A novel route to 2,3-pyrazol-1(5H)-ones via palladium-catalyzed carbonylation of 1,2-diaza-1,3-butadienes

Article abstract of DOI:10.1021/ol016565x

Figure presented A novel Pd(0)-catalyzed carbonylation of both isolable 1,2-diaza-1,3-butadienes and those generated in situ by extrusion of SO₂ and CO₂ from heterocyclic precursors is described. The reaction proceeds at room temperature to 110°C under 1-2 atm of CO to afford 2,3-pyrazol-1(5H)-ones in good to excellent yields. The effect of catalyst structure and stability on the carbonylation reaction is evaluated.

Full text of DOI:10.1021/ol016565x

ORGANIC
LETTERS
2001
Vol. 3, No. 23
3651-3653
A Novel Route to 2,3-Pyrazol-1(5H)-ones
via Palladium-Catalyzed Carbonylation
of 1,2-Diaza-1,3-butadienes
Robert K. Boeckman, Jr.,* Jessica E. Reed, and Ping Ge
Department of Chemistry, UniVersity of Rochester, Rochester, New York 14627-0216
rkb@rkbmac.chem.rochester.edu
Received August 11, 2001
ABSTRACT
A novel Pd(0)-catalyzed carbonylation of both isolable 1,2-diaza-1,3-butadienes and those generated in situ by extrusion of SO and CO from
2
2
heterocyclic precursors is described. The reaction proceeds at room temperature to 110 °C under 1−2 atm of CO to afford 2,3-pyrazol-1(5H)-
ones in good to excellent yields. The effect of catalyst structure and stability on the carbonylation reaction is evaluated.
There is considerable current interest in developing envi-
ronmentally benign methods for preparation of heterocyclic
systems. As a class, 2,3-pyrazol-1(5H)-ones 1 have found
considerable utility as photographic couplers, pharmaceutical
agents, and intermediates.1,2 Transition metal catalysis po-
tentially offers considerable advantages in terms of simplicity,
lower costs, avoidance of the use of toxic reagents such as
phosgene, and a reduction in the waste stream. Accordingly,
we sought to develop a novel method for preparation of 1
via metal-catalyzed cyclocarbonylation of 1,2-diaza-1,3-
butadienes 2.
Fe, Ni, and Ti.4 However, no direct literature precedent
existed for the cyclocarbonylation of vinyl azo species such
as 2 (Figure 1) except for the early work of Tsuji on the
Diazabutadienes 2 have been extensively investigated as
reactive intermediates (often unisolable) for the preparation
of heterocycles principally by nucleophilic addition.3 Cy-
clocarbonylation of 1,3-dienes to saturated and unsaturated
ketones is known to occur with a variety of metals, including
Figure 1.
Pd-catalyzed carbonylation of azobenzene and subsequent
studies of the cyclopalladated intermediates.5
Thus, we chose to begin our investigation by examination
of the palladium-catalyzed carbonylation of the stable, well-
characterized monomeric diazabutadiene 3.6
Treatment of a bright red solution of 3 in toluene with
1-10 mol % of Pd(0) catalyst under an atmosphere of CO
(1) (a) Whitaker, A. J. Soc. Dyers Colour. 1995, 111, 66-72. (b)
Furutachi, N. Nippon Shashin Gakkaishi 1992, 55, 192-8.
(2) Brune, K., Ed. Agents and Actions Supplements, Vol. 19: 100 Years
of Pyrazolone Drugs. An Update; Birkhaeuser Verlag: Basil, Switzerland,
1986; p 355.
(3) (a) Arcadi, A.; Attanasi, O. A.; De Crescentini, L.; Rossi, E.; Serra-
Zanetti, F. Synthesis 1996, 533-6. (b) Arcadi, A.; Attanasi, O. A.; Liao,
Z.; Serra-Zanetti, F. Synthesis 1994, 605-8. (c) Schantl, J. G.; Karpellus,
P.; Prean, M. Tetrahedron 1982, 38, 2643-52.
10.1021/ol016565x CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/17/2001

(1-2 atm) at room temperature or 100 °C for 0.15-30 h
resulted in the discharge of the red color to afford a colorless
to tan solution which ultimately deposited black metallic Pd
if heating was continued. Isolation and purification of the
organic product afforded generally excellent yields (78-
90%) of the desired 2,4,5-triphenyl-2,3-pyrazol-1(5H)-one
(4) (Table 1).
elimination of pyridine using triethylamine in the presence
of CO and Pd(PPh3)4, failed to afford any of the desired
pyrazolone. The only observed product arose from cyclo-
dimerization of the diazadiene intermediate as had been
previously documented.7
It was evident that the desired carbonylation could not
effectively compete with [4 + 2] cycloaddition if the
diazadiene was present in high concentration with respect
to the Pd(0) catalyst under conditions where the cyclo-
palladation/carbonylation was slow. Thus, we set out to
identify suitable stable precursors for diazadienes which
would afford the required intermediates by thermal decom-
position under conditions where cyclopalladation/carbonyl-
ation would be rapid. We have developed several such
precursors in the form of heterocycles 7-11, as described
in the preceding Letter (Figure 2).8
Table 1. Carbonylation of 3
catalyst
mol(%) CO (atm) temp (°C) time (h) yield (%)
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(dppe)2
Pd(PPh3)4
10
10
10
1
2
1
2
2
1
25
100
100
100
100
30
0.75
0.25
4
81
78
90
83
51a
10
0.67
a Reaction conducted in acetonitrile.
Although no intermediates were detected, by rough anal-
ogy to the cyclopalladation of azobenzene, we surmise that
the reaction takes the course shown in Scheme 1.5 However,
Figure 2.
This strategy proved successful although optimal condi-
tions (precursor, ligand/catalyst, CO pressure, temperature,
and time) must be developed for each substrate owing to
the need to match the decomposition rate of the precursor
to the rate of cyclopalladation/carbonylation. If the ligand
employed is too strongly coordinating at ∼110 °C, a
temperature at which the carbonylation generally proceeds
efficiently, the diazadiene undergoes dimerization. If the
ligand is too weakly bound, the catalyst aggregates and
precipitates from solution, prematurely terminating the
catalytic cycle.
Scheme 1
As shown in Table 2, we began with the triphenyl
derivatives 7a-9a since we knew the diazadiene 3 produced
upon decomposition of these substrates would (1) not
undergo dimerization, (2) undergo carbonylation to 4, and
(3) be stable enough to persist in solution.
(4) (a) Franck-Neumann, M.; Vernier, J. M. Tetrahedron Lett. 1992, 33,
7365-8. (b) Franck-Neumann, M.; Michelotti, E. L.; Simler, R.; Vernier,
J. M. Tetrahedron Lett. 1992, 33, 7361-4. (c) Hicks, F. A.; Kablaoui, N.
M.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118, 9450-1. (d) Llebaria,
A.; Camps, F.; Moreto, J. M. Tetrahedron 1993, 49, 125. (e) Thompson, J.
M.; Heck, R. F. J. Org. Chem. 1975, 40, 2667-74.
(5) (a) Takahashi, H.; Tsuji, J. J. Organomet. Chem. 1967, 10, 511-17.
(b) Bruce, M. I.; Goodall, B. L.; Stone, F. G. A. J. Chem. Soc., Chem.
Commun. 1973, 558-9. (c) Ghedini, M.; Pucci, D.; Crispini, A.; Aiello, I.;
Barigelletti, F.; Gessi, A.; Francescangell, O. Appl. Organomet. Chem. 1999,
13, 565-81.
(6) Schantl, J.; Karpellus, P. Monatsh. Chem. 1978, 109, 1081-92.
(7) Schantl, J. Monatsh. Chem. 1974, 105, 322-6.
(8) Boeckman, R. K., Jr.; Ge, P.; Reed J. E. Org. Lett. 2001, 3, 3647-3650.
it is possible that CO enters the ligand sphere of Pd prior to
σ f π isomerization and migratory insertion of CO precedes
cyclopalladation.
Having verified that the overall transformation is feasible,
we attempted to utilize less stable 1,2-diazabutadienes.
Attempts to intercept 1,3-diphenyl-1,2-diazabutadiene 5, by
in situ generation of 5 from the pyridinium salt 67 by
3652
Org. Lett., Vol. 3, No. 23, 2001

our laboratory had established that substitution of sulfur for
one or more of the oxygen atoms of oxadiazinone 8 had the
beneficial effect of lowering the temperature at which de-
composition to the diazadiene occurred.8 The oxadiazine-
thiones 9 proved optimal, undergoing decomposition at ∼50
°C lower than the corresponding oxadiazinone. Treatment
of 9a with CO in the presence of Pd(dppe)2 (5 mol %) at
110 °C for 12 h afforded pyrazolone 4 after purification in
81% yield.
Table 2. In Situ Diene Generation and Carbonylation
We also examined whether heteroatoms were tolerated at
C5 since derivatives of this type can have particular utility.1
Oxadiazinone 8b was carbonylated at 110 °C using Pd(PPh3)4
(Table 2) and afforded the expected pyrazolone 12a in 62%
yield. When the related aryloxy derivative 8c was employed,
the yield of 12b diminished to 40%. On the basis of control
experiments, we attribute the lower yields in these cases to
decreased catalyst and product stability resulting from the
extended reaction time.
The thiadiazole dioxides 7 proved to be generally more
reactive substrates, undergoing thermal decomposition be-
tween 90 and 110 °C.8 Thus, 7a was carbonylated in CO-
saturated hot toluene solution (110 °C) in the presence of
Pd(PPh3)4 generated in situ from Pd(OAc)2 and 4 equiv of
PPh3. This procedure afforded pyrazolone 4 in 78% yield,
comparable to that obtained from the diene 3 under similar
conditions. Derivatives lacking a C5 substituent bearing both
C4 aryl and alkyl substituents were prepared using this
procedure. Similar treatment of 7b and 7c under the
conditions described above for the triphenyl derivative
afforded the expected pyrazolones 12c and 12d in 54% and
74% yields, respectively.
starting
material
LnPd(0)a
(mol %)
CO
temp (°C)
yieldb
(%)
(atm) time (h)
prdt
7a
Pd(PPh3)4 (10)
Pd(PPh3)4 (10)
Pd(PPh3)4 (10)
Pd(dppe)2 (5)
Pd(PPh3)4 (10)
Pd(PPh3)4 (10)
Pd(dppe)2 (5)
1
1
1
2
1
1
2
100
18
4
78
54
74
58
62
40
81
R1 ) Ph
R2 ) Ph
7b
100
18
12c
12d
4
R1 ) Ph
R2 ) H
7c
100
18
R1 ) CH3
R2 ) Ph
8a
135
24
R1 ) Ph
R2 ) Ph
8b
110
20
12a
12b
4
R1 ) Ph
R2 ) OPhpCl
8c
110
20
R1 ) Ph
R2 ) OPh
9a
Further work is necessary to establish the optimal ligands
and reaction conditions for efficient formation of pyrazolones
possessing wide structural diversity. However, clearly cata-
lytic cyclocarbonylation of thermally generated 1,2-diaza-
butadienes provides a new and potentially useful route to
2,3-pyrazol-1(5H)-ones.
110
12
R1 ) Ph
R2 ) Ph
a The catalyst was generated in situ by combination of the appropriate
stoichiometry of Pd2dba3 with the phosphine or reduction of Pd(OAc)2 by
phosphine. b Unoptimized.
Acknowledgment. We thank Mr. Piero Ruggerio for
performing some of the experiments and Dr. Wojcieck
Slusarek of Eastman Kodak for his assistance. The authors
also thank the Eastman Kodak Company and National
Institutes of Health (CA-29108 and GM-30345) for research
grants in support of these studies.
The oxadiazinone 8a was examined first. It was noted that
rapid decomposition with gas evolution was evident at ∼140
°C for 8a.8 Thus, 8a and Pd(dppe)2 (5 mol %) were heated
at 135 °C in toluene under CO (2 atm) for 24 h. Isolation
and purification of the products afforded the expected
pyrazolone 4 in 58% yield.
Our experience with this substrate suggested that the yield-
limiting feature of the reaction was the high decomposition
temperature of the oxadiazinone 8a which limited the catalyst
lifetime under the reaction conditions. Concurrent work in
Supporting Information Available: General experimen-
tal procedures and characterization data for 4, 12a, 12b, 12c,
and 12d. This information is available free of charge via
the Internet at http://pubs.acs.org.
OL016565X
Org. Lett., Vol. 3, No. 23, 2001
3653