Regioselective synthesis of N-aminoisoindolones and mono-N- and di-N,N′-substituted phthalazones utilizing hydrazine nucleophiles in a palladium-catalyzed three-component cascade process

Article abstract of DOI:10.1021/jo800822p

(Chemical Equation Presented) A palladium-catalyzed three-component cascade process for the synthesis of isoindolone and phthalazone derivatives is reported. The cascade process involves carbonylation of an aryl iodide/Michael acceptor to give an acylpalladium species which is intercepted by a hydrazine nucleophile. Intramolecular Michael addition follows to give either N-aminoisoindolones or mono-N- and di-N,N′-phthalazones depending on whether a monosubstituted or 1,2-disubstituted hydrazine nucleophile is used.

Full text of DOI:10.1021/jo800822p

Regioselective Synthesis of N-Aminoisoindolones and Mono-N- and
Di-N,N′-substituted Phthalazones Utilizing Hydrazine Nucleophiles
in a Palladium-Catalyzed Three-Component Cascade Process
Ronald Grigg,*,† Visuvanathar Sridharan,† Mufakhrul Shah,† Simon Mutton,† Colin Kilner,†
David MacPherson,‡ and Peter Milner‡
Molecular InnoVation DiVersity and Automated Synthesis (MIDAS) Centre, School of Chemistry,
UniVersity of Leeds, Leeds LS2 9JT, U.K., and GlaxoSmithKline, New Frontiers Science Park (North),
Third AVenue, Harlow, Essex CM19 5AW, U.K.
r.grigg@leeds.ac.uk
ReceiVed April 27, 2008
A palladium-catalyzed three-component cascade process for the synthesis of isoindolone and phthalazone
derivatives is reported. The cascade process involves carbonylation of an aryl iodide/Michael acceptor to
give an acylpalladium species which is intercepted by a hydrazine nucleophile. Intramolecular Michael
addition follows to give either N-aminoisoindolones or mono-N- and di-N,N′-phthalazones depending on
whether a monosubstituted or 1,2-disubstituted hydrazine nucleophile is used.
Introduction
isoindolones from easily accessible starting materials.2 Substi-
tuted isoindolones of general structure 1, which are known to
possess pharmacological activity,3 were synthesized using a
palladium-catalyzed three-component carbonylation/amination/
Michael addition cascade sequence (Scheme 1) from the cor-
responding aryl iodide/Michael acceptor 2, carbon monoxide
3, and primary amine 4 in 43-99% yield.2b
In an effort to further diversify this cascade process, we
evaluated the use of monosubstituted hydrazines 6 as cascade
nucleophiles. These could lead to the formation of N-ami-
noisoindolones 8 or phthalazones of general structure 9 (Scheme
2). Both isoindolone and the dihydro-4-substituted phthalaz-1-
one motifs 8 and 9 are of pharmacological interest with the
former appearing as a subunit in potential sedatives4 and the
latter appearing as a subunit in the diuretic BTS3954.5
Organic synthesis has classically involved the stepwise
formation of individual bonds in the construction of a target
molecule. However, it is substantially more efficient if several
bonds are formed in a single synthetic operation without the
need to isolate intermediates. Reactions that enable this are
known as cascade processes and work through a sequence of
discrete chemical transformations in which the preceding
reaction creates the functionality to trigger the subsequent
reaction, through a series of reactive intermediates, until the
final product is formed. Cascade reactions have long attracted
interest due to their many benefits including high atom economy,
labor and waste saving attributes and ability to rapidly access
structurally complex compounds from relatively simple starting
materials.1
Prior literature on the synthesis and applications of phthala-
zones is almost entirely concerned with 4-substituted phthalaz-
Our group has previously described two novel palladium-
catalyzed cascade processes for the synthesis of N-substituted
(2) (a) Grigg, R.; Zhang, L.; Collard, S.; Keep, A. Tetrahedron Lett. 2003,
44, 6979. (b) Gai, X.; Grigg, R.; Khamnaen, T.; Rajviroongit, S.; Sridharan, V.;
Zhang, L.; Collard, S.; Keep, A. Tetrahedron Lett. 2003, 44, 7441.
(3) (a) Takahashi, I.; Kawakami, T.; Hirano, E.; Yokota, H.; Kitajima, H.
Synlett 1996, 353. (b) Sobera, L. A.; Leeson, P. A.; Silvestre, J.; Castaner, J.
Drugs Future 2001, 26, 651. (c) Anzini, M.; Capelli, A.; Vomero, S.; Giorgi,
G.; Langer, T.; Bruni, G.; Rome, M. K.; Baile, A. S. J. Med. Chem. 1996, 39,
4275. (d) Limeres, R.; Garcia, R.; Bayod, M.; Blieva, R. Tetrahedron: Asymmetry
1997, 8, 995.
† University of Leeds.
‡ GlaxoSmithKline.
(1) (a) Nicolau, K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem., Int.
Ed. 2006, 45, 7134. (b) Dondas, H. A.; Fishwick, C. W. G.; Gai, X.; Grigg, R.;
Kilner, C.; Dumronchai, N.; Kongkathip, B.; Kongkathip, N.; Ploysuk, C.;
Sridharan, V. Angew. Chem., Int. Ed. 2005, 44, 7570. (c) Grigg, R.; Sridharan,
V. J. Organomet. Chem. 1999, 576, 65. (d) Tietze, L. F. Chem. ReV. 1996, 96,
115. (e) Parsons, P. J.; Penkett, C. S.; Shell, A. J. Chem. ReV. 1996, 96, 195. (f)
Grigg, R.; Inman, M.; Kilner, C.; Koppen, I.; Marchbank, J.; Selby, P. J.;
Sridharan, V. Tetrahedron 2007, 63, 6152.
(4) Toyoka, K.; Kanamitsu, N.; Yoshimra, M. Patent WO2004048332, 2004.
(5) Cooling, M. J.; Sim, M. F. Br. J. Pharmacol. 1981, 74, 359.
8352 J. Org. Chem. 2008, 73, 8352–8356
10.1021/jo800822p CCC: $40.75 2008 American Chemical Society
Published on Web 10/10/2008

RegioselectiVe Synthesis of N-Aminoisoindolones
SCHEME 1
FIGURE 1. Products and intermediates of previously reported ph-
thalazone syntheses.
SCHEME 2
FIGURE 2. Michael acceptors and hydrazines used in the syntheses
of N-aminoisoindolones 15a-j.
amidic N-atom to give isoindolone 8 via a 5-exo-trig ring closure
or the nonamidic N-atom to give phthalazone 9 via a 6-exo-
trig ring closure.
Results and Discussion
1-ones 10 (Figure 1). The majority of approaches involve
phthaloyl derivatives as precursors and proceed via isoindolone
intermediates.6 Pyridyl versions 10b and 10c have also been
reported.6f Katritzky has reported the 1,3-dipolar cycloaddition
of 1-oxido-3-phenylphthalazinium 11 with the dipolarophiles
diphenylacetylene and dimethyl acetylenedicarboxylate to afford
bridged ring phthalaz-1-ones 12.7 These latter adducts are at
the same oxidation level as the phthalaz-1-ones delivered by
the palladium chemistry described herein.
It was anticipated that formation of general motifs 8 and 9
via our cascade methodology would involve nucleophilic attack
on an intermediate acylpalladium species 5, produced by the
carbonylation of aryl iodide/Michael acceptor 2 in the presence
of carbon monoxide and Pd(0), by the primary nitrogen of
hydrazine 6 to give acylhydrazide 7 (Scheme 2). The terminating
Michael addition step of the cascade could then involve the
The competing terminating pathways were initially examined
by reacting dual aryl iodide/Michael acceptors 13a-c (Figure
2)8a (1.0 molar equiv) with 2,5-difluorophenylhydrazine 14a or
2,2,2-trifluoroethylhydrazine 14b (1.2 molar equiv), carbon
monoxide (1 atm), Pd(OAc)2 (0.03-0.05 molar equiv), PPh3
(0.06-0.10 molar equiv), and Cs2CO3 (2 molar equiv) in toluene
at 90 °C for 18 h. Analysis of the crude reaction mixtures by
NMR revealed that only a single ABX spin system had been
created. This suggested that a single cyclized product had been
formed. Subsequent NMR and X-ray analysis of the isolated
cyclized products revealed that N-aminoisoindolones 15 (Table
1) (see the Supporting Information for X-ray data for 15c, 15e,
and 15g) had been formed in preference to the phthalazone ring
system.
This exclusive formation was explained in terms of the 5-exo-
trig process being kinetically favored over the competing 6-exo-
trig process and occurred both with initial use of electron-
deficient hydrazines (Table 1, entries 1-6) and on subsequent
use of phenylhydrazine 14c (Table 1, entry 7). However, when
using hydrazine 14d, analysis of the crude reaction mixture by
NMR suggested that a 1:1 mixture of products 15h and 15i
had been formed (Table 1, entry 8). This was indicated by the
presence of two distinct ABX spin systems for each compound.
(6) (a) Peters, A. T.; Rowe, F. M.; Brodrick, C. I. J. Chem. Soc. 1948, 1249.
(b) Vaughan, W. R.; McCane, D. I.; Sloan, G. J. J. Am. Chem. Soc. 1951, 73,
2298. (c) Johnson, A. L. J. Org. Chem. 1976, 41, 836. (d) Ismail, M. F.; El-
Bassiouny, F. A.; Younes, H. A. Tetrahedron 1984, 40, 2983. (e) Fahmy, A. F.;
Sauer, J.; Youssef, M. S. K.; Halim, M. S. A.; Hasan, M. A. Synth. Commun.
1998, 28, 2871. (f) Saito, Y.; Sakamoto, T.; Kikugawa, Y. Synthesis 2001, 221.
(g) Chun, T. G.; Kim, K. S.; Lee, S.; Jeong, T. S.; Lee, H. Y.; Kim, Y. H.; Lee,
W. S. Synth. Commun. 2004, 34, 1301. (h) Cheng, L.; Ying, L.; Feng, J.; Wang,
C. Y.; Li, J. L.; Xu, Z. J. Polymer Sci. Part A 2007, 45, 1525. (i) Feldeak, S.;
Puodzyunas, A. S.; Daugirdene, D. A.; Puodzhyunene, I. P.; Kost, A. Khim.
Farm. Zh. 1969, 3, 5.
(8) (a) Grigg, R.; Gai, X.; Khamnaen, T.; Rajviroongit, S.; Sridharan, V.;
Zhang, L.; Collard, S.; Keep, A. Can. J. Chem. 2005, 83, 990. (b) Bull, S. D.;
Davies, S. G.; Smith, A. D. J. Chem. Soc., Perkin Trans. 1 2001, 22, 2931.
(7) Dennis, N.; Katritzky, A. R.; Ramaiah, M. J. Chem. Soc., Perkin Trans.
1 1976, 2281.
J. Org. Chem. Vol. 73, No. 21, 2008 8353

Grigg et al.
TABLE 1. Cascade Synthesis of N-Aminoisoindolones from the
Corresponding Aryl Iodide/Michael Acceptors and Primary
Hydrazinesa
versus formation of the phthalazone motif was dependent on
the nucleophilicity of the hydrazine used with more electron-
rich nucleophiles permitting six-membered ring formation as
well as five-membered ring formation.
Subsequent probing of the reaction mechanism also revealed
that a small amount (∼5% relative to unreacted Michael ac-
ceptor) of direct Michael adduct was formed when reacting
Michael acceptor 13a with phenylhydrazine 14c in the absence
of carbon monoxide under standard reaction conditions. This
suggested that the cascade proceeded primarily through the
amide intermediate 7 although direct Michael adduct formation
was thought to be more likely as the nucleophile became more
electron-rich.
Pursuing the 6-exo-trig mode of ring closure, it was antici-
pated that the phthalazone motif could be accessed by using
1,2-disubstituted hydrazines as cascade nucleophiles. Thus,
1-acetyl-2-phenylhydrazine 16a (1.2 molar equiv) was reacted
with aryl iodide/Michael acceptor 13a (1.0 molar equiv), carbon
monoxide (1 atm), Pd(OAc)2 (0.05 molar equiv), PPh3 (0.10
molar equiv), and Cs2CO3 (2.0 molar equiv) in acetonitrile (10
mL) at 85 °C for 20 h. Analysis of the crude reaction mixture
by NMR indicated the formation of a single ABX spin system.
This suggested that a single phthalazone product had been
formed regioselectively. Subsequently, phthalazone 18a (Table
2, entry 1) was isolated from the complex reaction mixture in
19% yield and the regiochemistry confirmed by X-ray crystal-
lography (see the Supporting Information). Evidently, the more
nucleophilic aniline hydrazine subunit had attacked the inter-
mediate acylpalladium species leaving the less nucleophilic
acetamide hydrazine subunit to take part in the Michael addition
step of the cascade to give the [6,6]-heterocyclic system.
In an effort to improve the efficiency of the reaction and to
simplify the synthetic procedure, reaction conditions employing
palladacycle 17 were then explored. Our group has previously
shown that palladacycle 17 is rapidly converted into catalytically
active and ligand-less palladium(0) nanoparticles under an
atmosphere of carbon monoxide.9 Thus, 1-acetyl-2-phenylhy-
drazine 16a (1.2 molar equiv) was reacted with aryl iodide/
Michael acceptor 13a (1.0 molar equiv), carbon monoxide (1
atm), palladacycle 17 (0.05 molar equiv), and Cs2CO3 (2.0 molar
equiv) in DMF (5 mL) at 100 °C. The reaction was found to
go to completion after 3 h and phthalazone 18a was isolated as
the sole cyclized product in 55% yield (Table 2, entry 1).
In subsequent exemplification, 1-acetyl-2-phenylhydrazine
13a (1.4 molar equiv) or 1,2-diethylhydrazine dihydrochloride
13b (1.3 molar equiv) was reacted with aryl iodide/Michael
acceptors 13a-e8 (1.0 molar equiv), carbon monoxide (1 atm),
palladacycle 17 (0.05 molar equiv), and Cs2CO3 (2.0 molar
equiv) in DMF to give the corresponding phthalazones 18b-h
in 43-77% yield (Table 2). Reducing the reaction temperature
from 100 to 60 °C avoided the formation of more complex
reaction mixtures for the syntheses of phthalazones 18c and 18e
(Table 2, entries 3 and 5). The regiochemistry of products
18b-e was assumed on the basis of the X-ray structure for 18a,
and this was supported by NOE data.
a Reaction conditions: aryl iodide (1.0 mmol), hydrazine (1.2 mmol),
CO (1 atm), Pd(OAc)2 (0.03-0.05 mmol), PPh3 (0.06-0.10 mmol),
Cs2CO3 (2.0 mmol), toluene (20 mL), 90 °C, 18 h. b Reaction time: 3 h.
c Cosolvent: acetonitrile (1 mL). d Reaction time: 6 h.
The reasons for the generally moderate yields obtained in
Tables 1 and 2 are unclear. Generally, no significant NMR
signals, apart from those belonging to the subsequently isolated
products, were observed in the crude reaction mixtures. The
exception to this was the use of Michael acceptor 13a with
Unfortunately, neither of these products could be isolated cleanly
by chromatography due to close-running impurities, although
the suggested regiochemistry of 15i was supported by mutual
coupling of the NH proton to the corresponding ABX spin
system. It was evident that formation of the isoindolone motif
(9) Grigg, R.; Zhang, L.; Collard, S.; Ellis, P.; Keep, A. J. Organomet. Chem.
2004, 689, 170.
8354 J. Org. Chem. Vol. 73, No. 21, 2008

RegioselectiVe Synthesis of N-Aminoisoindolones
TABLE 2. Cascade Synthesis of Di-N,N′-substituted Phthalazones
from the Corresponding Aryl Iodide/Michael Acceptors and
Disubstituted Hydrazinesa
SCHEME 3
FIGURE 3. Hydrazines and precatalyst used in the syntheses of
phthalazones 18a-h.
In seeking access to regioselective mono-N-substituted ph-
thalazones, we took advantage of a prior observation arising
from our synthesis of isoindolones where trifluoroacetamide was
shown to be an excellent cascade nucleophile with hydrolytic
cleavage of the trifluoroacyl moiety being achieved in situ.2b
Hence, hydrazine 16c (1.2 molar equiv) was reacted with
Michael acceptor 13a (1.0 molar equiv), carbon monoxide (1
atm), palladacycle 17 (0.025 molar equiv), and Cs2CO3 (2.0
molar equiv) in nondistilled dioxane at 100 °C for 16 h (Scheme
3). Analysis of the product by 1H NMR spectroscopy confirmed
ring formation had taken place as characterized by the formation
of a single ABX spin system while mass spectrometry and 13
C
NMR spectroscopy suggested that hydrolysis of the exocyclic
N-CO bond had occurred to give phthalazone 18j regioselec-
tively in 54% yield. On the basis of previous observations, it
was suggested that the reaction proceeded through amide in-
termediate 18i although it is unclear whether hydrolysis of the
exocyclic N-CO bonds occurs before or after the Michael
addition ring-closing step.
Conclusion
Both N-aminoisoindolone and phthalazone derivatives have
been synthesized in a three-component carbonylation/amination/
Michael addition cascade sequence using substituted hydrazines
as cascade nucleophiles. In general using monosubstituted hy-
drazines, 5-exo-trig ring closure was found to be kinetically
favored over the competing 6-exo-trig process and resulted in
[6,5]-heterocyclic products (isoindolones). However use of
isobutylhydrazine showed evidence of competitive 5-and 6-exo-
trig processes suggesting a link to the nucleophilicty of the
hydrazine. Use of 1,2-disubstituted hydrazines facilitated regi-
oselective 6-exo-trig ring closure and gave N,N′-disubstituted
phthalazones. Use of trifluoroacyl-substituted phenylhydrazine
provides access to mono-N-substituted phthalazones regiose-
lectively. These heterocyclic motifs occur as subunits in mole-
cules of pharmacological interest, and work continues to further
exploit the cascade methodology described.
a Reaction conditions: aryl iodide (0.5 mmol), 1-acetyl-2-phenylhydra-
zine 16a (0.7 mmol), CO (1 atm), palladacycle 17 (0.025 mmol), Cs2CO3
(1.0 mmol), DMF (5 mL). b Aryl iodide (0.5 mmol), 1-acetyl-2-phenyl-
hydrazine 16a (0.6 mmol), CO (1 atm), Pd(OAc)2 (0.025 mmol), PPh3
(0.05 mmol), Cs2CO3 (1.0 mmol), MeCN (10 mL), 85 °C, 20 h. c Aryl
iodide (0.5 mmol), Et2NH.2HCl 16b (0.65 mmol), CO (1 atm), palladacycle
17 (0.025 mmol), Cs2CO3 (1.5 mmol), water (0.2 mL), DMF (5 mL).
hydrazine 14d to give products 15h and 15i. It is possible that
some products may have undergone retro-Michael addition
during column chromatography, contributing toward poorer
yields.
J. Org. Chem. Vol. 73, No. 21, 2008 8355

Grigg et al.
mg, 1.0 mmol) in DMF (5 mL) at 60 °C for 3 h. The crude product
was purified by flash chromatography (eluting with EtOAc) to give
18e (172 mg, 77%) as colorless prisms: mp 215-217 °C (from
DCM-hexane); Rf 0.42 (EtOAc); δH (500 MHz, CDCl3, 60 °C)
8.15 (1H, d, J 7.6), 7.83 (2H, br m), 7.50 (1H, td, J 7.6 and 1.2),
7.43 (1H, td, J 7.6 and 1.2), 7.38 (3H, m), 7.17 (1H, t, J 7.3), 6.40
(1H, br s), 3.89 (4H, br m), 3.79 (1H, br m), 3.61 (1H, br m), 3.18
(2H, br m), 2.99 (1H, br m), 2.59 (1H, dd, J 16.3 and 4.6), 2.02
(3H, br s), 1.48 (2H, br m), 1.31 (2H, br m); δC (75 MHz, CDCl3)
174.8 (C),167.0 (C), 163.0 (C), 142.9 (C), 142.0 (C), 133.7 (CH),
129.8 (CH), 129.6 (CH), 128.9 (CH), 127.5 (C), 125.9 (CH), 120.8
(CH), 119.5 (CH), 106.9 (C), 64.8 (CH2), 51.8 (CH), 43.6 (CH2),
Experimental Section
General Procedure (A) for the Synthesis of Isoindolones. The
reagents were stirred in toluene (presaturated with carbon monoxide)
in a round-bottomed flask with palladium acetate added last. A
balloon containing carbon monoxide (CO) was used to flush the
system of air and maintain an atmosphere of CO while the stirred
reaction mixture was heated.
General Procedure (B) for the Synthesis of Phthalazones. A
carousel tube was loaded with the reagents and the solvent added
last. A balloon containing carbon monoxide (CO) was used to flush
the system of air via a PTFE cap fitted with septum and to maintain
an atmosphere of CO while the stirred reaction mixture was heated.
General Procedure (C) for the Synthesis of Phthalazones. A
carousel tube was loaded with the hydrazine salt, cesium carbonate,
water, and DMF and allowed to stir at 25 °C for 5 min before the
remainder of the reagents were added. A balloon containing carbon
monoxide (CO) was used to flush the system of air via a PTFE
cap fitted with septum and to maintain an atmosphere of CO while
the reaction was heated.
Methyl {2-[(2,5-difluorophenyl)amino]-3-oxo-2,3-dihydro-1H-
isoindol-1-yl}acetate (15a). Prepared by general procedure A from
methyl 3-(2-iodophenyl)acrylate 13a (144 mg, 0.5 mmol), 2,5-
difluorophenylhydrazine 14a (86 mg, 0.6 mmol), palladium acetate
(6 mg, 0.025 mmol), triphenylphosphine (13 mg, 0.05 mmol), and
cesium carbonate (324 mg, 1.0 mmol) in toluene (10 mL) at 90 °C
over 3 h. The crude product was purified by flash chromatography
(eluting with 3:7 v/v EtOAc-hexane) to give 15a (100 mg, 60%)
as a pale brown gum: Rf 0.25 (3:7 v/v EtOAc-hexane); δH (300
MHz, CDCl3) 7.91 (1H, d, J 7.7), 7.66 (1H, t, J 7.7), 7.65 (1H, d,
J 7.7), 7.54 (1H, t, J 7.7), 7.00 (1H, ddd, JHF 10.7, JHH 8.7, and
4JHF 5.1), 6.56-6.48 (1H, m), 6.46 (1H, br s), 6.44-6.38 (1H, m),
5.19 (1H, t, J 6.2), 3.65 (3H, s), 3.02 (1H, dd, J 15.9 and 6.2), 2.82
(1H, dd, J 15.9 and 6.2); δC (75 MHz, CDCl3) 171.0 (C), 167.4
(C), 162.9 (CF, d, J 235), 147.6 (CF, d, J 235), 143.4 (C), 136.5
(C, d, J 23), 133.3 (CH), 130.1 (C), 129.5 (CH), 124.8 (CH), 123.4
(CH), 116.4 (CH, dd, J 21 and 10), 107.3 (CH, dd, J 24 and 8),
101.9 (CH, d, J 28), 58.4 (CH), 52.5 (CH3), 37.3 (CH2); νmax/cm-1
(film) 3278, 2955, 1716 (CdO), 1633 (CdO), 1515, 1471; m/z
(ES+) 333 (100, MH+); HRMS (ES+) found MH+ 333.1046,
C17H14F2N2O3 requires MH+ 333.1045.
40.4 (CH2), 36.2 (CH2), 35.4 (CH2), 35.1 (CH2), 22.3 (CH3); νmax
/
cm-1 (film) 3062, 2961, 2930, 2884, 1696 (CdO), 1674 (CdO),
1642 (CdO), 1596, 1489, 1456; m/z (ES+) 921 (100, M2Na+),
472 (36, MNa+), 450 (14, MH+); HRMS (ES+) found MH+
450.2016, C25H27N3O5 requires MH+ 450.2023.
Methyl (2,3-Diethyl-4-oxo-1,2,3,4-tetrahydrophthalazin-1-yl)ac-
etate (18f). Prepared by general procedure C from methyl 3-(2-
iodophenyl)acrylate 13a (144 mg, 0.5 mmol), 1,2-diethylhydrazine
dihydrochloride 16b (104 mg, 0.65 mmol) in water (0.5 mL),
palladacycle 17 (19 mg, 0.025 mmol), and cesium carbonate (326
mg, 1.0 mmol) in DMF (5 mL) at 70 °C over 3 h. The crude product
was purified by flash chromatography (eluting with 1:9 v/v
EtOAc-DCM) to give 18f (76 mg, 55%) as a colorless gum: Rf
0.56 (1:9 v/v EtOAc-DCM); δH (500 MHz, CDCl3) 8.03 (1H, dd,
J 7.7 and 1.1), 7.48 (1H, td, J 7.7 and 1.1), 7.39 (1H, td, J 7.7 and
1.1), 7.20 (1H, d, J 7.7), 4.52 (1H, dd, J 9.0 and 5.6), 4.15 (1H,
dq, J 13.7 and 7.3), 3.71 (3H, s), 3.13 (1H, dq, J 13.7 and 7.3),
2.90-2.80 (2H, m), 2.70 (1H, dq, J 12.4 and 7.3), 2.53 (1H, dd, J
15.8 and 5.6), 1.26 (3H, t, J 7.3), 1.05 (3H, t, J 7.3); δC (75 MHz,
CDCl3) 171.6 (C), 162.6 (C), 137.8 (C), 132.8 (CH), 128.5 (CH),
127.9 (CH), 127.3 (C), 126.6 (CH), 56.1 (CH), 52.2 (CH3), 49.5
(CH2), 42.3 (CH2), 40.2 (CH2), 13.3 (CH3), 12.8 (CH3); νmax/cm-1
(film) 2975, 2951, 2853, 1741 (CdO), 1650 (CdO), 1605; m/z
(ES+) 277 (51, MH+), 299 (100, MNa+), 575 (70, M2Na+); HRMS
(ES+) found MNa+ 299.1375, C15H20N2O3 requires MNa+ 299.1366.
3
3
Acknowledgment. We thank Leeds University for technical
support and for the award of a Mary and Alice Smith
Scholarship (to S.M.) and GlaxoSmithKline for funding.
3-Acetyl-4-[2-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-2-oxoethyl]-
2-phenyl-3,4-dihydro-2H-phthalazin-1-one (18e). Prepared by
general procedure B from a stirred mixture of 8-[(2E)-3-(2-iodo-
phenyl)prop-2-enoyl]-1,4-dioxa-8-azaspiro[4.5]decane 13e (200 mg,
0.5 mmol), 1-acetyl-2-phenylhydrazine 16a (105 mg, 0.7 mmol),
palladacycle 17 (19 mg, 0.025 mmol), and cesium carbonate (326
Supporting Information Available: 1H and 13C NMR spec-
tra and CIF files of the X-ray structures. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO800822P
8356 J. Org. Chem. Vol. 73, No. 21, 2008