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Bravo et Vila RBQ Vol. 34, No.5, pp. 142-149, 2017

Received 12 01 2017
MECHANISTIC THEORETICAL Accepted 12 28 2017
Published 12 30 2017
PROPOSALS FOR: ALKENES BY
CLAISEN REARRANGEMENT OF - Vol. 34, No.5, pp. 142-149, Nov./Dic. 2017
34(5), 142-149, Nov./Dec. 2017
ALLYLTHIO CARBENES; AZA-COPE Bolivian Journal of Chemistry
REARRANGEMENT OF 4-
BUTENYLIMINIUM IONS; 2-
SUBSTITUTED PYRROLIDINE
DERIVATIVES; SYNTHESIS OF
PERHYDROGEPHYROTOXIN, KEY
STEP; PART V; THE ORGANIC
CHEMISTRY NOTEBOOK, Nº 13

PROPUESTAS MECANICISTAS
TEÓRICAS PARA ALQUENOS POR
REORDENAMIENTO DE CLAISEN DE
CARBENOS-ALILTIO;
REORDENAMIENTO AZA-COPE DE
IONES 4-BUTENILIMINIO;
DERIVADOS PIRROLIDÍNICOS
SUBSTITUIDOS EN 2; SÍNTESIS DE
PERHIDROGEPIROTOXINA, PASO
CLAVE; PARTE V; EL CUADERNO DE
QUIMICA ORGANICA, Nº 13

Short review Peer-reviewed

José A. Bravo1,*, José L. Vila2


1Natural Product Laboratory, Phytochemistry, Chemical Sciences Department, School of Pure and Natural
Sciences FCPN, Universidad Mayor de San Andres UMSA, P.O. Box 303, Calle Andrés Bello s/n, Ciudad
Universitaria Cota Cota, phone +59122792238, La Paz, Bolivia, jabravo@umsa.bo, www.umsa.bo
2Natural Product Laboratory, Green Chemistry, Chemical Sciences Department, School of Pure and Natural
Sciences FCPN, Universidad Mayor de San Andres UMSA, P.O. Box 303, Calle Andrés Bello s/n, Ciudad
Universitaria Cota Cota, phone +59122772269, La Paz, Bolivia, jlvila@umsa.bo, www.umsa.bo

Keywords: Organic Chemistry, Alkenes, -Allylthio carbenes, 4-butenyliminium ions, 2-


Substituted pyrrolidine derivatives, Perhydrogephyrotoxin, Claisen rearrangement, Aza-Cope
rearrangement, Mechanisms of Reactions, W. Carruthers.

ABSTRACT

This is the thirteenth theoretical assay in the series: “The Organic Chemistry Notebook Series, a Didactical
Approach”.
The aim of this series of studies is to help students to have a graphical view of organic synthesis reactions of
diverse nature. We have taken a series of reactions compiled by W. Carruthers in ‘Some modern methods of organic

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synthesis’, and we have proposed didactical and mechanistic views for them. This theme is included in the chapter
“Formation of carbon-carbon double bonds” in the mentioned text.
-sulphured alkenescan be obtained by Claisen rearrangement of -allylthio carbenes. A theoretical reaction
pathway is proposed here. A short mechanism is proposed for the aza-Cope rearrangement from 4-butenyliminium
ions. From this, 2-substituted pyrrolidine derivatives are explained in their reaction step by step under a theoretical
approach. With hydroxyl and amino groups as substituents, bicyclic pyrrolidine derivatives are reached. The
synthesis of perhydrogephyrotoxin, a natural product, is explained mechanistically here by the using of the preceding
reactions.

*Corresponding author: jabravo@umsa.bo

RESUMEN

Este es el décimo tercer ensayo teórico en la serie: “El cuaderno de química orgánica, un enfoque didáctico”.
El objetivo de esta serie de estudios es ayudar a los estudiantes a disponer de una visión gráfica de reacciones
de síntesis orgánicas de diversa naturaleza. Hemos tomado una serie de reacciones compiladas por W. Carruthers en:
‘Some modern methods of organic synthesis’, para las cuales hemos propuesto vistas mecanicistas y didácticas. Este
tema está incluido en el capítulo “Formation of carbon-carbon double bonds” del mencionado texto.
Los alquenos -sulfurados pueden obtenerse por reordenamiento de Claisen de carbaniones -aliltio o carbenos
-aliltio. Aquí se propone una ruta de reacción teórica para el reordenamiento de carbenos -aliltio. Se propone un
mecanismo breve para la transposición de aza-Cope a partir de iones 4-buteniliminio. De acá, los derivados de
pirrolidina 2-sustituidos se explican en su reacción paso a paso bajo un enfoque teórico. Con grupos hidroxilo y
amino como sustituyentes, se alcanzan derivados de pirrolidina bicíclicos. La síntesis de la perhidrogefirotoxina, un
producto natural, se explica con enfoque mecánicista aquí mediante el uso de las reacciones precedentes.

INTRODUCTION

Master classes of organic chemistry showed us the difficulties experimented by students due to lack of knowledge of
classical mechanisms. A mechanistic proposal is naturally mandatory if a rational explanation of products emerging
from a synthesis is going to be formally accepted and understood. As academics we are committed with the didactics
and we have designed a series of articles exposing mechanistic theoretical proposals, articles have a character of
review, meaning thus the use of published works on varied themes on synthesis. The present contribution:
Mechanistic theoretical proposals for: alkenes by Claisen rearrangement of -allylthio carbenes; aza-cope
rearrangement of 4-butenyliminium ions; 2-substituted pyrrolidine derivatives; synthesis of perhydrogephyrotoxin,
key step; part V; the organic chemistry notebook, Nº 13, is the thirteenth study in the series: “The Organic Chemistry
Notebook Series, a Didactical Approach” [1-12].

REVIEW OF REACTIONS, MECHANISTIC THEORETICAL PROPOSALS, DISCUSSION

-allylthio carbenes [13]

The rearrangement of -allylthio carbanions and -allylthio carbenes is feasible. For example, ,-ene-carboxylic
acids can be obtained from -allylthio carbenes, as shown schematically in Figure 1. The presence of six electrons to
achieve the electrocyclic reaction is mandatory [13-15]. Figure 2 shows a theoretical mechanistic proposal for the
reaction of Figure 1.

SCH3 NaH
CH3S HO
NaOH, CH3OH
CH3SC [15]
TosNHN
S THF, reflux S S O

Figure 1. 2,3-Sigmatropic rearrangement of nucleophilic carbenes, reviewed by W. Carruthers [15]

Comments

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In Figure 2 the strong base H- provided by NaH performs a nucleophilic attack over sulphur in the tosylate moiety of
compound 45. After resonance of the  electrons the electronic charge excess breaks the bond S-N to establish a new
 N=N bond finally situating the charge excess over carbon. Substrate is now free of tosylate, the protective group,
and the breaking of the N=N-C bond generates the expected carbene. Carbene is responsible then of the Claisen
rearrangement once the appropriate conformer forms to become intermediate 46. Under alkaline conditions
intermediate 46 transforms into the carboxylic acid 47, under the form of carboxylate given the alkaline conditions of
the reaction.
Mechanism for 47

SCH3 SCH3 SCH3


N Na+H- N N
N S N S N S
-
O S H O S H- O S H
O O O

45

H 3C H 3C H 3C
H
SCH3 SCH3
O S O S
N N carbene N N C
+ formation Na+ S
S S C
H H
carbene

Na+
OH O
S S
S :C :C + -
conformerism S S C Na OH
S
C S S S CH3OH S SH
S Na+
H
[2,3]-sigmatropic rearrangement 46

S HO
Na+OH-
+ - + -
+ Na SH + Na SCH3
O O
47
Figure 2. 2,3-Sigmatropic rearrangement of nucleophilic carbenes, reviewed by W. Carruthers [15].
Theoretical mechanistic proposals by the authors

Aza-Cope rearrangement of 4-butenyliminium ions [13]

4-Butenyliminium ions (48) can suffer aza-Cope rearrangements [13]. This is a carbon-carbon formation reaction
[13]. The reaction takes place easily, mean mild conditions, but its reversibility character gives it no much utility in
synthesis [13]. However, hydroxyl or alkyl substituents can change such condition and drive the reaction toward
products (49), depending on the substitution pattern, concretely C-3 substituted in the butenyl group [13]. According
to Figure 3, 48 with R4=OH, the reaction can be addressed to products (49) with an alkyl or hydroxyl as substituent
at the C-3 position of butenyl by capturing the iminium salt in an intramolecular Mannich reaction [13,16]. See
Figure 3 for the reaction and its comparison with the oxy-Cope rearrangement. This is an excellent pathway for the
synthesis of 2-substituted pyrrolidines [13,16].
R2 R2
R2 R2 H H H OH OH
N R1 N R1
R3 4 N R1 R3 N R1
R3 R3
R6
HO R6 HO
but

R4 3 1
R6 R4 R6 H 5 H 5
en y

2
R R
5
R5
l gr

R
oup

48 49 48 49

Aza-Cope rearrangement Oxy-Cope rearrangement

Figure 3. Aza-Cope rearrangement of 4-butenyliminium ions, reviewed by W. Carruthers [13]. One-step concerted pericyclic
mechanism. Theoretical mechanistic proposals by the authors
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In Figure 3, the transition state can be imagined as a chair-like conformer. The driving force to provoke the
pericyclic reaction (substrate 48) is evidently the charge deficiency of nitrogen. The demand of the iminium ion for
neutrality makes possible the electronic movement through p orbitals from the electron-rich double bond C1=C2 to
polarize bonds until the rupture of the  bond C-3-C-4 (48). Without an oxygen (an electron donor group) or an alkyl
group (an electron donor group) as the R4 substituent, the reaction becomes reversible, since the driving force (the
electron demanding iminium ion) works also for the reaction in the inverse sense, is worth to say, bond polarization
occurs from the electron-rich double bond C2=C3 through p orbitals until the iminium ion. Once the electron donor
group is introduced in the molecule as a substituent at C-3, the reaction can be driven toward products quantitatively,
since once the rupture C-3-C-4 occurs, and taking into account the considerations done in a previous contribution by
us [12], the center C-3 that supports the OH (or R) group becomes cationic (eventually). This cationic charge (+ or
+) is thus stabilized by the electron donor: O (OH) or C (R). In absence of OH (R), it is logical to think that the C+-3
(formed in the direct reaction) also induces the reverse reaction.

Substituted pyrrolidine derivatives; synthesis of acetylnicotine 53 and a bicyclic derivative 54 [17]

In the synthesis of an acetylnicotine derivative [17], pyridine 3-aldehyde was mixed with N-methyl-2-
hydroxybutenamine (50) under thermal conditions in a benzene medium, camphor sulfonic acid was added as
catalyst [17]. The yield was 84%. The iminium salt (51) passes by an aza-Cope rearrangement to intermediate 52.
Intermediate 52 is then driven to an intramolecular Mannich reaction to afford acetylnicotine 53 [17]. Figure 4 and
Figure 5 show the succinct reaction scheme and the mechanistic proposal respectively.

H O H
CH3
CHO OH COCH3
HO CH3 RSO3H CH3
+
CH3NH N [17]
N benzene N N
CH3 CH3 CH3
N N N

50 51 52 53

Figure 4. Aza-Cope and intramolecular Mannich rearrangement of 51 and 52 respectively, in the synthesis of acetylnicotine, a
pyrrolidine derivative 53; reviewed by W. Carruthers [17]

Mechanism for 53

O O- OH OH2
HO CH HO CH H+ HO CH
3 3 3
H H H
N H N N
N N H N N
HO CH
.. 3
H N

H H
N
OH
..
HO OH aza-Cope OH Mannich
H N N N
N N
CH3 CH3
N N CH3 CH3
51 52

H H H H

OH -H+ O
N N N N
CH3 CH3
CH3 CH3
53

Figure 5. Mechanistic views for the aza-Cope and intramolecular Mannich rearrangement of 51 and 52 respectively, in the
synthesis of acetylnicotine, a pyrrolidine derivative 53; reviewed by W. Carruthers [17]. Theoretical mechanistic proposals by
the authors

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In a first step a nucleophilic attack from the basic nitrogen of N-methyl-2-hydroxybutenamine (50) provokes the
breaking of the double bond of carbonyl, placing thus the electron excess over the oxygen atom. This attack converts
the secondary amine into a quaternary ammonium, which subsequently frees a proton that neutralizes the negative
charge of oxygen of the alcoxy function. We count now a tertiary amine and a diol in the adduct. By acid catalysis
(camphor sulfonic acid) the alcohol derived from the ketone becomes protonated. This activates the substrate for an
intramolecular nucleophilic attack over the carbon of the protonated alcohol function. The nucleophile is the nitrogen
of the tertiary amine which converts after the attack in an iminium ion by dehydration of the protonated alcohol (-
H2O). The iminium ion adopts a chair-like transition state for an aza-Cope rearrangement (51). After the pericyclic
reaction (aza-Cope rearrangement) we obtain compound 52, which is still an iminium ion giving the substrate
reactivity enough to induce a Mannich intramolecular reaction. Thus, as discussed previously regarding the reactivity
of iminium ions, the wish of neutrality of nitrogen makes possible the concerted electronic movement to neutralize
the iminium ion. The result is the pyrrolidine derivative 53, after returning the H+ to the catalyst.
Another pyrrolidine derivative coming from iminium ion aza-Cope rearrangement is compound 54 in Figure 6
[17]. To form this bicyclic pyrrolidine derivative 54, the hydroxyl and amino must be neighboring substituents on a
ring [17]. Due to this reaction the original ring is expanded by one carbon [17]. When OH and NHR are cis to each
other, the product, the cis-fused bicyclic compound, is the result of high stereoselectivity [17]. There isn’t much
selectivity when the OH and NHR group are in a trans mutual position [17]. Figure 7 is the theoretical mechanism
approach.

Ar Ar Ar O
OH H H Ar

N N
OH OH N
NHCH3
H CH3 CH3 H CH3

54

Figure 6. Synthesis of bicyclic pyrrolidine derivative 54 by Aza-Cope rearrangement and Mannich intramolecular reaction;
reviewed by W. Carruthers [17]

Ar Ar Ar 54 Ar

H -
O OH H+ OH2
OHH O OHH H OHH H OHH H
H H H .. H
N N N N
H CH3 H CH3 CH3 CH3

Ar O
Ar
H Ar H Ar H Ar
OH aza-Cope Mannich
H
N
N N N H
N CH3
CH3OH CH3O H CH3O
CH3 54

Figure 7. Synthesis of bicyclic pyrrolidine derivative 54 by Aza-Cope rearrangement and Mannich intramolecular reaction;
reviewed by W. Carruthers [17]. Theoretical mechanistic proposals by the authors

Comments

The synthetic route according to Figure 7 is the same to that described in Figure 5 for the synthesis of acetylnicotine and it
corresponds to the same type of mechanistic comments there.

Synthesis of perhydrogephyrotoxin, key step

This synthetic sequence has found plenty of applications when synthesizing natural products [17]. For instance,
during the synthesis of perhydrogephyrotoxin, the key step involves the using of butanylamine 55 which becomes the
tricyclic 56 (79% yield) [17-19]. See the key step of this synthesis in Figure 8 as compiled by W. Carruthers and first
investigated by Overman et al. [18,20]. The mechanistic proposals are shown in Figure 9.

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H 5C 6 O H 5C 6 O H 5C 6 O
OCH3
H H H
OCH3
pCH3C6H4SO3H H
NH benzene reflux
N (rearranges across N
H H the convex face) H
COCH3
OCH3 OCH3 H
(79%)
55 56

Figure 8. Key step of the synthesis of perhydrogephyrotoxin by Aza-Cope rearrangement and Mannich intramolecular reaction;
reviewed by W. Carruthers [18,20]

Ph Ph Ph Ph
H H H H
O O O O
pCH3C6H4SO3H H
H H H H
OMe OMe OMe
+ MeOH H
NH benzene reflux
OMe ..NH OMe N
H
N
.. OMe

OMe OCH3 OCH3 OCH3

Ph Ph Ph H 5C 6 O
H H H
O O O H

H H H
H
+ H
N N N
OMe N H
MeO MeO COCH3
H H H
OCH3

Ph Ph Ph H 5C 6 O
H H H
O O O H
H H H

H H H

N H N N N
H
COCH3
O H
OCH3 H
O CH3 56
aza-Cope Mannich CH3

Figure 9. Key step of the synthesis of perhydrogephyrotoxin by Aza-Cope rearrangement and Mannich intramolecular reaction;
reviewed by W. Carruthers [18,20]. Theoretical mechanistic proposals by the authors

Also the sequence is employed in model studies for the synthesis of alkaloids from the genus Aspidosperma [17,18]
where the tricyclic ketone 57 was obtained in 83% yield [20]. See Figure 10 for the reaction and Figure 11 for its
mechanistic proposals.

R H
N N CH2=O
camphor N
H
O O C6H5 C6H5 O C6H5 sulfonic acid,
benzene, reflux O C6H5
C6H5
HO
O
57 (83%)

Figure 10. Model studies for the synthesis of alkaloids from Aspidosperma, by employing Aza-Cope rearrangement and
Mannich intramolecular reaction; reviewed by W. Carruthers [18,20]

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O O O

.. H H+
H H .. H MgCl
N N N
H H H

R O R O H O NuR
Ph - Ph Ph
Nu:
-
O OH OH OH
Ph Ph Ph O- Ph
OH
H+ H
.. H .. H + O H H
N N H N N
..
H H H H

H O H O H O O
Ph Ph Ph Ph
OH
OH +
O H2 OH Ph
Ph
O+H2
Ph ..
Ph Ph OH
OH OH
H+ aza-Cope Mannich
H H H H H
N
.. N
.. N
.. N N
H H H H H
O O O O O
Ph Ph Ph Ph Ph

Ph Ph N
OH O H
+
-H O C 6H 5
H H C 6H 5
N N
H H O
O O 57
Ph Ph

Figure 11. Model studies for the synthesis of alkaloids from Aspidosperma, by employing Aza-Cope rearrangement and
Mannich intramolecular reaction; reviewed by W. Carruthers [18,20]. Theoretical mechanistic proposals by the authors

ACKNOWLEDGEMENT

The authors express their gratitude to Prof. Eduardo Palenque, Department of Physics, Universidad Mayor de San
Andrés, for his bibliographic support.

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Bravo et Vila RBQ Vol. 34, No.5, pp. 142-149, 2017
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