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Critical Review of a research paper

The Palladium(II)- Catalyzed


Nazarov Reaction
Bee, C.; Leclerc, E.; Tius, M. A. Org. Lett. 2003, 5, 4927–4930.

By:
Atul C. Yelpale
Under the guidance of:
Prof. K. G. Akamanchi
Nazarov Cyclization
• Nazarov discovered in 1
̴ 950.

• Shoppee elucidated mechanism in 1969.1

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• A broader definition of the Nazarov cyclization includes a
variety of precursors that under specific reaction conditions
also produce 2-cyclopentenones via divinyl ketones or their
functional equivalents.2

• Nazarov reaction is promoted by one or more equivalents of a


Lewis or Brønsted acid (BF3, SnCl4, TiCl4, or AlCl3).3
1. Shoppee, C.W.; Lack, R.E. J. Am. Chem. Soc. 1969, 1346-1349. 2
2. Habermas, K. L.; Denmark,S.; Jones, T. K. In Organic Reactions; Paquette, L. A., Ed.; John Wiley & Sons: New
York, 1994; Vol. 45, pp 1.
3. Pellissier, H. “Recent developments in the Nazarov process,” Tetrahedron 2005, 61, 6479–6517.
Cont..

• The Nazarov reaction is classically formulated as a 4π-electron

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conrotation of pentadienyl cation 2, which is formed by proton
transfer to the dienone . The allyl cation 3 is formed as an
intermediate. Proton loss from 3 terminates the reaction and
leads to cyclopentenone 4.4

5. Tius, M. “Some New Nazarov Chemistry,” Eur. J. Org. Chem. 2005, 2193–2206.
Synthetic utility of Nazarov reaction2

• Several variants of the Nazarov cyclization have been

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employed in synthesis endeavors. e.g.
 Simple cyclopentanoids such as cis-jasmone.
 Prostaglandin analogs, (±)-valleranal, (±)-methylneomycin B,
and (±)-xanthocin.
 More recently the Nazarov cyclization has been used in the
synthesis of polyquinane natural products such as (±)-
hirsutene, (±)-modhephene, (±)-siliphinene, (±)-
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pentalenene, (±)-capnellene and (±)-cedrene.
2. Habermas, K. L.; Denmark,S.; Jones, T. K. In Organic Reactions; Paquette, L. A., Ed.; John Wiley & Sons: New
York, 1994; Vol. 45, pp 1.
Cont..

 The synthesis of yuehchukene alkaloid analogs has also


emplyed a Nazarov cyclization as a key step.

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 Nazarov cyclization employing propargyl alcohols has been
successfully applied to synthesis of (±)-strigol, (±)-nor-
sterepolide, (±)-nookatone, (±)-muscone, and (±)-
muscopyridine.
 Industrially, an aromatic nazarov cyclization is used in the
synthesis of (+)-indacrinone.
 The cyclization has been postulated in the biosynthetic
pathways for cis-jasmonic acid, and marine derived prostanoids
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such as preclavulone A.
About the paper

• The Pd(OAc)2-catalyzed reaction leads to cross-


conjugated cyclopentenones through an oxidative

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process (a).
• The PdCl2-catalyzed cyclization of α-alkoxy dienones
leads to 2-hydroxycyclopentenones (b).

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Important features of the paper

• It is the first palladium-catalysed reaction of Nazarov

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cyclisation of divinyl ketones.3
• Depending upon the choice of catalyst, simple hydrolysis
of an intermediate Pd-enolate leads to 2-
hydroxycyclopentenones, 2a, or β-hydride elimination
leads to cross-conjugated cyclopentenones, 12a.
• This paper revealed enhanced reactivity in substrates
with α-alkoxy substituents.4
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3. Pellissier, H. “Recent developments in the Nazarov process,” Tetrahedron 2005, 61, 6479–6517.
4. Frontier, A. J.; Collison, C. “The Nazarov cyclization in organic synthesis. Recent advances,” Tetrahedron,
2005, 61, 7577–7606.
Review points for the paper

• Title:

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 The title The Palladium(II)-Catalyzed Nazarov
Reaction seem very general instead of this

 The title The Palladium(II)-Catalyzed Nazarov


Reaction of α-alkoxy dienones, would be more
precise.

 Another title The Palladium(II)-Catalyzed


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Asymmetric Nazarov Cyclization also be better.
Review points for the paper

Abstract
About present abstract:

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1. Length of abstract is satisfactory.

2. It brings out the main points of the paper.

3. It does not gives idea about yield, and other conditions


such as temperature, solvent, time etc.

Suggestions:
1. The abstract should also include yield, and other
conditions such as temperature, solvent, time etc.
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Review points for the paper

Assumptions and Illustrations


1. The logic of using HCl in scheme 1 (b), was hopeful (from

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Kocienski6); but the result obtained were totally
different; here
i. Author does not summarizes the reason for formation of α-
diketone(3) rather than formation of 2-hydroxycyclopentenone.

ii. Author directly moved up to carry out Pd-catalyzed reaction

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6. Casson, S.; Kocienski, P. J. Chem. Soc., Perkin Trans. 1 1994, 1187-1191.


Review points for the paper

Assumptions and Illustrations


2. For the summery of Dienone starting materials 1j-l,

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author uses chemical equation (Scheme 2a); whereas for
the dienone starting materials 1a-i, author gives text.
 It Prevented needless duplication.

 Relatively also the illustration of dienone starting materials 1a-i,


in the form of chemical equation would be better.

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Review points for the paper

Assumptions and Illustrations


3. In the discussion, author states that, “The

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stereochemistry of 2g is cis, upon standing, slow
isomerization to the trans isomer takes place. Author
does not comment on
standing time for total conversion.

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Review points for the paper

Assumptions and Illustrations


4. The reasoning made by author to explain the failure of
cyclization of 8-11, is logical.

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8- Conformational preferences
9- The electron-withdrawing effect of fluorine.
A more extensive examination of a withdrawing substituent
effects is necessary (and ongoing).3
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10, 11- α-alkoxy group is required
3.Frontier, A. J.; Collison, C. “The Nazarov cyclization in organic synthesis. Recent advances,” Tetrahedron, 2005, 61,
7577–7606.
Review points for the paper

Assumptions and Illustrations


4. For the reactions performed with Pd(OAc)2 in DMSO:

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Reaction products of 1c, 1f, 1g, 1h, 1j, 1k and 1l author
neither illustrates product in scheme nor in text.

For product 12a, 12d and 12i author gives to yield, it


makes confusion.

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3.Frontier, A. J.; Collison, C. “The Nazarov cyclization in organic synthesis. Recent advances,” Tetrahedron, 2005, 61,
7577–7606.
Review points for the paper

Technical usefulness
• These Cyclizations studies by revealed enhanced reactivity in

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substrates with α-alkoxy substituents
 Since these early findings the Tius group, in particular, has
developed synthetically valuable cyclopentannulation
methodology based on α-oxygen substitutedpentadienyl cation
precursors.5

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5. Tius, M. A. Acc. Chem. Res. 2003, 36, 284-290.


Review points for the paper

Alternative interpretations
• The point is not discussed
 Why are substrates with α-oxygen substitution so reactive?3

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 The electron-donating substituent is thought to increase electron
density on the terminal carbon of the pentadienyl cation

 It lowers the activation barrier to cyclization

 After cyclization, the heteroatom is able to stabilize the oxyallyl


cation intermediate.

 Finally, the heteroatom effectively localizes the positive charge at


one α-carbon, which leads to highly regioselective elimination.
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3.Frontier, A. J.; Collison, C. “The Nazarov cyclization in organic synthesis. Recent advances,” Tetrahedron,
2005, 61, 7577–7606.
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Thank you…

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