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This is an Accepted Manuscript, which has been through the Royal Society of Chemistry peer review process and has been accepted for publication. Accepted Manuscripts are published online shortly after acceptance, before technical editing, formatting and proof reading. Using this free service, authors can make their results available to the community, in citable form, before we publish the edited article. We will replace this Accepted Manuscript with the edited and formatted Advance Article as soon as it is available. You can find more information about Accepted Manuscripts in the Information for Authors. Please note that technical editing may introduce minor changes to the text and/or graphics, which may alter content. The journal’s standard Terms & Conditions and the Ethical guidelines still apply. In no event shall the Royal Society of Chemistry be held responsible for any errors or omissions in this Accepted Manuscript or any consequences arising from the use of any information it contains.
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Organic & Biomolecular Chemistry View Article Online
DOI: 10.1039/C4OB02365J
Journal Name
Published on 25 November 2014. Downloaded by University of Texas Libraries on 26/11/2014 08:59:13.
ARTICLE
Cite this: DOI: 10.1039/x0xx00000x
Domino Reaction Involving the Bestmann-Ohira Reagent and α,β-Unsaturated Aldehydes: Efficient α,β Synthesis of Functionalized Pyrazoles† Shakir Ahamad,ab Ashis Kumar Gupta,ab Ruchir Kantc and Kishor Mohanan*ab
Received 00th January 2012, Accepted 00th January 2012 DOI: 10.1039/x0xx00000x www.rsc.org/
A mild, efficient and rapid domino reaction involving the Bestmann-Ohira reagent (BOR) and α,βunsaturated aldehydes has been developed for the synthesis of densely functionalized vinylpyrazoles. This reaction demonstrates the dual reactivity of BOR as a homologation reagent as well as a cycloaddition partner, thus constituting a domino reaction in an operationally simple procedure. The application of this efficient synthesis of pyrazoles has been demonstrated for the synthesis of phosphonyl analogue of pyrrolopyrazole alkaloids.
Introduction The Bestmann-Ohira reagent, (BOR, dialkyl α-diazo-β oxopropylphosphonate) is a well-known reagent for the homologation of aldehydes to terminal alkynes under mild conditions (Scheme 1, eq 1).1,2 This bench-stable and readily accessible reagent, is a valuable modification of SeyferthGilbert reagent,3 providing an efficient and convenient alternate route to the classical Corey-Fuchs reaction4 for the synthesis of terminal alkynes (which are key intermediates for numerous synthetic transformations). This strategy is particularly useful for the homologation reactions of delicate substrates. In an attempt to synthesize the enynes by the reaction of BOR 2 with α,β-unsaturated aldehyde 1, Bestmann and co-workers reported the facile synthesis of homopropargylic methyl ether when the reaction was carried out in methanol under basic conditions (eq 2).2 This reaction proceeds via the initial conjugate addition of methanol to 1 followed by the reaction of aldehyde moiety with 2 to install the alkyne. In the context of our efforts in exploring the synthetic potential of BOR for the synthesis of valuable nitrogen heterocycles, we envisioned that BOR 2 can react with both the C-C double bond as well as the CHO moieties in 1 in a domino process if the reagent 2 is used in excess. If successful, the reaction proceeds through a cascade cycloaddition/homologation sequence resulting in the formation of pyrazole derivatives. Herein, we report a domino process involving the reaction of α,β-unsaturated aldehyde with excess BOR leading to the efficient synthesis of vinyl pyrazole derivatives in moderate to excellent yields (eq 3). It is noteworthy that the reaction proceeds under mild conditions, and completes in just six minutes, to afford functionalized pyrazoles. It is important to note in this context that the synthesis of pyrazoles has received considerable attention over the past decade due to the discovery of numerous interesting biologically relevant properties exhibited by them. Pyrazoles are ubiquitous in various pharmaceutically and agriculturally relevant molecules.5,6
This journal is © The Royal Society of Chemistry 2013
Aldehyde homologation using BOR O
O
O R
P
+
H
OMe
base
OMe
N2
Attempted reaction of BOR with O
R
O
O P
+
-unsaturated aldehydes
OMe
base
OMe
solvent
N2
2 (1.2 equiv)
1 Reaction of
O O
O P
+ N2
1
OMe
(2)
R
Ref. 2
-unsaturated aldehydes with excess BOR
H R
(1)
Ref. 1
2
H
R
solvent
O OMe
base
P
R
OMe
solvent (this work)
2 (2.5 equiv)
OMe OMe
(3)
N N H
3
Scheme 1. Reaction of Aldehydes with BOR
For example, Celecoxib, Lonazolac and Doramapimod are pharmaceutical compounds bearing pyrazole scaffold (Figure 1). Apart from this, they also found significant place as ligands in transition metal-catalyzed reactions.7 The two conventional approaches for the synthesis of pyrazoles are the condensation reaction of 1,3-dicarbonyl compounds with hydrazines for the formation of two C-N bonds and 1,3-dipolar cycloaddition reactions of diazocompounds with various activated alkenes.8,9 However, despite the development of several strategies for the synthesis of functionalized pyrazoles, the control over regioselectivity still remains as a challenge. For these reasons, the development of new methods for the efficient regioselective
J. Name., 2013, 00, 1-3 | 1
Organic & Biomolecular Chemistry Accepted Manuscript
RSCPublishing
Organic & Biomolecular Chemistry
Journal Name DOI: 10.1039/C4OB02365J
construction of functionalized pyrazoles has always been a major area of research. OH t-Bu
F3C
O N
N
N
N Me
N
Cl HN
N Me
O HN O
N
SO2NH2 O
Celecoxib Anti-inflammatory drug
Lonazolac Anti-inflammatory drug
Doramapimod p-38 MAP kinase inhibitor
Figure 1. Examples of biologically active molecules containing pyrazole scaffold
The Bestmann-Ohira reagent was proven to be a versatile reagent for the synthesis of phosphonylpyrazoles, isosteric, biologically active analogues of carboxylates,10 via dipolar cycloaddition reactions with electron deficient alkenes such as dicyanoalkyl/arylidenes, nitroalkenes and vinyl sulfones.11,12 For instance, base mediated reactions of BOR with various nitrostyrenes have been reported by Namboothiri and co-workers to yield the corresponding phosphonylpyrazoles in good yield.13 Densely functionalized phosphonylpyrazoles were obtained through a domino three-component reaction involving aldehydes, cyanoacid derivatives and BOR.14 More recently, Namboothiri and co-workers uncovered an attractive one-pot, two-step strategy for the synthesis of phosphonylpyrazoles from aldehydes via a sequential HWE homologation/Cu(I) catalyzed dipolar cycloaddition reaction.15
K2CO3 in methanol. To our delight, the reaction proceeded smoothly to furnish 5-vinylpyrazole phosphonate 3a in 51% yield in just 6 min. Notably, under this condition, the homopropargylic methyl ether was not observed (eq 2). A systematic optimization study was carried out using various organic and inorganic bases in protic solvents (Table 1). Inorganic bases such as NaOMe, Kt-OBu, and KOH afforded the product in good yields (entries 1-4) where as weak organic bases like triethylamine failed to afford the product even after 24 h (entry 6). Notably, the reaction in the presence of DBU afforded the product in 63% yield. When the reaction was performed in the presence of NaOH, the product was obtained in a similar yield, but in a longer reaction time of 30 min (entry 7). Moreover, solvents other than methanol/ethanol did not affect the expected cascade process even after 24 h. Further screening revealed that KOH/methanol is the best condition for the present reaction. Having the optimized reaction conditions in hand, we next evaluated the scope of employing BOR in domino process for the synthesis of vinylpyrazoles (Table 2). The reaction course was found to be independent of the substituent pattern on aldehyde moiety and interestingly, the reaction showed broad tolerance to electrondonating and electron-withdrawing substituents on the aromatic ring. Table 2. Scope of the synthesis of vinylpyrazolesa
Results and discussion The initial evaluation of the present domino process was carried out by treating trans-cinnamaldehyde 1a with the BOR 2 and Table 1. Optimization of the reaction conditionsa
entry
base
solvent
time
1
yield of 3a (%)b 51
NaOMe
MeOH
6 min
2
KOH
MeOH
6 min
3
K2CO3
MeOH
6 min
51
4
Kt-OBu
MeOH
6 min
44
5
DBU
MeOH
30 min
63
6
Et3N
MeOH
24 h
Organic & Biomolecular Chemistry
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Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: S. Ahamad, A. K. Gupta, R. Kant and K. Mohanan, Org. Biomol. Chem., 2014, DOI: 10.1039/C4OB02365J.
This is an Accepted Manuscript, which has been through the Royal Society of Chemistry peer review process and has been accepted for publication. Accepted Manuscripts are published online shortly after acceptance, before technical editing, formatting and proof reading. Using this free service, authors can make their results available to the community, in citable form, before we publish the edited article. We will replace this Accepted Manuscript with the edited and formatted Advance Article as soon as it is available. You can find more information about Accepted Manuscripts in the Information for Authors. Please note that technical editing may introduce minor changes to the text and/or graphics, which may alter content. The journal’s standard Terms & Conditions and the Ethical guidelines still apply. In no event shall the Royal Society of Chemistry be held responsible for any errors or omissions in this Accepted Manuscript or any consequences arising from the use of any information it contains.
www.rsc.org/obc
Page 1 of 8
Organic & Biomolecular Chemistry View Article Online
DOI: 10.1039/C4OB02365J
Journal Name
Published on 25 November 2014. Downloaded by University of Texas Libraries on 26/11/2014 08:59:13.
ARTICLE
Cite this: DOI: 10.1039/x0xx00000x
Domino Reaction Involving the Bestmann-Ohira Reagent and α,β-Unsaturated Aldehydes: Efficient α,β Synthesis of Functionalized Pyrazoles† Shakir Ahamad,ab Ashis Kumar Gupta,ab Ruchir Kantc and Kishor Mohanan*ab
Received 00th January 2012, Accepted 00th January 2012 DOI: 10.1039/x0xx00000x www.rsc.org/
A mild, efficient and rapid domino reaction involving the Bestmann-Ohira reagent (BOR) and α,βunsaturated aldehydes has been developed for the synthesis of densely functionalized vinylpyrazoles. This reaction demonstrates the dual reactivity of BOR as a homologation reagent as well as a cycloaddition partner, thus constituting a domino reaction in an operationally simple procedure. The application of this efficient synthesis of pyrazoles has been demonstrated for the synthesis of phosphonyl analogue of pyrrolopyrazole alkaloids.
Introduction The Bestmann-Ohira reagent, (BOR, dialkyl α-diazo-β oxopropylphosphonate) is a well-known reagent for the homologation of aldehydes to terminal alkynes under mild conditions (Scheme 1, eq 1).1,2 This bench-stable and readily accessible reagent, is a valuable modification of SeyferthGilbert reagent,3 providing an efficient and convenient alternate route to the classical Corey-Fuchs reaction4 for the synthesis of terminal alkynes (which are key intermediates for numerous synthetic transformations). This strategy is particularly useful for the homologation reactions of delicate substrates. In an attempt to synthesize the enynes by the reaction of BOR 2 with α,β-unsaturated aldehyde 1, Bestmann and co-workers reported the facile synthesis of homopropargylic methyl ether when the reaction was carried out in methanol under basic conditions (eq 2).2 This reaction proceeds via the initial conjugate addition of methanol to 1 followed by the reaction of aldehyde moiety with 2 to install the alkyne. In the context of our efforts in exploring the synthetic potential of BOR for the synthesis of valuable nitrogen heterocycles, we envisioned that BOR 2 can react with both the C-C double bond as well as the CHO moieties in 1 in a domino process if the reagent 2 is used in excess. If successful, the reaction proceeds through a cascade cycloaddition/homologation sequence resulting in the formation of pyrazole derivatives. Herein, we report a domino process involving the reaction of α,β-unsaturated aldehyde with excess BOR leading to the efficient synthesis of vinyl pyrazole derivatives in moderate to excellent yields (eq 3). It is noteworthy that the reaction proceeds under mild conditions, and completes in just six minutes, to afford functionalized pyrazoles. It is important to note in this context that the synthesis of pyrazoles has received considerable attention over the past decade due to the discovery of numerous interesting biologically relevant properties exhibited by them. Pyrazoles are ubiquitous in various pharmaceutically and agriculturally relevant molecules.5,6
This journal is © The Royal Society of Chemistry 2013
Aldehyde homologation using BOR O
O
O R
P
+
H
OMe
base
OMe
N2
Attempted reaction of BOR with O
R
O
O P
+
-unsaturated aldehydes
OMe
base
OMe
solvent
N2
2 (1.2 equiv)
1 Reaction of
O O
O P
+ N2
1
OMe
(2)
R
Ref. 2
-unsaturated aldehydes with excess BOR
H R
(1)
Ref. 1
2
H
R
solvent
O OMe
base
P
R
OMe
solvent (this work)
2 (2.5 equiv)
OMe OMe
(3)
N N H
3
Scheme 1. Reaction of Aldehydes with BOR
For example, Celecoxib, Lonazolac and Doramapimod are pharmaceutical compounds bearing pyrazole scaffold (Figure 1). Apart from this, they also found significant place as ligands in transition metal-catalyzed reactions.7 The two conventional approaches for the synthesis of pyrazoles are the condensation reaction of 1,3-dicarbonyl compounds with hydrazines for the formation of two C-N bonds and 1,3-dipolar cycloaddition reactions of diazocompounds with various activated alkenes.8,9 However, despite the development of several strategies for the synthesis of functionalized pyrazoles, the control over regioselectivity still remains as a challenge. For these reasons, the development of new methods for the efficient regioselective
J. Name., 2013, 00, 1-3 | 1
Organic & Biomolecular Chemistry Accepted Manuscript
RSCPublishing
Organic & Biomolecular Chemistry
Journal Name DOI: 10.1039/C4OB02365J
construction of functionalized pyrazoles has always been a major area of research. OH t-Bu
F3C
O N
N
N
N Me
N
Cl HN
N Me
O HN O
N
SO2NH2 O
Celecoxib Anti-inflammatory drug
Lonazolac Anti-inflammatory drug
Doramapimod p-38 MAP kinase inhibitor
Figure 1. Examples of biologically active molecules containing pyrazole scaffold
The Bestmann-Ohira reagent was proven to be a versatile reagent for the synthesis of phosphonylpyrazoles, isosteric, biologically active analogues of carboxylates,10 via dipolar cycloaddition reactions with electron deficient alkenes such as dicyanoalkyl/arylidenes, nitroalkenes and vinyl sulfones.11,12 For instance, base mediated reactions of BOR with various nitrostyrenes have been reported by Namboothiri and co-workers to yield the corresponding phosphonylpyrazoles in good yield.13 Densely functionalized phosphonylpyrazoles were obtained through a domino three-component reaction involving aldehydes, cyanoacid derivatives and BOR.14 More recently, Namboothiri and co-workers uncovered an attractive one-pot, two-step strategy for the synthesis of phosphonylpyrazoles from aldehydes via a sequential HWE homologation/Cu(I) catalyzed dipolar cycloaddition reaction.15
K2CO3 in methanol. To our delight, the reaction proceeded smoothly to furnish 5-vinylpyrazole phosphonate 3a in 51% yield in just 6 min. Notably, under this condition, the homopropargylic methyl ether was not observed (eq 2). A systematic optimization study was carried out using various organic and inorganic bases in protic solvents (Table 1). Inorganic bases such as NaOMe, Kt-OBu, and KOH afforded the product in good yields (entries 1-4) where as weak organic bases like triethylamine failed to afford the product even after 24 h (entry 6). Notably, the reaction in the presence of DBU afforded the product in 63% yield. When the reaction was performed in the presence of NaOH, the product was obtained in a similar yield, but in a longer reaction time of 30 min (entry 7). Moreover, solvents other than methanol/ethanol did not affect the expected cascade process even after 24 h. Further screening revealed that KOH/methanol is the best condition for the present reaction. Having the optimized reaction conditions in hand, we next evaluated the scope of employing BOR in domino process for the synthesis of vinylpyrazoles (Table 2). The reaction course was found to be independent of the substituent pattern on aldehyde moiety and interestingly, the reaction showed broad tolerance to electrondonating and electron-withdrawing substituents on the aromatic ring. Table 2. Scope of the synthesis of vinylpyrazolesa
Results and discussion The initial evaluation of the present domino process was carried out by treating trans-cinnamaldehyde 1a with the BOR 2 and Table 1. Optimization of the reaction conditionsa
entry
base
solvent
time
1
yield of 3a (%)b 51
NaOMe
MeOH
6 min
2
KOH
MeOH
6 min
3
K2CO3
MeOH
6 min
51
4
Kt-OBu
MeOH
6 min
44
5
DBU
MeOH
30 min
63
6
Et3N
MeOH
24 h
