Silver(I)-catalyzed addition of zirconocenes to epoxy esters: A new entry to 1,4-dicarbonyl compounds and pyridazinones

Article abstract of DOI:10.1021/ol990924v

(matrix presented) The Ag(I)-catalyzed tandem epoxy ester rearrangement-dioxycarbenium ion addition reaction with alkenyl zirconocenes provides 1,4-keto esters that can be further converted to substituted pyridazinones. The use of a fluorous tag in a cyclization-assisted cleavage strategy demonstrates the feasibility of extending this methodology to high-throughput organic synthesis.

Full text of DOI:10.1021/ol990924v

ORGANIC
LETTERS
1999
Vol. 1, No. 8
1253-1255
Silver(I)-Catalyzed Addition of
Zirconocenes to Epoxy Esters: A New
Entry to 1,4-Dicarbonyl Compounds and
Pyridazinones
Peter Wipf* and Joey-Lee Methot
Department of Chemistry, UniVersity of Pittsburgh, Pittsburgh, PennsylVania 15260
pwipf+@pitt.edu
Received August 9, 1999
ABSTRACT
The Ag(I)-catalyzed tandem epoxy ester rearrangement−dioxycarbenium ion addition reaction with alkenyl zirconocenes provides 1,4-keto
esters that can be further converted to substituted pyridazinones. The use of a fluorous tag in a cyclization-assisted cleavage strategy
demonstrates the feasibility of extending this methodology to high-throughput organic synthesis.
Though not commonly found in nature, pyridazinones have
been used as scaffolds in the pharmaceutical industry for a
wide range of SAR studies.1 For example, azelastine (1) is
an antihistamine while zardaverine (2) exhibits PDE III and
PDE IV inhibitory activity (Figure 1). SR-46559 (3) is a
congestive heart failure, antidepressants, R1/R2 antagonists,
potassium channel activators, antiasthmatics, and others.1,2
As part of our program in organozirconocene chemistry,3
we now report a versatile new protocol for the synthesis of
1,4-dicarbonyl compounds and highly substituted pyridazi-
nones from fumarate-derived epoxy esters.
Our general approach is outlined in Scheme 1. Epoxy ester
4 is readily available from monoethyl fumarate by DCC
coupling to â-methallyl alcohol followed by m-CPBA
oxidation (90% overall yield). The epoxide is converted in
a single step to divinyl acetal 5 via a cationic alkenyl
(1) Coates, W. J. In ComprehensiVe Heterocyclic Chemistry; Katritzky,
A. R., Rees, C. W., Scriven, E. F. V., Eds.; Elsevier: Exeter, U.K., 1996;
Vol. 6, pp 1-91.
(2) See, for example: (a) Tisler, M.; Stanovnik, B. AdV. Heterocycl.
Chem. 1990, 49, 385. (b) Kuroda, S.; Akahane, A.; Itani, H.; Nishimura,
S.; Durkin, K.; Kinoshita, T.; Tenda, Y.; Sakane, K. Bioorg. Med. Chem.
Lett. 1999, 9, 1979.
Figure 1. Therapeutically relevant pyridazinones.
(3) (a) Wipf, P.; Xu, W.; Takahashi, H.; Jahn, H.; Coish, P. D. G. Pure
Appl. Chem. 1997, 69, 639. (b) Wipf, P.; Takahashi, H.; Zhuang, N. Pure
Appl. Chem. 1998, 70, 1077. (c) Wipf, P.; Tsuchimoto, T.; Takahashi, H.
Pure Appl. Chem. 1999, 71, 415.
(4) (a) Wipf, P.; Xu, W. J. Org. Chem. 1993, 58, 825. (b) Wipf, P.; Xu,
W. J. Org. Chem. 1993, 58, 5880. (c) Wipf, P.; Xu, W.; Kim, H.; Takahashi,
H. Tetrahedron 1997, 53, 16575. (d) Jordan, R. F. AdV. Organomet. Chem.
1991, 32, 325. (e) Suzuki, K. Pure Appl. Chem. 1994, 66, 1557.
selective muscarinic M1 receptor agonist of potential use in
treating Alzheimer’s disease. The significant commercial
interest in the pharmaceutical uses of pyridazinones is further
illustrated by the large number of patents filed in this area
that cover positive inotropic agents for the treatment of
10.1021/ol990924v CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/23/1999

obtained in 73% yield from 1-hexyne. Benzyl ether- and
pivaloate ester-functionalized alkynes gave 5b and 5d in 69%
and 66% yields, respectively. Benzyl ether-protected 2-meth-
yl-3-butyn-1-ol gave the desired acetal 5c in 31% yield with
42% of recovered starting material.
Scheme 1
The mechanism of the key zirconocene reaction is likely
to involve coordination of the cationic species to epoxy ester
II, and by anchimeric assistance, the epoxide opens to give
intermediate III (Figure 2).4a The observed generally >95%
zirconocene mediated epoxide rearrangement-addition reac-
tion.4 This mild room-temperature tandem process is quite
functional group compatible and provides acetals with high
diastereocontrol. Upon acidic hydrolysis, this reaction pro-
vides a direct route to R,â-unsaturated ketones from the
corresponding alkyne and epoxy ester.
Figure 2. Proposed mechanism of tandem epoxide opening-
rearrangement-addition reaction with cationic zirconocenes.
Divinyl acetals 5 were further elaborated to enones 6a-g
by a sequence of conjugate addition, enolate alkylation, and
hydrolysis steps. A second cuprate addition provided δ-keto
esters 7a-g. Cyclization with hydrazines and oxidation
completed the pyridazinone synthesis (Table 1).5
Our original cationic zirconocene protocol4a-c was modi-
fied to include 5 mol % of triphenyl phosphite as an additive
as well as adsorption of AgClO4 onto Celite to ensure a high
level of reproducibility in the epoxy ester addition step.
Typically, a solution of the alkyne in CH2Cl2 (0.3 M) was
treated with a slight excess of zirconocene hydrochloride6
and stirred for 20 min. At 0 °C, 5 mol % of P(OPh)3, the
epoxy ester 4, and 5 mol % of AgClO4/Celite7 were added
sequentially and the mixture was stirred at room temperature
overnight. Under these conditions, divinyl acetal 5a was
diastereoselectivity of acetal formation suggests an intramo-
lecular alkoxide-directed mode of attack onto the cyclic
dioxycarbenium ion. The chain reaction continues with
chloride ion abstraction, thus providing new cationic zir-
conocene I and releasing acetal V. The triphenyl phosphite
likely serves to stabilize the cationic metal species, allowing
for longer reaction times and greater catalytic turnover.
Preadsorption of AgClO4 onto Celite provides a uniform,
easy to handle source of Ag(I).
Conjugate addition to divinyl acetals 5 proceeded smoothly
with lower-order cuprates (5 equiv) in the presence of
TMSCl8 in THF upon warming from -78 to -30 °C. Little
diastereoselectivity was observed in this step. TsOH-medi-
ated hydrolysis of the acetal in refluxing acetone/water led
to enones 6a-c,e,f. The two-step yields ranged from 82 to
Table 1. Conversion of Acetals 5a-d to Pyridazinones 8a-h (Overall Yields)
entry
acetal
R1
R2
R3
R4
R5
R6
yield, %
pyridazinone
1
2
3
4
5
6
7
8
5a
5a
5a
5a
5b
5b
5c
5d
C4H9
C4H9
C4H9
C4H9
(CH2)3OBn
(CH2)3OBn
CH(Me)OBn
(CH2)2OPiv
Me
H
H
H
Me
H
Me
H
H
H
H
H
H
H
Me
H
86
53
68
44
56
64
60
41
8a
8b
8c
8d
8e
8f
C4H9
CH2CH2Ph
Me
Me
Me
C4H9
CH2CH2Ph
C4H9
Ph
Ph
C4H9
Me
CH2OBn
H
H
H
H
Bn
Ph
H
C4H9
C6H13
8g
8h
Me
Me
1254
Org. Lett., Vol. 1, No. 8, 1999

97%. Diphenethyl cuprate was prepared from excess phen-
ethyl iodide and tert-butyllithium,9 followed by cannulation
at -78 °C to CuBr‚SMe2.
Our new route to pyridazinones was highly suitable for
the first demonstration of a fluorous version of cyclization-
assisted ester cleavage.13 Fumarate 10 was readily obtained
in 83% yield by DCC coupling of acid 914 with 1H,1H,2H,2H-
perfluorooctanol and epoxidation with m-CPBA (Scheme 2).
For the introduction of an R3 substituent after the first
cuprate addition, the primary alcohol was protected as a TBS
ether. Ester deprotonation (LDA) and alkylation (R3-X) at
-78 °C followed by acidic hydrolysis gave enones 6d (R3
) CH2OBn) and 6g (R3 ) Me) in 68% and 56% overall
yields, respectively.
Scheme 2
The lower-order cuprate addition to enones 6a-g pro-
ceeded uneventfully at -78 °C to provide 1,4-dicarbonyl
compounds 7a and 7c-g in yields ranging from 90% to 99%.
Trapping of the intermediate enolate with excess MeI gave
7b in 79% yield upon warming to room temperature.
Diphenyl cuprate addition was assisted with TMS-Cl, and
the resulting silyl enol ether was cleaved with TBAF/H2O
to give 7e.
Cyclocondensation of keto esters 7 with hydrazines and
acetic acid (20 equiv of each) in EtOH was complete after
stirring overnight or heating at reflux for several hours.
Sterically hindered ketones (7b) required 2 d at reflux. The
use of substituted hydrazines did not significantly retard the
rate of cyclization. Oxidation of the dihydropyridazinones
10
to 8a-h was best achieved with 2.0 equiv of CuCl2 in
refluxing MeCN for 30-90 min. Yields for the two-step
process ranged from 64 to 92%.
Recent interest in the rapid synthesis of heterocyclic
scaffolds has led to an explosive development in solid-phase
techniques that facilitate purification.11 The use of fluorous
tags and liquid/liquid extraction schemes is an attractive
solution phase alternative to SPOS.12 This technique takes
advantage of the affinity of partially fluorinated compounds
toward highly fluorinated solvents during liquid-liquid
extractions, while nonfluorinated reagents and byproducts
remain in the organic phase. Advantages of fluorous tags
include minimal reoptimization requirements, reaction moni-
toring by TLC, and intermediate characterization by standard
methods.
Diester 10 is soluble in most common organic solvents, yet
extracts into excess FC-7215 from MeOH/H2O (2:1). The
cationic zirconocene reaction with 1-hexyne provided 11 in
46% yield. At this stage, unreacted epoxide was removed
chromatographically.
Conjugate addition with Me2CuLi and acid hydrolysis
proceeded well on substrate 11. At each step the product
was extracted into FC-72 from MeOH/H2O. The crude keto
ester 12 was cyclized with NH2NH2/AcOH, and the fluorous
alcohol tag was removed by an FC-72/MeCN extraction
providing dihydropyridazinone 13 in 66% yield from 11. GC-
MS analysis indicated >98% purity. Oxidation of this
material provided pyridazinone 8a.
(5) All new compounds were fully characterized by 300 or 500 MHz
1H NMR, 75 or 125 MHz 13C NMR, IR, MS, and HR-MS. Copies of NMR
spectra are included in the Supporting Information.
In conclusion, the Ag(I)-catalyzed cascade reaction of
alkenyl zirconocenes with epoxy esters was extended toward
an efficient synthesis of highly branched 1,4-dicarbonyl
compounds 7 and pyridazinones 8. Introduction of a chemi-
cally inert fluorous tag facilitates purification of intermediates
and illustrates the first application of a fluorous cyclization-
assisted cleavage strategy.
(6) (a) Buchwald, S. L.; La Maire, S. J.; Nielson, R. B.; Watson, B. T.;
King, S. M. Tetrahedron Lett. 1987, 28, 3895. (b) Wipf, P.; Jahn, H.
Tetrahedron 1996, 52, 12853.
(7) A total of 20 wt % of AgClO4 adsorbed onto Celite from an aqueous
solution and dried in vacuo.
(8) Corey, E. J.; Boaz, N. W. Tetrahedron Lett. 1985, 26, 6015.
(9) Bailey, W. F.; Punzalan, E. R. J. Org. Chem. 1990, 55, 5404.
(10) Csende, F.; Szabo, Z.; Bernath, G. Synthesis 1995, 1240.
(11) Nefzi, A.; Ostresh, J. M.; Houghton, R. A. Chem. ReV. 1997, 97,
449.
(12) (a) Studer, A.; Hadida, S.; Ferritto, R.; Kim, S.-Y.; Jeger, P.; Wipf,
P.; Curran, D. P. Science 1997, 275, 823. (b) Studer, A.; Jeger, P.; Wipf,
P.; Curran, D. P. J. Org. Chem. 1997, 62, 2917. (c) Wipf, P.; Reeves, J. T.
Tetrahedron Lett. 1999, 40, 4649. (d) Wipf, P.; Reeves, J. T. Tetrahedron
Lett. 1999, 40, 5139. (e) Ro¨ver, S.; Wipf, P. Tetrahedron Lett. 1999, 40,
5667.
(13) For a pioneering solid support version of this strategy, see: Camps,
F.; Cartells, J.; Pi, J. An. Quim. 1974, 70, 848. Review: Obrecht, D.;
Villalgordo, J. M. Solid-supported combinatorial and parallel synthesis of
small-molecular weight compound libraries; Pergamon: Oxford, 1998.
(14) Prepared in 56% yield by slow addition of NEt3 to a cold (-75 °C)
solution of fumaryl chloride and â-methallyl alcohol, followed by hydrolysis.
(15) FC-72 is a commercially available (3M; $389/gallon) fluorocarbon
solvent consisting of C6F14 isomers (bp 56 °C). It is immiscible with most
common organic solvents.
Acknowledgment. We are grateful for support for this
project from Boehringer-Ingelheim and the National Science
Foundation. J.M. thanks the F.C.A.R. for a graduate fellow-
ship.
Supporting Information Available: Full experimental
1
procedures as well as H and 13C NMR spectra for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL990924V
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