they shake
off all the sand.

FOOTNOTES:
[28] Notice that the woodpecker uses its stiff pointed tail feathers
to brace its body when it rises to the full length of its legs to aid it
in giving a heavy blow, as it draws down its legs and dashes its
beak into the tree with the force of all its weight.
 LESSON XXXIV.
THE BIRDS OF SONG.
The woods and the fields would be very dull and silent without the
song of the birds. Even the shrill chirp of the sparrow is a pleasant
sound to hear. It gives us an idea of happy life.

A JOYFUL SONG.
We will now talk a little about our best song birds. Let us take the
catbird first, as that is common in all parts of the country. It is a pretty
drab and black bird, about nine inches long.
Tom said to me, “A catbird cannot sing; it gets its name because it
squalls like a cat.” True, Tom, the bird has that harsh note for you,
and to frighten off snakes and other enemies. But you listen to him
when he sits in the shade, and sings to himself, or makes his best
song for Mrs. Catbird.
Ah, there is a song for you! Mellow and full, and rich as the tones of
a mocking-bird! Now he trills, now he whistles, now he imitates the
songs of all the sweetest singers of the wood. He can almost outdo
the mocking-bird. He sits in his shady covert, and seems to be
laughing at all the other singers, as he borrows their music.
First, he breaks out into the oriole’s song; then he calls like a jay;
next he chatters like a sparrow; then he whistles like a thrush; then
he gives you a little warble from the bluebird’s music-book. In every
song he gives exactly the notes he copies.
A pair of catbirds built in a honeysuckle by my window. I found they
were very loving birds. At a cry of pain from Mrs. Catbird or the little
ones, the father-bird would come flying back, almost in fits with
distress.
He would fly round and round to seek the cause of their trouble. If he
found any enemy, which he could not drive away, he called so loudly
and sadly that all the birds near came in haste to help him.
The catbird is one of the bravest of the feathered race. He will fight
and drive off a snake. I have seen him defend his home against a
jay, a crow, or a squirrel.
A near relative of the catbird is the blackbird. This is a gay and
happy creature. All the warm weather it pipes sweetly, as it flies here
and there. The red-wing, or colonel blackbird, lives in swamps. The
green-breasted blackbird likes a drier home.
Blackbirds are social in their habits. You seldom see one or two
alone. If you see one near your home, you will soon see or hear
more. They build their nests early in the spring. Young blackbirds are
among the first birds fledged in a season.
The nest is large, and often lined with mud. When the mud dries, the
nest is like a rude cup. Then a soft lining is put in for a bed. In this
nest are laid five eggs of a blue-gray color, dashed with red or
brown.
The blackbird is very brave, and will drive a cat or a snake from his
home. I have seen him chase a squirrel from his tree.
Pleasant as is the blackbird’s note, he cannot rival the thrush.
Among all our birds of song, I think the thrush is best known and
best loved. This is a small bird, of dusky brown and white, the under
part of its body being yellowish white, with black spots. These birds
are fond of woody places, and live alone or in pairs. During the
middle of the day they are silent.
If you wish to hear the thrush at his best, listen to him in the early
morning, or about sundown, when he takes his place on the top twig
of the tallest tree he can find. He begins with a clear, sweet sound,
like a German flute. Next he trills some notes like the tinkle of a
chime of silver bells. Then he pours out a full, rich song, and repeats
it several times.
Soon you will hear some other thrush, from another tall tree, answer
him. They seem to try which can sing the best. They keep up the
concert until the stars come out, and the fireflies flit among the
grasses.
The food of the thrush is insects and berries. While he chooses a
high place to sing from, he builds low. He finds a laurel or alder bush
which is hung with some kind of wild vine, as the Virginia creeper.
There he piles up a quantity of withered beech-leaves. On these he
makes a nest of grass, plastered with mud. It is lined with fine root-
fibres. In this nest are laid four or five light-blue eggs, without spots
or marks.
Often, if you follow the windings of a shaded brook, you may see the
thrush playing along above the waters.
When the thrush migrates, he travels by day, and rests at night.
When he alights to sleep, he erects his tail-feathers, and ruffles up
the feathers on his head. Then he gives a few low calls, hops along
the branches, and bends his head down to peep below, and see if all
is safe for the night. In fact, from first to last, the song-thrush is a
dear and well-behaved little bird.
 LESSON XXXV.
THE OTHER PARTNER.
You know I told you that the flowers had gone into business, and
taken the birds and insects for their partners. Now these partners are
not good friends to each other. In fact, the bird partner is given to
eating up the insect partner.
We will now look at some birds that prefer insects to any other food.
But these, like all birds, will change their diet and eat almost anything
if very hungry.
Our first bird shall be the “nuthatch.” It has been given this name
because people think it can crack nuts. No doubt it can crack beech
and hazel nuts, and chestnuts. Its object is not to get the meat of the
nut, but the grubs that lie in it.
The nuthatch is of a light bluish-gray color, with some white and
black in its feathers. It is not much larger than a thrush.
Early in April, the nuthatch finds a hole in a tree, or in a fence rail or
an old roof. There he makes a nest by piling up dead leaves and any
soft wool or hairs he can find.
In this nest are laid five white eggs, with brown spots on one end.
While the mother bird sits on these eggs, the mate spends all his
time near her. If any danger comes, he flies to the nest. He hunts for
nice fat grubs and worms, and takes them to the sitting bird to eat.
He searches for insects and larvæ, and little can escape his big
bright eyes. When he takes something to his mate, he gives a soft,
low, glad chirp. He never passes the door of the nest-hole without
putting in his head, to make a few cheerful remarks. He seems to be
telling the news.
When the mother-bird flies out, to have a chance to find food for
herself, her mate keeps calling her, as if to say, “Are you quite safe?”
“Are you there?” And she replies with a little note of joy.
The nuthatch finds most of his food under the bark of trees. He flies
round and round the tree and strips off pieces of bark. Hidden there,
he finds worms, spiders, caterpillars, eggs and larvæ of insects. He
seems very curious, and pries into every crack and hole.
The nuthatch seldom migrates. If food is scarce, he will fly to the
barns, and even pick up seeds with the fowls. But he does not like
that food. He prefers insects.
Another bird that feeds chiefly on insects, is, in many respects, the
loveliest and dearest of birds. Can you not guess that I mean the
bluebird? This bird, with its blue back and wings, and ruddy breast is
the first to tell us of the return of spring.
On warm days in February, or early March, we see him flitting above
the last melting wreaths of snow, or sitting on the top rail of the
fence. If a few cold snowy days come, he vanishes. But back he flies
with his mate, and they skim low over the ground to pick up the first
beetles, worms, and spiders that venture out.
For a few days the two are very busy eating insects. If Mr. Bluebird
finds a very nice, fat bug, he does not keep it for himself, but flies
with it to his mate. He gives a glad cry, spreads his wings wide, and
drops it into her mouth.
But soon the pair set about cleaning and rebuilding last year’s nest.
If there is a box on a tree in your garden or orchard, or a hole in a
branch, they will build there year after year.
While the bluebirds are busy setting their house in order, Mrs.
House-Wren gets back from her winter trip. She peeps in, and
seems much vexed that such a nice house was let before she
arrived. As soon as the bluebirds go off, for some more grass, or
hairs, Mrs. Wren steps in, and pulls a few twigs out of the new nest.
She does this to show her feelings. But she hurries away, before the
blue owners return.
Mrs. Bluebird puts five or six pale blue eggs in her nest. She raises
two, or even three, broods in a summer. While she is sitting on the
second eggs, the father bird watches over the young of the first
brood. He feeds them, and takes great care of them, and lets them
perch by him at night.
Now and then, in the autumn, you will see a pair of old bluebirds with
ten or twelve young ones, of their various broods. Then they may be
feeding on gum-tree or smilax berries. But spiders and beetles are
their chosen food.
The note of the bluebird is a soft, sweet warble. He loves sunshine
and springtime. In the fall his note becomes sad and low, as if he
mourns because winter is coming.
When the cold winds, and frosts, and bare trees, make the country
desolate, the bluebird migrates. He goes to the Southern States, the
West Indies, and Mexico. We are all glad to welcome him back. He is
the prophet of fine weather. The farmers like him because he eats so
many harmful insects.
Of all the insect-eating birds, none is more famous than the
flycatcher, or kingbird. In some places he is called the field-martin,
and the tyrant. The name flycatcher comes from his food. He
catches living, full-grown insects, such as flies, gnats, wasps, and
some bees. I am sorry that he is accused of picking up bees.
The name king, or tyrant, bird comes to this brisk little fellow from his
manners. He is very strong, very swift on the wing, and very bold. He
is fond of his brood and mate, and bold in their defence. He watches
to drive off birds which might harm them.
The big blue jay dares not rob a kingbird’s nest. The kingbird will
chase a jay, a crow, even an eagle, or a hawk. His bill is sharp and
strong, and as he flies under or over his enemy, he darts at him, and
drives his bill into him with a peck.
He is so fierce only when he has a young brood to defend. At other
times he is quiet enough. When his young brood is in the nest, he
feels so proud that he seems to think himself the lord of all birds.
The purple martin can fly faster than the kingbird and likes to tease
him. It is also very funny to see a big woodpecker and a kingbird
having a conflict on a fence rail. The woodpecker whirls round and
round like a boy turning springs over a bar. The kingbird flies from
side to side and tries to get a peck at him but cannot.
The kingbird is not a singer. He is a silent, dark bird. His plumes are
brown, black, and white. On his head he has a crest, or crown of
raised feathers. He seems very particular about his food. It is not
every insect that he will eat.
Many farmers, who have watched him carefully, say that he does not
pick up worker-bees, but takes only the drones. He also eats many
gad-flies that trouble and bite the horses. He devours hundreds of
insects and worms which eat fruit, cucumbers, and pumpkins.
In fact, even if the kingbird does eat a few bees, he more than pays
for that damage by the good he does in destroying harmful insects.
When a farmer shoots a kingbird he shoots one of his best friends.
Besides all this, as we are not quite sure that the kingbird does eat
worker-bees, I think we should give him the benefit of the doubt and
let him live.
 LESSON XXXVI.
A BRIGADE OF BIRDS.
In some of the lessons in these Nature Readers, you have been told
of crabs that are street-cleaners of the sea. You have also been told
of insects that are cleaners of the air. I shall now tell you of some
birds that are cleaners of fields and woods.
This lesson will be about a brigade of birds that do street-cleaning
work. I shall head the list with the crow. You have seen that big,
black bird standing all alone on a dead tree, looking the country over.
You have seen him following the farmer’s rake and plough in the
spring.
You have seen hundreds of crows come together in the fall, to
discuss their migration. You know their loud, harsh note. You have
seen them in their sleek, black coats, stepping over the snow in
winter time. You know in cold weather they become very tame, and
draw near the houses for food.
One day I heard a loud cawing of crows, and looking out saw about
twenty of them flying in a long, low line over some bushes, in a field.
Every now and then they stooped to the earth. I watched. They were
chasing a cat. The cat hid in the bushes. He was trying to escape
from the crows.
They flew over the bushes and scolded. Then, as he ran from one
shelter to the next, they stooped and pecked him. They chased the
poor cat all across a big field. I think he was very glad when he got
under a barn. I suppose the crows saw that he was watching them,
and so they drove him away.
When a number of crows are in a field, they keep one crow on a high
place, to warn them if danger is near. They seem to be very wise
birds. They know a man with a gun, as far as they can see him.
Crows do some harm by pulling up and eating the planted corn and
sown grain. But they are of use, as they eat many worms and insects
which destroy crops. You often see crows following a farmer as he
ploughs. They are after the grubs and worms in the new furrow.
Crows eat lizards, mice, toads, and moles. They also feed on any
dead and decaying flesh which they can find. A company of crows
will pluck off all the flesh from a decaying animal, and leave the
bones white and clean.
The crow is about as large as a large pigeon. It is jet black, and not
handsome. Like all flesh-eating birds it has a large strong beak and
large strong feet. These are for tearing their prey.
As crows kill young chicks and pull up grain, farmers dislike them.
Have you not seen images placed in fields, to scare the crows from
the crops?
Crows are very noisy except when they are rearing a young brood.
Then they are quiet. They do not wish the nest to be found. The nest
is large and made of moss, sticks, leaves, bark, and hairs. It is built
in a high tree. In it are four pale-green eggs, with olive spots.
Mr. Crow helps brood the eggs. He keeps a sharp lookout for danger
for half a mile about his nest. He hunts for food and brings some to
Mrs. Crow as she sits on her eggs.
Toward the end of summer, the young crows can fly well. Then many
families of crows go to pass the night together in some place that
they have chosen. I used to like to watch great flocks of crows going
at sunset towards their roost. In the morning they returned.
Crows like to live near the sea. They catch small fish. They carry
shell-fish high up in the air in their claws, and let them drop on a
rock. The fall breaks the shells and the crows fly down and pick out
what is inside.
The jackdaw and the magpie are cousins of the crow. They also eat
flesh. They are larger than the crow, and have some white in their
plumage. They can both be taught to speak.
The jackdaw likes to carry off and hide things. I knew one that lived
in a garden, where some swans were kept on a pond. The naughty
jackdaw would go and carry off all the swans’ food and hide it.
If we walked near his hiding-places, he would run after us and peck
our shoes. The gardener had to put a wire fence all around the pond,
and clip the daw’s wings so that he could not fly over the fence to rob
the swans.
A much larger bird than these is the turkey buzzard. He is about the
size of a small turkey, and is of a faded black color. His head and
neck are bare of feathers. The skin of the head and neck is reddish
and wrinkled. It has a little black hair and down on it. The bill is very
large and hooked. The feet are also very large.
This is the least handsome of all our birds, and no one likes it. The
reason of the dislike is, the bad odor the bird has. This odor comes
from the decayed animal food which the buzzard eats. But it is this
very habit of eating spoiled food which makes the poor bird so useful
to us.
The buzzard has a swift flight and a keen eye. It can see its dead
food far off. When you see three or four buzzards wheeling in the air,
you may be sure that some dead animal lies on the ground below
them.
Any one who knows how the carcass of a sheep, cow, dog, or cat
will infect the air for miles about, will feel glad that the buzzards like
to eat such things. The buzzards strip off all the ill-smelling flesh, and
leave only clean white bones.
The buzzard is a very mild, quiet bird. It never fights, and never eats
any live prey. It tears up no corn, and carries off no little chicks. In
most States there is a law against killing a buzzard.
The buzzard makes no nest. It finds a hollow stump, or a broken
tree, and lays two or four eggs on the decayed wood. The eggs are
about the size of goose eggs. They have brown spots on them. The
young ones are covered with down like young goslings. Buzzards
are American birds.
The large carrion crow, or black vulture, is a bird much like the
buzzard in its habits. But it lives farther south, is seen in greater
numbers, and is not so shy. They are often tamed, and kept near the
markets to clean up offal. They like to sit on the chimney tops to
enjoy the warm air that rises.
Dogs and black vultures will feed together on a carcass. But if the
dogs crowd the birds too much, the vultures will hiss at them. These
black vultures do good service by eating up alligators’ eggs.
Another of our brigade of flesh-eating birds is the raven. The raven is
a handsomer bird than the others. His glossy black feathers have
blue and green tints on them. Ravens are often found in sea-side
cliffs and trees. They feed on dead fish.
The raven is noted as one of the most long-lived of birds. They are
said to live a hundred years. They are found in nearly all climates
and countries. While they eat all kinds of dead animal matter, they
will also carry off young ducks and chickens.
 LESSON XXXVII.
THE BIRDS IN THE WOODS.
I have told you how the crows chased a cat. That was not the only
cat chase I have seen. One summer I had a house near a wood.
Through the wood ran a brook, and near it was a marshy place. This
is just such a spot as birds love.
In that township no one was allowed to shoot birds, so birds of many
kinds were plentiful.
One day, as I stood on my porch, I heard a queer noise. Then
around the corner of the house rushed a cat. After him, screaming,
and flying low, came about twenty birds. They were headed by a
blue jay. The jay flew down on the cat, and gave him a sharp peck.
He pulled out some of the cat’s fur.
Among these birds I saw the robin, oriole, wren, catbird, yellow-bird,
yellow-hammer, blackbird, and several sparrows. They may have
their little quarrels among themselves, but they all make common
cause when the cat prowls in the woods to kill them.
Once, when I lived in the southwest, I had many forest trees on my
lawn. In these trees lived such birds as I have just named, also the
peewee, the titmouse, and the bluebird. I had a tame squirrel that
went up the trees and frightened the birds.
After that they kept a sentinel always on a bough. If the squirrel left
the grass for any tree, the alarm was sounded at once. Then all the
birds near came in haste, and attacked the squirrel. They pecked
and screamed at him, until he was glad to keep out of the trees.
Soon he did not dare to touch a tree trunk.
Among the wood birds the woodpecker is one of my favorites. He is
a very fine fellow. There are many kinds of woodpeckers. We have
the red-headed, the yellow-breasted, the gold-winged, the hairy, the
 UNDER THE TREES.

downy, and others.

They are very intelligent, diligent, and merry birds. They make their
nests in holes in trees. It is wonderful how they know where to find a
decayed spot in a tree that looks quite sound. The woodpecker will
eat fruit and grain, but prefers insects. He, no doubt, saves many
forest trees by eating up grubs and worms, which would destroy
them.
The woodpecker is a noisy bird. He is full of chatter to his mate. He
talks to himself constantly when alone. His “drum” can be heard over
all the wood.
It is a fine sight to see him on a brown tree trunk. His plumage,
black, white, green, scarlet, gold, can be seen from far. He whirls
about, looking for grubs. He holds fast with his strong claws, and
gives blow after blow with his great bill upon the tree.
When he tears off a large piece of bark, and lays bare a fine fat grub,
he throws back his head, and laughs with joy. He laughs almost as
well as the loon, of which I told you.
It seems a great shame to kill such a handsome and happy bird. He
really does very little harm, and much good. Now and then, he
carries off a pear or an apple to eat, but he saves the lives of many
trees.
Among the joyous birds of the wood, let us now take a look at the
bird which is every one’s friend. There is a bird that every one loves,
and no one says an ill word of. Can you guess that this is the
cheerful robin? He is our friend the year round. His red vest shines
against the summer green and the winter snow.
The robin is a large bird, with black and brown head and wings; most
of the rest of the body is of a dull, yellowish red. Of all our birds this
is the least shy. He is brave and merry, and goes and comes as he
pleases. Scarcely a month of the year passes without bringing the
robin.
Robins seem equally happy in wood, field, garden or orchard. If they
cannot find insects to eat, they will take fruit, berries, crumbs or
seeds. If food grows scarce, they hop down to the door, and feed
with the chicks, or expect a fine breakfast thrown out to them alone.
Some people think that robins eat fruit rather as drink than as food.
They take the fruit because they are thirsty. It is said that if a pail of
water is set near the fruit trees, the birds will drink from that and not
rob the trees. You might try it sometime, and find out if this is so.
The robin builds a large nest of straw and fibres. She plasters it with
mud, and lines it with fine grass. She will come back to the same
nest year after year. In this nest she lays five eggs of a bright blue-
green color.
If the robin has taken a winter trip, he comes back early in March to
settle in the Northern and Middle States. Sometimes he does not
leave his home in winter. Sometimes he goes and comes a number
of times, as if he wanted to keep an eye on his house.
In March and April you see these birds in pairs. They will be running
about the short grass, hunting for leaves, or sitting in the bare
branches, trying a song. The robin cannot sing so well as the thrush;
but he is fond of singing, and his note is merry if not rich.
As soon as day breaks, you will hear the robin chorus. All day long
robin rests himself from work by singing. In the wood he quarrels
with no other bird, and no other bird quarrels with him. The robin can
be seen in the autumn, feasting wherever there are poke or elder
berries. He is a long-lived bird, and, if he meets with no accident,
may live fifteen or eighteen years.
A larger and gayer bird than the robin, and living often in the same
wood, is the blue jay. I have told you of some of this fine fellow’s
naughty ways. Did you ever see him? Did you notice his big black
bill, his great keen eyes, his saucy crest, standing up like a helmet,
his fine blue back, his blue and white wings and tail, with black bars?
Oh, he is a kingly bird! And he knows it!
Of all our birds none is more pert and saucy than the jay. His voice is
loud, and he likes to hear it. He is the trumpeter in the bird band. He
has a varied note, and can mock the songs of other birds. He
chatters like a duck; he screams like an angry catbird; he whistles;
he laughs; and then he goes into the shade, and talks to his mate in
a soft musical tone.
He seems to be vain of his fine clothes. Sometimes he stands on a
branch, and makes such wild noises that all the birds in the wood fly
to see what is the matter. Then, when he has a number of birds to
gaze at him, he bows, nods, jerks, flirts, whirls, and makes all
manner of the queerest motions. He seems to be giving some sort of
a show.
One of the jay’s family names is “the gabbler.” It is said that, like the
crow and some other birds, he is a weather prophet, and most noisy
before a rain-storm.
The jay will eat almost any kind of food. He eats the eggs and young
of smaller birds. He eats chestnuts, acorns, corn, cherries, insects.
When very hungry, he will take a small potato, or go to the barn for
corn and oats.
Of all the bird partners of the plant in seed-carrying, the jay is chief.
One man, who studied this bird very carefully, said, “The jays are
able, in a few years’ time, to replant all our waste lands.” No bird is
more useful in carrying about nuts and hard seeds.
The jay is especially the bird of North America. He is not a very great
traveller. Usually each pair lives alone, and then with their young
brood. But sometimes in the autumn forty or fifty will go together to
look for acorns.
The jay likes to build in a quiet wood, near a stream. He builds a
large nest in a tree, and watches over it, but does not often go very
near it. The mother jay lays five eggs of olive color, with brown spots.
When the young birds come from the shell, both parents take great
care of them.
One day I saw in a wood five new-fledged jays, sitting on a branch.
They were not at all afraid of me. But the old birds came near, and
seemed in such distress at seeing me, that I went away. A few
weeks after I saw the whole family, carrying stores of chestnuts,
acorns, and seeds to hide, for they are given to laying up a hoard of
food.
The jay is the great enemy of the owl. As soon as he finds an owl
hidden in the shade, he calls all the other birds to the battle. Then,
headed by the jay, they scold and scream, and fly at the owl, until
they drive him off.
He quarrels also with the small sparrow-hawk. But in that quarrel
poor Mr. Jay sometimes is killed. When he fights the hawk, he calls