Straightforward strategy for the stereoselective synthesis of spiro-fused (C-5)isoxazolino- or (C-3)pyrazolino-(C-3)quinolin-2-ones from Baylis-Hillman adducts by 1,3-dipolar cycloaddition and reductive cyclization

FULL PAPER

DOI: 10.1002/ejoc.200800746

Straightforward Strategy for the Stereoselective Synthesis of Spiro-Fused

(C-5)Isoxazolino- or (C-3)Pyrazolino-(C-3)quinolin-2-ones from Baylis–

Hillman Adducts by 1,3-Dipolar Cycloaddition and Reductive Cyclization^[‡]

Virender Singh,^[a]Vijay Singh,^[a]and Sanjay Batra*^[a]

Keywords: Baylis–Hillman reactions / Cycloadditions / Reductive cyclizations / Spiro compounds / Quinolines

A straightforward and general approach for the stereoselec-

tive synthesis of spiro-fused (C-5)isoxazolino- or (C-3)pyrazo-

lino-(C-3)quinolin-2-ones from the adducts offorded from the

Baylis–Hillman reaction of 2-nitrobenzaldehyde and ethyl

acrylate by sequential 1,3-dipolar cycloaddition and re-

ductive cyclization is presented. It was found that the re-

ductive cyclization of the isoxazoline derivatives proceeded

ductions of pyrazolines gave better yields when carried out

in the presence of an Fe/AcOH mixture. However, similar

attempts employing the Baylis–Hillman adduct of 2-ni-

trobenzaldehyde and methyl vinyl ketone did not yield the

desired compounds.

efficiently in the presence of In/HCl, whereas similar re- Germany, 2008)

quinolines, and 3-benzyl-2-quinolones from derivatives of

Introduction

Baylis–Hillman adducts.^[3,4]In our continued interest to de-

velop facile and general routes to pharmacologically impor-

tant heterocyclic systems, which can be constructed from

the derivatives obtained from the Baylis–Hillman reaction,

we envisaged the synthesis of spiro-fused (C-5)isoxazolino-

and (C-3)pyrazolino-(C-3)quinolin-2-ones. In principle,

products afforded from the 1,3-dipolar cycloaddition of a

dipole to the methylene group of the adducts of the Baylis–

Hillman reaction of 2-nitrobenzaldehyde with acrylate,

upon reductive cyclization between the aromatic amino

group and the alkoxycarbonyl group, should lead to the

desired spiro-fused system.

Spirocyclic systems are of considerable importance owing

to their ubiquitous presence in several natural products and

pharmacologically active compounds.^[5,6]The recent litera-

ture reflects a renewed interest in the syntheses of different

spirocyclic molecules employing diverse approaches.^[7]Due

to the propensity to deliver the α-anion equivalent of an

electron-deficient alkene, the Baylis–Hillman adducts or

their derivatives have already been demonstrated to be suit-

able starting materials for the synthesis of spiro-fused sys-

tems.^[8]In most of these endeavors the cycloaddition reac-

tion is the key step, which may be either conducted on the

Baylis–Hillman derivative or the exocyclic methylene group

of a heterocyclic system afforded from the Baylis–Hillman

adduct to produce the spiro system. A literature search re-

vealed that Yong et al. have reported the synthesis of 3Ј-

spirocyclic oxoindoles by a strategy that is analogous to the

one envisaged by us.^[9]However, to the best of our knowl-

edge, only a few methods known to date describe the syn-

thesis of a spiro-fused quinoline core.^[10]Therefore, we were

Applications of substituted quinolines are profound and

wide-ranging from pharmaceuticals and agrochemicals to

electronics. In order to meet the requirements of differently

substituted quinolines for various purposes, chemists have

been relentlessly developing new synthetic strategies for

their syntheses. These protocols may involve the discovery

of a new catalyst or condition for known reactions or the

use of novel substrates to engineer the synthesis of substi-

tuted quinolines in an innovative fashion or by robust well-

optimized procedures. Recently, we have assimilated all the

efforts reported during the last couple of years in the litera-

ture towards the synthesis of substituted quinolines and

quinoline-annulated ring systems.^[1]Of several methodolo-

gies currently in use, the Baylis–Hillman-reaction-assisted

route for the synthesis of diverse substituted quinoline or

quinoline-annulated ring systems has received considerable

attention.^[1,2]A critical analysis of different strategies devel-

oped for the synthesis of substituted quinolines through

Baylis–Hillman chemistry revealed that the majority of

them involve the reductive cyclization of adducts of 2-ni-

trobenzaldehyde and acrylate or (cyclo)alkeneone as the key

step.^[2]In this context, we have disclosed general approaches

for the synthesis of 4-vinylquinolines, 2-amino-3-benzyl-

[‡] CDRI Communication no. 7580

[a] Medicinal and Process Chemistry Division, Central Drug Re-

search Institute,

P. O. Box 173, Lucknow 226001, India

Fax: +91-522-2623405, -2623938

E-mail: batra_san@yahoo.co.uk

Supporting information for this article is available on the

WWW under http://ww w .eurjoc.org or from the author.

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Spiro-Fused Quinolin-2-ones from Baylis–Hillman Adducts

inspired to explore the feasibility of our strategy. During hydroximoyl chlorides, led to the corresponding substituted

the present study, the 1,3-dipolar cycloadditions of nitrile 2-isoxazolines 3a–d (Scheme 1). It has been reported that

oxides or nitrile imines to the Baylis–Hillman adducts of 2- such 1,3-dipolar additions of nitrile oxides to allylic

nitrobenzaldehyde or substituted 2-nitrobenzaldehyde were alcohols are diastereoselective in favor of the syn isomer,^[11]

stereoselective, furnishing only the syn isomer. Further- but we observed that the addition yielded exclusively the

more, the reductive cyclization of the isoxazoline derivatives syn isomer of 3, as evident from the NMR analysis. The

to yield the spiro system was accomplished efficiently in the NOE between the CH₂signal at δ = 3.7 ppm and the ben-

presence of an In/HCl mixture. On the other hand, similar zylic proton signal at δ = 6.07 ppm in the NOESY spectrum

reactions of pyrazoline derivatives proceeded better in the of 3c indicated the stereochemical assignment of these

presence of an Fe/AcOH mixture but took a longer time to products. On the basis of literature precedence, we pre-

complete. The details of these results are presented in this sumed that a transition state, as shown in Figure 1, may

paper.

exist owing to the hydrogen bonding between the nitrile ox-

ide and the hydroxy group of the Baylis–Hillman adduct.

This transition state favors the formation of the syn isomer.

In order to investigate the generality of this phenomenon,

adduct 2, afforded from the Baylis–Hillman reaction be-

tween 4,5-dimethoxy-2-nitrobenzaldehyde and ethyl acry-

late, was also subjected to 1,3-dipolar cycloadditions with

nitrile oxide. This resulted in the formation of 4a–d having

syn stereochemistry, as evident from the spectral assign-

ments. With the desired isoxazoline derivatives 3a–d,4a–d in

hand, we next investigated the reductive cyclization of these

compounds. It is noteworthy that reductive cyclizations in-

volving aromatic nitro groups in Baylis–Hillman derivatives

have been executed previously with a variety of reducing

agents such as In/HCl, Fe/AcOH, and SnCl₂·2H₂O.^[2]Ad-

ditionally, in view of our earlier observation that a substi-

tuted 2-isoxazoline carrying a nitro-substituted phenyl

group did not undergo ring cleavage under catalytic hydro-

genation,^[12]the option of performing reductive cyclizations

through catalytic hydrogenation was also available to us. In

an attempt to discover efficient conditions that could be

applied to all substrates, the aforementioned reagents were

screened in reductive cyclizations on model substrate 3a. As

evident from the results summarized in Table 1, the reaction

performed in the presence of In/HCl at 70 °C under aque-

ous condition was clean and provided the best yield of the

desired spiro-fused 4Ј-hydroxy-(C-5)isoxazolino-(C-3)quin-

olin-2-one in a short period of time. If the same reaction

was conducted at room temperature, the reaction was com-

pleted within 10 min and yielded a mixture of products,

from which 45% of 5a was recovered (Table 1, Entry 1).

Surprisingly, if HCl was added to the reaction mixture at

0 °C, and then heated at reflux, the reaction did not go to

completion, even if the mixture was refluxed for more than

12 h (Table 1, Entry 3). An Fe/AcOH mixture was unsuit-

Results and Discussion

Synthesis of Spiro-Fused 4Ј-Hydroxy-(C-5)isoxazolino-

(C-3)quinolin-2-ones

Our synthesis commenced with the Baylis–Hillman reac-

tion of 2-nitrobenzaldehyde and ethyl acrylate to deliver ad-

duct 1. The 1,3-dipolar cycloaddition of several nitrile ox-

ides, which were generated in situ from the corresponding

Scheme 1. Reagents and conditions: (i) DABCO, neat, room temp.,

10–24 h; (ii) Et₃N, anhydrous diethyl ether, –78 °C to room temp.,

3 h; (iii) In/HCl, 70 °C, THF/H₂O (3:2), 5–7 min.

Table 1. Result of the optimization study of reductive cyclization under different conditions with model substrate 3a.

Entry

Reagent and conditions

Yield [%] of 5a

1

2

3

In (4.0 equiv.) + HCl (6.0 equiv.), THF/H₂O, room temp., 10 min

In (4.0 equiv.) + HCl (6.0 equiv.), THF/H₂O, 70 °C, 7 min

In (4.0 equiv.) + HCl (6.0 equiv.), THF/H₂O, HCl added at 0 °C,

then reflux for 1.5 h

45 + unidentified side products

64

33 + starting material + side products

4

Fe (6.0 equiv.) + AcOH, 120 °C, N₂, 1.5 h

nil (reaction was completed, but TLC analysis showed

several spots)

5

6

7

SnCl₂·2H₂O (6.0 equiv., anhydrous MeOH, 80 °C, 3.0 h)

31 + other unidentified products

27 + other unidentified products

Pd/C (10%), MeOH, 40 psi, 3.0 h

Zn (1.5 equiv.) + HCO₂NH₄, anhydrous MeOH, room temp., 12.0 h mixture of products

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5447

V. Singh, V. Singh, S. Batra

FULL PAPER

able for this reaction, since only a polymeric material was

obtained. The SnCl₂·2H₂O and Pd/C reagents successfully

produced the desired product 5a, albeit in lower yields than

the In/HCl-mediated reaction. Gratifyingly, the relative ste-

reochemistry of the product was unaltered during the re-

ductive cyclization to provide the product with syn geome-

try only. As a result, compounds 3b–d,4a–d were also

treated with In/HCl at reflux to furnish the corresponding

spiro-fused 4Ј-hydroxy-(C-5)isoxazolino-(C-3)quinolin-2-

ones 5b–d,6a–d in good yields.

Figure 1. Hydrogen-bonded transition state favoring the formation

of the syn isomer.

Synthesis of Spiro-Fused (C-3)Pyrazolino-4Ј-hydroxy-

(C-3)quinolin-2-ones

Scheme 2. Reagents and conditions: (i) C₆H₆, room temp. to reflux,

2–15 min; (ii) NCS, DMF, room temp., 30 min to 1 h; (iii) Et₃N,

anhydrous C₆H₆, reflux, 5 d; (iv) Fe/AcOH, reflux, 3 h.

In order to diversify the scope of the strategy, we envis-

aged the synthesis of (C-3)pyrazolino-4Ј-hydroxy-(C-3)-

quinolin-2-ones by carrying out similar 1,3-dipolar cycload-

ditions employing nitrile imines on 1–2, followed by re-

ductive cyclization. Accordingly, the hydrazonyl chlorides

required for the in situ generation of nitrile imines were

prepared by the reaction of N-chlorosuccinimide with hy-

drazones, which were afforded by the treatment of phenyl-

hydrazine with several benzaldehydes. Since the hydrazonyl

chlorides were highly corrosive (skin irritant), they were uti-

lized without purification or spectral analysis. Unlike the

dipolar cycloadditions with nitrile oxides, which were com-

plete in 3–4 h, the cycloadditions with nitrile imines took

almost 5 d to go to completion (Scheme 2). With the objec-

tive to expedite the reaction, several solvents were screened

Table 2. Results of solvent screening for expediting the formation

of pyrazoline with model substrate 1d.

Entry

Solvent and conditions

Yield [%] of 7d

1

2

3

4

5

anhydrous C₆H₆, Et₃N, reflux for 5 d

anhydrous 1,4-dioxane, Et₃N, reflux for 5 d 27, reaction complete

anhydrous CH₂Cl₂, reflux for 5 d

anhydrous diethyl ether, reflux for 6 d

anhydrous toluene, reflux for 5 d

36, reaction complete

25, reaction incomplete

32, reaction complete

31, reaction complete

with 1d as a model substrate with one of the nitrile imines isolated only a single product, which was established as 7d.

(R¹= 4-Me-C₆H₄). The results of this study are summa- A careful NMR analysis ascertained that one of the phenyl

rized in Table 2.

rings was substituted at the 4-position. In order to examine

Although the best isolated yields were obtained in anhy- whether this was a general trend for this series of com-

drous benzene, we observed that the reaction proceeded pounds, 1 and 2 were treated with several nitrile imines to

sluggishly, and the yields were low irrespective of solvent. yield 7a–c,e,8a in moderate yields only. The mass spectra

This may be attributed to the choice of base used for the of all products displayed an [M + 34]⁺peak. A possible

generation of the nitrile imine.^[13]Nevertheless, similar to explanation for the larger than expected mass was that the

the cycloadditions with the nitrile oxides, this reaction also generation of the hydrazonyl chloride by N-chlorosuc-

resulted in a single product. However, the mass spectrum cinimide involved the regiospecific chlorination of the

of this product distinctly displayed an [M + 34]⁺peak (vide phenyl ring derived from phenylhydrazine. These com-

infra). A review of the literature revealed that during the pounds (7a–e,8a) were then subjected to reductive cycliza-

preparation of a hydrazonyl bromide with N-bromosuc- tion. Contrary to the reductive cyclization of substituted 2-

cinimide, Reinov et al.^[14]reported that regioselective bromi- isoxazoline derivatives, we observed that the reductive cycli-

nation took place at the 4-position of the phenyl ring de- zation of 7d with In/HCl was not clean. Chromatographic

rived from phenylhydrazine. Indeed, the formation of a side purification of the crude product furnished the desired com-

product reported by these workers during the synthesis of pound in 55% yield only. In view of this result, we em-

a pyrazoline with an N-hydrazonyl bromide as the source ployed an Fe/AcOH mixture to carry out the reductive cy-

of nitrile imine was attributed to this reaction. However, we clization of 7d. To our delight, heating at reflux provided a

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Spiro-Fused Quinolin-2-ones from Baylis–Hillman Adducts

clean reaction and furnished the required spiro-fused (C-3)-

pyrazolino-4Ј-hydroxy-(C-3)quinolin-2-one derivative 9d in

73% yield. This reagent worked well for other substrates

(7a–c,e,8a) to furnish the corresponding spiro-fused systems

9a–c,e,10a in 71–96% yields. In order to provide additional

evidence for an 4-chloro-N-phenyl group by X-ray crystal-

lography, we attempted to prepare crystals of these analogs.

However, we failed to achieve the desired objective due to

the poor solubility of these analogs in different organic sol-

vents.

Synthesis of Spiro-Fused (C-3)Pyrazolino-(C-3)pyrolidin-2-

ones

We recently reported the synthesis of the spiro-fused (C-5)-

isoxazolino-(C-3)pyridine-2-ones from 3-methylene-2-pyr-

idone, the structure and relative stereochemistry of which

were unambiguously established on the basis of X-ray crys-

tallographic analysis.^[8a]In principle, the nitrile imine, gen-

erated through the above-described protocol, upon reaction

with 3-methylene-2-pyridone, should furnish the spiro-fused

pyrazoline–2-pyridone unit. A crystallographic analysis of

such a system would provide evidence for the regiospecific

chlorination of the phenyl ring derived from phenylhydraz-

ine during the formation of the hydrazonyl chloride with

N-chlorosuccinimide. Consequently, 3-methylene-2-pyr-

idones (11–14,15) were generated as reported and treated

with several nitrile imines, resulting in the formation of

16a–d,17a–d,18a–d,19a–d,20a–c (Scheme 3). Like the 1,3-

dipolar cycloaddition reactions of nitrile imines with

Baylis–Hillman adducts, these reactions were also slow and

produced only moderate yields. Nevertheless, the strategy

was general in nature. The attempted crystallization of sev-

eral analogs resulted in crystals for 17d and 19c, which were

finally subjected to X-ray crystallographic analysis.^[14–16]

The results of this analysis provided unambiguous evidence

that the phenyl ring originating from phenylhydrazine was

regiospecifically chlorinated at the 4-position (Figures 2

and 3). Additionally, the X-ray structure also made it evi-

dent that the 2-pyridone and pyrazoline rings were perpen-

dicular to each other in the spiro-fused (C-3)pyrazolino-(C-

Figure 2. ORTEP structure of 17d. The ellipsoids are drawn at a

probability level of 20%.

Figure 3. ORTEP structure of 19c with a molecule of chloroform.

The ellipsoids are drawn at a probability level of 20%.

Synthesis of Spiro-Fused (C-5)Isoxazolino-4Ј-hydro-(C-3)-

quinolin-2-ones

With a focus to further enhance the scope of this strat-

3)pyrolidin-2-ones, demonstrating that the addition of the egy, we decided to perform similar syntheses employing 27–

nitrile imine to the 3-methylene-2-pyridone was diastereo- 29 as substrates, which, in turn, could be readily synthesized

selective.

from the NaBH₄-mediated S_N2Ј-S_N2Ј displacement reac-

Scheme 3. Reagents and conditions: (i) Anhydrous C₆H₆, reflux, 5 d.

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5449

V. Singh, V. Singh, S. Batra

FULL PAPER

tion of Baylis–Hillman acetates 24–26 in the presence of Synthesis of Spiro-Fused (C-3)Pyrazolino-4Ј-hydro-(C-3)-

DABCO in an aqueous medium.^[2]Accordingly, 27–29 were quinolin-2-ones

prepared, and their 1,3-dipolar cycloaddition to different

Having achieved the synthesis of isoxazolino-fused spiro-

nitrile oxides was conducted to obtain the corresponding

tetrahydroquinolines, we turned our attention to similar re-

substituted 2-isoxazolines 30a–d,31a–d,32a–d in good yields

actions of 27 with nitrile imines. The 1,3-dipolar cycload-

(Scheme 4). The reductive cyclization of 30a–d,31a–d,32a–

dition of different nitrile imines to 27 resulted in the forma-

d in the presence of In/HCl resulted in the synthesis of

tion of pyrazolines 36a,c–e (Scheme 5). As expected, the

spiro-fused (C-5)isoxazolino-4Ј-hydro-(C-3)quinolin-2-ones

phenyl group originating from the hydrazine contained a

33a–d,34a–d,35a–d in 50–77% yields and in short reaction

chloro group at the 4-position for these analogs, too. Treat-

times. The spectral analysis confirmed the assigned struc-

ment of these pyrazolines with Fe/AcOH at reflux furnished

ture for these compounds.

the expected spiro-fused systems 37a,c–e in 71–94% yields.

Attempted Synthesis of Spiro-Fused (C-5)Isoxazolino-4Ј-

hydroxy-2-methyl-(C-3)quinolines

The reductive cyclization between an amino group and a

keto moiety is more facile than that between an amino and

an ester group.^[3]Therefore, we envisaged that the 1,3-di-

polar cycloaddition of a dipole to the Baylis–Hillman ad-

duct of 2-nitrobenzaldehyde and methyl vinyl ketone, fol-

lowed by a reductive cyclization, should lead to spiro-fused

2-methylquinolines. Consequently, Baylis–Hillman adduct

38 was prepared by a reaction between 2-nitrobenzaldehyde

and methyl vinyl ketone. The 1,3-dipolar cycloaddition of

different nitrile oxides to 38 led to the formation of 39a–

d. Unlike the cycloaddition reaction of the acrylate-based

Baylis–Hillman derivatives, the reaction was stereoselective

for the syn isomer, but a minor amount of the anti isomer

was also formed, as evident from the NMR analysis. How-

ever, attempts to separate the two isomers by silica gel col-

umn chromatography did not give the desired results. Nev-

ertheless, 39a–d were subjected to reductive cyclization in

the presence of In/HCl. Interestingly, substrate 39a yielded

two products, while all other substrates (39b–d) furnished a

Scheme 4. Reagents and conditions: (i) DABCO, neat, room temp.,

single product. Careful analysis of the spectroscopic data of

the common product afforded by all the substrates led to

the assignment of its structure as 40a–d. The presence of a

singlet signal for the aromatic proton indicated that the hy-

droxy group present at the 4-position of the quinoline nu-

cleus was lost during the reductive cyclization. However, the

second product isolated for 39a was established as 41a. We

presumed that after the reductive cyclization, the isoxaz-

oline ring of the generated spiro-fused (C-5)isoxazolino-4Ј-

hydroxy-2-methyl-(C-3)quinoline underwent ring cleavage

to produce an unstable intermediate, which dehydrated to

produce oxime 40. In the presence of HCl, the oxime may

have been transformed into 41a. In order to ascertain

whether or not 41a was derived from 40a, 40a was treated

with 35% aqueous HCl at reflux temperature. The reaction

was completed in 1 h to give the product, which was iden-

tical to 41a in all respects. In the light of this observation,

we desired to examine whether such transformations are

limited to 40a or if other substrates undergo similar trans-

formations. Consequently, 40c was heated with 35% aque-

ous HCl in aqueous THF and, to our satisfaction, the cor-

responding product 41c was formed in 1 h. Furthermore,

we envisaged that the treatment of 41 with hydroxylamine

10–36 h; (ii) AcCl, pyridine, anhydrous CH₂Cl₂, 0 °C to room

temp., 2–3 h; (iii) DABCO, THF/H₂O, room temp., 15 min, then

NaBH₄, room temp., 5 min; (iv) Et₃N, anhydrous diethyl ether,

–78 °C to room temp., 3–4 h; (v) In/HCl, 70 °C, 5–7 min.

Scheme 5. Reagents and conditions: (a) Et₃N, C₆H₆, reflux, 5 d; (b)

Fe/AcOH, reflux, 3 h.

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Spiro-Fused Quinolin-2-ones from Baylis–Hillman Adducts

a MICROMASS Quadro-II LCMS or a JEOL SX/102/DA 6000

system. The HR mass spectra were recorded in the EI mode with

a JEOL system or as DART-HR (in the ES+ mode) with a JEOL-

AccuTOF JMS-T100LC mass spectrometer with a DART (Direct

Analysis in Real Time) source. Elemental analyses were performed

with a Carlo Erba 108 or an Elementar Vario EL III microanalyzer.

hydrochloride should result in the formation of 40. Thus,

the reaction of 41a,c with hydroxylamine hydrochloride in

methanol at reflux furnished the expected products 40a,c,

respectively (Scheme 6). This transformation provided ad-

ditional evidence that products 40a–d were oximes. In con-

trast, the 1,3-dipolar cycloadditions of nitrile imines with

38 were unsuccessful, leading to a mixture of unidentified General Procedure for the Synthesis of 3a–d, 4a–d, 30a–d, 32a–d,

and 39a–d, as Exemplified for 3a: To a stirred solution of 1a (1.0 g,

3.98 mmol) and N-hydroxybenzenecarboximidoyl chloride (0.926 g,

5.98 mmol) in anhydrous diethyl ether (15 mL) was added dropwise

a solution of Et₃N (0.83 mL, 5.98 mmol) in anhydrous diethyl ether

(5 mL) at –78 °C. The reaction was allowed to continue at room

temperature for 3 h. The reaction mixture was then quenched with

water (30 mL), and the ethereal layer was separated. The aqueous

layer was again extracted with EtOAc (2ϫ20 mL). The combined

organic layers were dried with anhydrous Na₂SO₄and concentrated

to yield a crude oily residue. The crude product was then purified

by column chromatography on silica gel (60–120 mesh) with hex-

ane/ethyl acetate (90:10, v/v) as the eluent to afford 1.24 g (85%)

of 3a as a white solid.

products.

Ethyl 5-[Hydroxy(2-nitrophenyl)methyl]-3-phenyl-4,5-dihydroisox-

azole-5-carboxylate (3a): M.p. 139–142 °C. R_f= 0.32 (70:30, hex-

ane/EtOAc). IR (KBr): ν = 1734 (CO Et), 3438 (OH) cm^–1. ¹H

˜

2

Scheme 6. Reagents and conditions: (i) DABCO, neat, 0 °C,

10 min; (ii) Et₃N, anhydrous diethyl ether, –78 °C to room temp.,

3 h; (iii) In/HCl, 70 °C, 5–7 min; (iv) 35% aqueous HCl, THF/H₂O,

reflux, 1 h; (v) NH₂OH·HCl, NaOAc, MeOH, reflux, 1 h.

NMR (300 MHz, CDCl₃): δ = 1.26 (t, J = 7.1 Hz, 3 H, OCH₂CH₃),

3.38 (d, J = 5.7 Hz, 1 H, CHOH), 3.68 (d, J = 0.8 Hz, 2 H, CH₂),

4.21 (q, J = 7.1 Hz, 2 H, OCH₂CH₃), 6.07 (d, J = 5.7 Hz, 1 H,

CHOH), 7.35–7.45 (m, 3 H, ArH), 7.48–7.51 (m, 1 H, ArH), 7.58–

7.63 (m, 2 H, ArH), 7.67 (d, J = 7.6 Hz, 1 H, ArH), 7.89–7.93 (m,

2 H, ArH) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 14.0, 40.5, 62.8,

69.3, 91.5, 124.6, 127.0, 127.7, 128.4, 128.9, 129.4, 129.5, 130.2,

130.7, 132.7, 133.3, 149.3, 157.0, 170.8 ppm. MS (ES⁺): m/z (%) =

371.0 (80) [M + H]⁺. C₁₉H₁₈N₂O₆(exact mass: 370.1165): calcd. C

61.62, H 4.90, N 7.56; found C 61.46, H 5.07, N 7.51.

Conclusions

We have disclosed a straightforward and general ap-

proachforthediastereoselectivesynthesisofspiro-fused(C-5)-

isoxazolino- or (C-3)pyrazolino-(C-3)quinolin-2-ones^[17]

from the Baylis–Hillman adducts of 2-nitobenzaldehyde by

sequential 1,3-dipolar cycloaddition and reductive cycliza-

tion. This synthetic achievement involves simple steps and

Ethyl 5-[(3,4-Dimethoxy-2-nitrophenyl)(hydroxy)methyl]-3-phenyl-

4,5-dihydroisoxazole-5-carboxylate (4a): Yield 73% (0.727 g from

0.725 g) as a white solid, m.p. 100–101 °C. R_f= 0.25 (70:30, hexane/

1

EtOAc). IR (KBr): ν = 1738 (CO Et), 3519 (OH) cm^–1. H NMR

˜

2

the use of readily available starting materials. Furthermore, (300 MHz, CDCl₃): δ = 1.32 (t, J = 7.1 Hz, 3 H, OCH₂CH₃), 3.28

(d, J = 5.2 Hz, 1 H, CHOH), 3.51 (d, J = 17.5 Hz, 1 H, CHH),

3.64 (d, J = 17.5 Hz, 1 H, CHH), 3.92 (s, 3 H, OCH₃), 4.00 (s, 3

H, OCH₃), 4.27 (q, J = 7.1 Hz, 2 H, OCH₂CH₃), 6.24 (d, J =

5.2 Hz, 1 H, CHOH), 7.36–7.40 (m, 3 H, ArH), 7.44 (s, 1 H, ArH),

7.51–7.56 (m, 3 H, ArH) ppm. ¹³C NMR (75 MHz, CDCl₃): δ =

14.1, 41.0, 56.4, 56.8, 62.8, 69.2, 91.5, 107.5, 111.5, 126.9, 127.0,

127.7, 128.4, 128.8, 128.9, 130.7, 141.6, 148.7, 153.3, 156.8,

171.3 ppm. MS (ES⁺): m/z (%) = 430.8 (45) [M + H]⁺. C₂₁H₂₂N₂O₈

(exact mass: 430.1376): calcd. C 58.60, H 5.15, N 6.51; found C

58.37, H 5.27, N 6.47.

in our hands, the N-chlorosuccinimide-mediated synthesis

of hydrazonyl chlorides invariably led to the regioselective

chlorination of the phenyl ring derived from phenyl hydraz-

ine. The synthesis of spiro-fused (C-3)pyrazolino-(C-3)pyr-

idin-2-ones accomplished during this study was stereo- and

regioselective and illustrated that regioselective chlorination

of the phenyl ring of the hydrazine unit occurred. The de-

tailed work encompassed herein illustrates the scope and

limitations of the strategy.

Methyl 5-(2-Nitrobenzyl)-3-phenyl-4,5-dihydroisoxazole-5-carboxyl-

ate (30a): Yield 91% (0.85 g from 0.62 g) as a white solid, m.p. 98–

Experimental Section

99 °C. R_f= 0.37 (80:20, hexane/EtOAc). IR (KBr): ν = 1754

˜

General: Melting points are uncorrected and were determined in

capillary tubes with a precision melting point apparatus containing

silicon oil. IR spectra were recorded with a Perkin–Elmer Spectrum

(CO₂Me) cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 3.28 (d, J =

17.4 Hz, 1 H, CHH), 3.68 (d, J = 14.5 Hz, 1 H, CHH), 3.74 (d, J

= 14.5 Hz, 1 H, CHH), 3.76 (s, 3 H, CO₂CH₃), 3.84 (d, J = 17.4 Hz,

1 H, CHH), 7.36–7.42 (m, 4 H, ArH), 7.50–7.63 (m, 4 H, ArH),

7.88 (d, J = 8.1 Hz, 1 H, ArH) ppm. ¹³C NMR (75 MHz, CDCl₃):

δ = 37.2, 42.9, 53.3, 88.6, 124.8, 126.9, 127.7, 128.6, 128.8, 128.9,

129.4, 130.2, 130.6, 132.9, 133.8, 150.6, 156.9, 171.6 ppm. MS

(ES⁺): m/z (%) = 341.0 (100) [M + H]⁺. C₁₈H₁₆N₂O₅(exact mass:

340.1059): calcd. C 63.52, H 4.74, N 8.23; found C 63.38, H 4.56,

N 8.02.

1

RX I FTIR spectrophotometer. H and ¹³C NMR spectra were re-

corded with either a Bruker DPX-200 FT or a Bruker Avance

DRX-300 spectrometer with TMS as an internal standard (chemi-

cal shifts in δ). The ¹³C NMR spectra of 2-fluorophenyl derivatives

display additional signals due to the C-F couplings. As 37c was

only partially soluble in [D₆]DMSO, its ¹³C NMR spectrum could

not be recorded. The ES and FAB mass spectra were recorded with

Eur. J. Org. Chem. 2008, 5446–5460

www.eurjoc.org

5451

V. Singh, V. Singh, S. Batra

FULL PAPER

Methyl 5-(3,4-Dimethoxy-2-nitrobenzyl)-3-phenyl-4,5-dihydroisox-

azole-5-carboxylate (31a): Yield 91% (1.36 g from 1.0 g) as a white

solid, m.p. 129–131 °C. R_f= 0.37 (70:30, hexane/EtOAc). IR (KBr):

H, CHH), 3.98 (q, J = 7.1 Hz, 2 H, OCH₂CH₃), 6.43 (s, 1 H,

CHOH), 7.17 (d, J = 7.4 Hz, 2 H, ArH), 7.25–7.26 (m, 4 H, ArH),

7.35–7.45 (m, 2 H, ArH), 7.51 (d, J = 7.4 Hz, 2 H, ArH), 7.86–788

(m, 2 H, ArH) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 13.7, 21.6,

ν = 1738 (CO Me) cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 3.24

˜

2

(d, J = 17.4 Hz, 1 H, CHH), 3.65 (d, J = 14.6 Hz, 1 H, CHH), 3.79 41.9, 62.5, 67.4, 119.0, 124.6, 126.1, 127.0, 128.9, 129.2, 129.4,

(s, 3 H, CO₂CH₃), 3.81 (d, J = 14.6 Hz, 1 H, CHH), 3.87 (d, J =

130.0, 133.0, 139.7, 143.0, 148.6, 149.4, 171.1 ppm. MS (ES⁺): m/z

17.4 Hz, 1 H, CHH), 3.91 (s, 3 H, OCH₃), 3.96 (s, 3 H, OCH₃), (%) = 494.2 (100) [M + H]⁺, 496.2 (33) [M + 3]⁺. C₂₆H₂₄ClN₃O₅

7.06 (s, 1 H, ArH), 7.33–7.44 (m, 3 H, ArH), 7.52 (s, 1 H, ArH), (exact mass: 493.1404): calcd. C 63.22, H 4.90, N 8.51; found C

7.56–7.59 (m, 2 H, ArH) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 62.96, H 4.74, N 8.36.

37.1, 42.2, 53.3, 56.4, 56.7, 89.0, 108.0, 115.1, 124.4, 126.9, 127.0,

Ethyl 1-(4-Chlorophenyl)-5-[(4,5-dimethoxy-2-nitrophenyl)(hydroxy)-

128.8, 128.9, 130.5, 130.6, 142.6, 148.2, 152.8, 157.3, 171.7 ppm.

methyl]-3-phenyl-4,5-dihydro-1H-pyrazole-5-carboxylate (8a): Yield

MS (ES⁺): m/z (%) = 401.1 (100) [M + H]⁺. C₂₀H₂₀N₂O₇(exact

51% (0.44 g from 0.50 g) as a pale yellow solid, m.p. 107–108 °C.

mass: 400.1271): calcd. C 60.00, H 5.03, N 7.00; found C 59.79, H

R = 0.80 (80:20, hexane/EtOAc). IR (KBr): ν = 1724 (CO Et)

˜

f

2

5.21, N 7.10.

cm^–1. H NMR (300 MHz, CDCl₃): δ = 1.04 (t, J = 7.1 Hz, 3 H,

OCH₂CH₃), 3.37 (s, J = 4.08 Hz, 1 H, CHOH), 3.52 (d, J =

17.5 Hz, 1 H, CHH), 3.74 (d, J = 17.5 Hz, 1 H, CHH), 3.88 (q, J

= 7.1 Hz, 2 H, OCH₂CH₃), 6.57 (s, 1 H, CHOH), 7.24–7.28 (m, 3

1

Methyl 5-[(6-Nitrobenzo[d][1,3]dioxol-5-yl)methyl]-3-phenyl-4,5-di-

hydroisoxazole-5-carboxylate (32a): Yield 96% (0.73 g from 0.50 g)

as a light yellow solid, m.p. 133–135 °C. R_f= 0.30 (70:30, hexane/

EtOAc). IR (KBr): ν = 1734 (CO Me) cm^–1. H NMR (300 MHz, H, ArH), 7.32–7.36 (m, 3 H, ArH), 7.44–7.48 (m, 3 H, ArH), 7.52–

1

˜

2

CDCl₃): δ = 3.25 (d, J = 17.4 Hz, 1 H, CHH), 3.63 (d, J = 14.6 Hz, 7.55 (m, 2 H, ArH) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 13.9,

1 H, CHH), 3.70 (d, J = 14.6 Hz, 1 H, CHH), 3.78 (s, 3 H,

CO₂CH₃), 3.85 (d, J = 17.4 Hz, 1 H,CHH), 6.08 (d, J = 3.2 Hz, 2 128.7, 128.8, 129.0, 129.3, 131.4, 141.3, 142.9, 147.2, 148.5, 153.0,

H, OCH₂O), 7.02 (s, 1 H, ArH), 7.37–7.51 (m, 4 H, ArH), 7.59 (t, 171.8 ppm. MS (ES⁺): m/z (%) H]⁺.

540.0 (100) [M

J = 5.5 Hz, 2 H, ArH) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = C₂₇H₂₆ClN₃O₇(exact mass: 539.1459): calcd. C 60.06, H 4.85, N

42.8, 56.3, 56.4, 62.7, 68.2, 107.6, 111.9, 117.1, 118.0, 125.9, 126.0,

=

+

37.4, 42.5, 53.3, 88.8, 103.1, 105.6, 112.5, 126.3, 126.9, 127.7, 128.7,

129.0, 130.2, 130.7, 144.4, 147.5, 151.6, 157.2, 171.6 ppm. MS

(ES⁺): m/z (%) = 401.9 (60) [M + H]⁺. C₁₉H₁₆N₂O₇(exact mass:

400.1271): calcd. C 59.38, H 4.20, N 7.29; found C 59.27, H 4.01,

N 7.39.

7.78; found C 59.84, H 4.72, N 7.89.

Methyl 1-(4-Chlorophenyl)-5-(2-nitrobenzyl)-3-phenyl-4,5-dihydro-

1H-pyrazole-5-carboxylate (36a): Yield 36% (0.37 g from 0.50 g) as

a pale yellow solid, m.p. 143–145 °C. R_f= 0.75 (80:20, hexane/

EtOAc). IR (KBr): ν = 1735 (CO Me) cm^–1. H NMR (300 MHz,

1

˜

2

1-{5-[Hydroxy(2-nitrophenyl)methyl]-3-phenyl-4,5-dihydroisoxazol- CDCl₃): δ = 3.37 (d, J = 17.6 Hz, 1 H, CHH), 3.58 (d, J = 17.6 Hz,

5-yl}ethanone (39a): Yield 68% (1.10 g from 1.05 g) as a white solid,

m.p. 113–115 °C. R = 0.35 (80:20, hexane/EtOAc). IR (KBr): ν =

1 H, CHH), 3.66 (d, J = 14.7 Hz, 1 H, CHH), 3.74 (s, 3 H,

CO₂Me), 4.00 (d, J = 14.7 Hz, 1 H, CHH), 7.07–7.10 (m, 1 H,

˜

f

1719 (COCH₃), 3424 (OH) cm^–1. H NMR (300 MHz, CDCl₃): δ ArH), 7.16 (d, J = 7.7 Hz, 1 H, ArH), 7.25–7.28 (m, 6 H, ArH),

= 2.35 (s, 3 H, COCH₃), 3.30 (d, J = 5.6 Hz, 1 H, OH), 3.41 (d, J 7.30–7.31 (m, 1 H, ArH), 7.34–7.37 (m, 1 H, ArH), 7.39–7.42 (m,

= 17.6 Hz, 1 H, CHH), 3.58 (d, J = 17.6 Hz, 1 H, CHH), 6.02 (d, 2 H, ArH), 7.72–7.76 (m, 1 H, ArH) ppm. ¹³C NMR (75 MHz,

J = 5.2 Hz, 1 H, CHOH), 7.35–7.41 (m, 2 H, ArH), 7.46–7.51 (m, CDCl₃): δ = 32.8, 44.3, 53.6, 72.3, 114.2, 115.2, 124.7, 125.4, 127.0,

2 H, ArH), 7.56–7.59 (m, 2 H, ArH), 7.65–7.70 (m, 1 H, ArH), 128.5, 128.9, 129.4, 129.6, 129.9, 132.7, 133.6, 135.0, 141.6, 145.7,

7.93–7.96 (m, 2 H, ArH) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 151.1, 172.8 ppm. MS (ES⁺): m/z (%) = 450.1 (50) [M + H]⁺.

1

27.8, 40.5, 69.3, 96.2, 124.6, 126.9, 127.0, 128.3, 128.8, 128.9, 129.4,

129.7, 130.9, 133.1, 133.6, 148.7, 157.5, 211.4 ppm. MS (ES⁺): m/z

(%) = 341.0 (70) [M + H]⁺. C₁₈H₁₆N₂O₅(exact mass: 340.1059):

calcd. C 63.52, H 4.74, N 8.23; found C 63.37, H 4.92, N 8.15.

C₂₄H₂₀ClN₃O₄(exact mass: 449.1142): calcd. C 64.07, H 4.48, N

9.34; found C 63.90, H 4.56, N 9.21.

Ethyl 1-(4-Chlorophenyl)-8-methyl-6-oxo-3,10-diphenyl-1,2,7-triaza-

spiro[4.5]deca-2,8-diene-9-carboxylate (16a): Yield 47% (0.09 g

from 0.10 g) as a white solid, m.p. 183–185 °C. R_f= 0.40 (80:20,

General Procedure for the Synthesis of 7a–e, 8a, 36a,c–e, 16a–d,

19a–d, and 20a–c, as Exemplified for 7d: To a stirred solution of 1d

(0.20 g, 0.80 mmol) and N-(4-chlorophenyl)-4-methylbenzenecar-

bohydrazonoyl chloride (0.67 g, 2.40 mmol) in anhydrous benzene

(15 mL) was added Et₃N (0.33 mL, 2.40 mmol) at room tempera-

ture whilst stirring. The reaction mixture was then refluxed at 80 °C

for 5 d. After completion of the reaction, as evident by TLC analy-

sis, the reaction was quenched with water (50 mL), and the re-

sulting mixture was partitioned in a separating funnel. The aqueous

layer was separated and further extracted with EtOAc (3ϫ40 mL).

The organic layers were pooled, washed with brine (50 mL), dried

with anhydrous Na₂SO₄, and concentrated in vacuo to afford an

oily residue, which was purified by silica gel (60–120 mesh) column

chromatography. Elution with hexane/EtOAc (95:5, v/v) furnished

0.14 g (36%) of 7d as a yellow solid.

hexane/EtOAc). IR (KBr): ν = 1639 (CONH), 1702 (CO Et) 3448

˜

2

(NH) cm^–1. H NMR (300 MHz, CDCl₃): δ = 1.21 (t, J = 7.1 Hz,

1

3 H, OCH₂CH₃), 1.93 (s, 3 H, CH₃), 3.05 (d, J = 16.9 Hz, 1 H,

CHH), 3.56 (d, J = 16.9 Hz, 1 H, CHH), 4.03 (q, J = 7.1 Hz, 2 H,

OCH₂CH₃), 4.62 (s, 1 H, CH), 7.00 (s, 1 H, ArH), 7.19 (t, J =

8.8 Hz, 4 H, ArH), 7.27–7.33 (m, 7 H, ArH), 7.43 (s, 1 H, NH),

7.58 (s, 2 H, ArH) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 14.3,

18.8, 40.9, 48.6, 60.3, 75.4, 109.0, 126.3, 127.4, 127.8, 128.5, 128.6,

129.0, 129.5, 129.6, 131.1, 131.7, 133.7, 134.3, 139.7, 141.5, 143.5,

152.3, 166.0, 168.0 ppm. MS (ES⁺): m/z (%) = 500.1 (100) [M +

H]⁺, 523.2 (35) [M + Na]⁺. C₂₉H₂₆ClN₃O₃(exact mass: 499.1663):

calcd. C 69.66, H 5.24, N 8.40; found C 69.45, H 5.18, N 8.49.

Ethyl

phenyl-1,2,7-triazaspiro[4.5]deca-2,8-diene-9-carboxylate

1-(4-Chlorophenyl)-5-[hydroxy(2-nitrophenyl)methyl]-3-(4- Yield 47% (0.12 g from 0.13 g) as a white solid, m.p. 210–212 °C.

1-(4-Chlorophenyl)-3-(2-fluorophenyl)-8-methyl-6-oxo-10-

(16b):

Ethyl

methylphenyl)-4,5-dihydro-1H-pyrazole-5-carboxylate (7d): M.p.

R = 0.25 (80:20, hexane/EtOAc). IR (KBr): ν = 1667 (CONH),

˜

f

1

159–161 °C. R = 0.70 (80:20, hexane/EtOAc). IR (KBr): ν = 1736

1704 (CO₂Et) cm^–1. H NMR (300 MHz, CDCl₃): δ = 1.16 (t, J =

˜

f

(CO₂Et) cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 0.95 (t, J =

7.1 Hz, 3 H, OCH₂CH₃), 2.37 (s, 3 H, ArCH₃), 3.23 (s, 1 H,

CHOH), 3.51 (d, J = 17.4 Hz, 1 H, CHH), 3.88 (d, J = 17.4 Hz, 1

7.1 Hz, 3 H, OCH₂CH₃), 1.98 (s, 3 H, CH₃), 3.29 (d, J = 16.3 Hz,

1 H, CHH), 3.64 (d, J = 16.3 Hz, 1 H, CHH), 4.03 (q, J = 7.1 Hz,

2 H, OCH₂CH₃), 4.58 (s, 1 H, CH), 7.12 (t, J = 7.5 Hz, 3 H, ArH),

5452

www.eurjoc.org

Eur. J. Org. Chem. 2008, 5446–5460

Spiro-Fused Quinolin-2-ones from Baylis–Hillman Adducts

7.18–7.27 (m, 9 H, ArH), 7.40 (s, 1 H, NH), 7.74 (t, J = 7.5 Hz, 1 132.4, 133.5, 135.5, 143.7, 144.4, 150.5, 165.6, 167.5 ppm. MS

H, ArH) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 14.2, 18.8, 43.5,

48.0, 60.5, 74.4, 108.8, 116.2, 124.3, 125.2, 127.7, 128.5, 128.9,

130.9, 139.2, 142.9, 143.1, 147.4, 166.2, 168.8 ppm. MS (ES⁺): m/z

(%) = 518.0 (100) [M + H]⁺. C₂₉H₂₅ClFN₃O₃(exact mass:

517.1568): calcd. C 67.24, H 4.86, N 8.11; found C 67.35, H 4.76,

N 8.02.

(ES⁺): m/z (%) = 536.1 (100) [M + H]⁺. C₂₉H₂₄ClF₂N₃O₃(exact

mass: 535.1474): calcd. C 64.99, H 4.51, N 7.84; found C 65.15, H

4.38, N 7.61.

Ethyl 1,3-Bis(4-chlorophenyl)-10-(2-fluorophenyl)-8-methyl-6-oxo-

1,2,7-triazaspiro[4.5]deca-2,8-diene-9-carboxylate (17c): Yield 53%

(0.22 g from 0.41 g) as a white solid, m.p. 218–220 °C. R_f= 0.37

Ethyl

1,3-Bis(4-chlorophenyl)-8-methyl-6-oxo-10-phenyl-1,2,7-tri-

(80:20, hexane/EtOAc). IR (KBr): ν = 1644 (CONH), 1703

˜

azaspiro[4.5]deca-2,8-diene-9-carboxylate (16c): Yield 34% (0.14 g

from 0.21 g) as a white solid, m.p. 228–230 °C. R_f= 0.41 (80:20,

(CO₂Et) cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 1.18 (t, J =

7.1 Hz, 3 H, OCH₂CH₃), 1.94 (s, 3 H, CH₃), 2.95 (d, J = 16.7 Hz,

1 H, CHH), 3.58 (d, J = 16.7 Hz, 1 H, CHH), 4.06 (q, J = 7.1 Hz,

2 H, OCH₂CH₃), 4.99 (s, 1 H, CH), 7.01–7.08 (m, 4 H, ArH), 7.21–

7.32 (m, 7 H, ArH and NH), 7.52 (d, J = 7.1 Hz, 2 H, ArH) ppm.

¹³C NMR (75 MHz, CDCl₃): δ = 14.1, 18.8, 40.9, 60.5, 74.6, 115.8,

116.1, 124.9, 126.3, 126.7, 127.4, 128.4, 128.8, 129.6, 129.7, 130.3,

132.1, 135.2, 143.3, 144.3, 150.7, 165.7, 167.8 ppm. MS (ES⁺): m/z

hexane/EtOAc). IR (KBr): ν = 1643 (CONH), 1699 (CO Et) cm^–1.

˜

2

¹H NMR (300 MHz, CDCl₃): δ = 1.16 (t, J = 7.1 Hz, 3 H,

OCH₂CH₃), 1.95 (s, 3 H, CH₃), 3.03 (d, J = 16.9 Hz, 1 H, CHH),

3.51 (d, J = 16.9 Hz, 1 H, CHH), 4.04 (q, J = 7.1 Hz, 2 H,

OCH₂CH₃), 4.55 (s, 1 H, CH), 7.06–7.12 (m, 3 H, ArH), 7.17–7.31

(m, 9 H, NH merged with ArH), 7.49 (d, J = 8.5 Hz, 2 H, ArH)

ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 14.5, 19.1, 41.6, 48.8, 60.8,

75.0, 109.1, 126.3, 127.1, 127.7, 128.1, 128.7, 129.2, 129.4, 130.6,

131.8, 135.5, 139.8, 143.3, 143.6, 150.4, 166.3, 168.7 ppm. MS

(ES⁺): m/z (%) = 534.1 (100) [M + H]⁺. C₂₉H₂₅Cl₂N₃O₃(exact

mass: 533.1273): calcd. C 65.17, H 4.71, N 7.86; found C 65.32, H

4.84, N 7.68.

(%)

= 552.2 (100) [M +

H]⁺. DART-HRMS: calcd. for

C₂₉H₂₅Cl₂FN₃O₃[M + H]⁺552.12570; found 552.12186.

Ethyl 1-(4-Chlorophenyl)-10-(2-fluorophenyl)-8-methyl-6-oxo-3-(4-

methylphenyl)-1,2,7-triazaspiro[4.5]deca-2,8-diene-9-carboxylate

(17d): Yield 66% (0.12 g from 0.10 g) as a white solid, m.p. 222–

224 °C. R_f= 0.38 (80:20, hexane/EtOAc). IR (KBr): ν = 1639

˜

Ethyl

1-(4-Chlorophenyl)-8-methyl-6-oxo-10-phenyl-3-(4-methyl- (CONH), 1705 (CO₂Et) cm^–1. ¹H NMR (300 MHz, CDCl₃): δ =

phenyl)-1,2,7-triazaspiro[4.5]deca-2,8-diene-9-carboxylate

Yield 42% (0.26 g from 0.34 g) as a white solid, m.p. 231–233 °C.

(16d):

1.18 (t, J = 7.1 Hz, 3 H, OCH₂CH₃), 1.94 (s, 3 H, CH₃), 2.35 (s, 3

H, ArCH₃), 2.96 (d, J = 16.7 Hz, 1 H, CHH), 3.61 (d, 1 H, J =

R = 0.48 (80:20, hexane/EtOAc). IR (KBr): ν = 1641 (CONH), 16.7 Hz, CHH), 4.04 (q, J = 7.1 Hz, 2 H, OCH₂CH₃), 4.98 (s, 1 H,

˜

f

1701 (CO₂Et) cm^–1. H NMR (300 MHz, CDCl₃): δ = 1.16 (t, J =

CH), 7.03–7.07 (m, 4 H, ArH), 7.14 (d, J = 8.1 Hz, 2 H, ArH),

7.22–7.27 (m, 5 H, ArH and NH), 7.49 (d, J = 8.1 Hz, 2 H, ArH)

1

7.1 Hz, 3 H, OCH₂CH₃), 1.95 (s, 3 H, CH₃), 2.35 (s, 3 H, ArCH₃),

3.03 (d, J = 16.9 Hz, 1 H, CHH), 3.56 (d, J = 16.9 Hz, 1 H, CHH), ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 14.1, 18.8, 21.5, 41.2, 60.5,

4.04 (q, J = 7.1 Hz, 2 H, OCH₂CH₃), 4.53 (s, 1 H, CH), 7.13 (d, J

= 7.9 Hz, 5 H, ArH), 7.23 (m, 7 H, NH merged with ArH), 7.47

(d, J = 8.1 Hz, 2 H, ArH) ppm. ¹³C NMR (75 MHz, CDCl₃): δ =

14.2, 18.9, 21.5, 41.5, 48.4, 60.5, 74.5, 108.9, 126.1, 126.2, 127.7,

128.4, 128.5, 129.0, 129.3, 131.3, 139.5, 139.6, 143.1, 151.5, 161.1,

168.7 ppm. MS (ES⁺): m/z (%) = 514.1 (100) [M + H]⁺. HRMS

(EI): calcd. for C₃₀H₂₈ClN₃O₃513.1819; found 513.1804.

74.3, 115.7, 124.9, 126.2, 126.6, 126.8, 128.3, 129.0, 129.5, 129.6,

131.9, 139.6, 143.8, 144.4, 152.1, 165.8, 168.0 ppm. MS (ES⁺): m/z

(%)

= 532.1 (100) [M +

H]⁺. DART-HRMS: calcd. for

C₃₀H₂₇ClFN₃O₃[M + H]⁺532.18032; found 532.17799.

Ethyl 1,10-Bis(4-chlorophenyl)-8-methyl-6-oxo-3-phenyl-1,2,7-tri-

azaspiro[4.5]deca-2,8-diene-9-carboxylate (18a): Yield 47% (0.17 g

from 0.20 g) as a white solid, m.p. 148–150 °C. R_f= 0.40 (80:20,

Ethyl

1-(4-Chlorophenyl)-10-(2-fluorophenyl)-8-methyl-6-oxo-3- hexane/EtOAc). IR (KBr): ν = 1643 (CONH), 1699 (CO Et) cm^–1.

˜

2

phenyl-1,2,7-triazaspiro[4.5]deca-2,8-diene-9-carboxylate

(17a): ¹H NMR (300 MHz, CDCl₃): δ = 1.21 (t, J = 7.1 Hz, 3 H,

OCH₂CH₃), 1.92 (s, 3 H, CH₃), 3.01 (d, J = 16.8 Hz,1 H, CHH),

Yield 48% (0.12 g from 0.14 g) as a white solid, m.p. 180–182 °C.

R = 0.36 (80:20, hexane/EtOAc). IR (KBr): ν = 1639 (CONH), 3.56 (d, J = 16.8 Hz, 1 H, CHH), 4.05 (q, J = 7.1 Hz, 2 H,

˜

f

1705 (CO₂Et) cm^–1. H NMR (300 MHz, CDCl₃): δ = 1.18 (t, J =

OCH₂CH₃), 4.60 (s, 1 H, CH), 7.11 (t, J = 8.5 Hz, 3 H, ArH),

7.20–7.29 (m, 5 H, ArH), 7.31–7.35 (m, 3 H, ArH), 7.44 (s, 1 H,

1

7.1 Hz, 3 H, OCH₂CH₃), 1.94 (s, 3 H, CH₃), 3.04 (d, J = 16.7 Hz,

1 H, CHH), 3.60 (d, J = 16.7 Hz, 1 H, CHH), 4.05 (q, J = 7.1 Hz, NH), 7.44–7.61 (m, 2 H, ArH) ppm. ¹³C NMR (50 MHz, CDCl₃):

2 H, OCH₂CH₃), 5.16 (s, 1 H, CH), 7.03–7.11 (m, 4 H, ArH), 7.19– δ = 14.3, 18.8, 48.0, 60.4, 75.2, 108.6, 126.0, 126.3, 127.5, 128.5,

7.44 (m, 7 H, ArH), 7.59–7.62 (m, 3 H, ArH and NH) ppm. ¹³C 128.7, 129.3, 129.6, 129.8, 131.0, 131.5, 133.6, 133.8, 138.2, 141.4,

NMR (75 MHz, CDCl₃): δ = 14.1, 18.8, 40.5, 60.3, 75.2, 116.0,

124.9, 126.3, 126.7, 127.4, 128.3, 128.6, 128.8, 129.5, 131.0, 131.6,

133.7, 134.4, 141.4, 144.7, 152.6, 165.8, 167.4 ppm. MS (ES⁺): m/z

(%) = 518.1 (100) [M + H]⁺. C₂₉H₂₅ClFN₃O₃(exact mass:

517.1568): calcd. C 67.24, H 4.86, N 8.11; found C 66.96, H 4.74,

N 8.20.

143.4, 151.1, 152.3, 165.8, 167.8 ppm. MS (ES⁺): m/z (%) = 534.1

(100) [M + H]⁺. C₂₉H₂₅Cl₂N₃O₃(exact mass: 533.1273): calcd. C

65.17, H 4.71, N 7.86; found C 65.39, H 4.63, N 7.70.

Ethyl 1,10-Bis(4-chlorophenyl)-3-(2-fluorophenyl)-8-methyl-6-oxo-

1,2,7-triazaspiro[4.5]deca-2,8-diene-9-carboxylate (18b): Yield 57%

(0.14 g from 0.13 g) as a white solid, m.p. 198–200 °C. R_f= 0.38

Ethyl 1-(4-Chlorophenyl)-3,10-bis(2-fluorophenyl)-8-methyl-6-oxo- (80:20, hexane/EtOAc). IR (KBr): ν = 1645 (CONH), 1697

˜

1,2,7-triazaspiro[4.5]deca-2,8-diene-9-carboxylate (17b): Yield 51%

(0.27 g from 0.30 g) as a white solid, m.p. 231–233 °C. R_f= 0.37

(CO₂Et) cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 1.13 (t, J =

7.1 Hz, 3 H, OCH₂CH₃), 1.97 (s, 3 H, CH₃), 3.24 (d, J = 15.6 Hz,

(80:20, hexane/EtOAc). IR (KBr): ν = 1643 (CONH), 1708 1 H, CHH), 3.64 (d, J = 15.6 Hz, 1 H, CHH), 4.03 (q, J = 7.1 Hz,

˜

(CO₂Et) cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 1.17 (t, J =

7.1 Hz, 3 H, OCH₂CH₃), 1.96 (s, 3 H, CH₃), 3.14 (d, J = 16.7 Hz,

2 H, OCH₂CH₃), 4.57 (s, 1 H, CH), 7.03–7.10 (m, 6 H, ArH), 7.16–

7.29 (m, 6 H, ArH and NH), 7.71–7.79 (m, 1 H, ArH) ppm. ¹³C

1 H, CHH), 3.72 (d, J = 16.7 Hz, 1 H, CHH), 4.06 (q, J = 7.1 Hz, NMR (75 MHz, CDCl₃): δ = 14.2, 18.8, 43.6, 47.3, 60.6, 74.2,

2 H, OCH₂CH₃), 4.99 (s, 1 H, CH), 7.04–7.14 (m, 6 H, ArH), 7.20– 108.3, 124.5, 125.0, 128.6, 128.8, 129.1, 129.8, 130.9, 133.6, 133.6,

7.30 (m, 6 H, ArH and NH), 7.80 (t, J = 7.7 Hz, 1 H, ArH) ppm. 137.7, 142.9, 143.1, 166.0, 168.5 ppm. MS (ES⁺): m/z (%) = 552.3

¹³C NMR (75 MHz, CDCl₃): δ = 14.3, 18.7, 40.6, 60.4, 74.8, 115.7,

116.4, 124.8, 126.6, 126.5, 127.7, 128.6, 128.4, 129.7, 129.8, 130.0,

(100) [M + H]⁺. C₂₉H₂₄Cl₂FN₃O₃(exact mass: 551.1179): calcd. C

63.05, H 4.38, N 7.61; found C 63.26, H 4.46, N 7.83.

Eur. J. Org. Chem. 2008, 5446–5460

www.eurjoc.org

5453

V. Singh, V. Singh, S. Batra

Ethyl 1,3,10-Tris(4-chlorophenyl)-8-methyl-6-oxo-1,2,7-triazaspiro- 38% (0.07 g from 0.10 g) as a white solid, m.p. 240–242 °C. R_f=

FULL PAPER

[4.5]deca-2,8-diene-9-carboxylate (18c): Yield 52% (0.30 g from

0.33 g) as a white solid, m.p. 138–140 °C. R_f= 0.40 (80:20, hexane/

0.34 (80:20, hexane/EtOAc). IR (KBr): ν = 1646 (CONH), 1702

˜

(CO₂Et) cm^{–1 1}H NMR (300 MHz, CDCl₃): δ = 1.09 (t, J =

.

EtOAc). IR (KBr): ν = 1643 (CONH), 1699 (CO Et) cm^–1. ¹H 7.1 Hz, 3 H, OCH₂CH₃), 1.99 (s, 3 H, CH₃), 2.70 (d, J = 16.6 Hz,

˜

2

NMR (300 MHz, CDCl₃): δ = 1.15 (t, J = 7.1 Hz, 3 H, OCH₂CH₃), 1 H, CHH), 3.75 (d, J = 16.6 Hz, 1 H, CHH), 4.01 (q, J = 7.1 Hz,

1.93 (s, 3 H, CH₃), 3.00 (d, J = 16.8 Hz, 1 H, CHH), 3.54 (d, J =

16.8 Hz, 1 H, CHH), 4.04 (q, J = 7.1 Hz, 2 H, OCH₂CH₃), 4.51 (s,

1 H, CH), 7.03 (d, J = 8.4 Hz, 2 H, ArH), 7.14–7.32 (m, 8 H, ArH),

7.45 (d, J = 8.4 Hz, 2 H, ArH), 7.65 (s, 1 H, NH) ppm. ¹³C NMR

(75 MHz, CDCl₃): δ = 14.2, 18.9, 41.4, 48.0, 60.7, 74.5, 108.5,

126.0, 127.3, 128.5, 128.9, 129.3, 129.7, 130.1, 131.7, 133.7, 135.3,

2 H, OCH₂CH₃), 5.75 (s, 1 H, CH), 7.00 (s, 1 H, ArH), 7.15 (t, J

= 8.0 Hz, 1 H, ArH), 7.26–7.31 (m, 7 H, ArH and NH), 7.35–7.38

(m, 1 H, ArH), 7.51 (d, J = 8.6 Hz, 2 H, ArH) ppm. ¹³C NMR

(75 MHz, CDCl₃): δ = 14.1, 19.2, 46.4, 60.4, 73.5, 102.7, 125.8,

127.5, 128.4, 128.8, 129.2, 129.8, 130.3, 131.7, 135.2, 136.4, 138.3,

143.2, 145.6, 150.9, 165.9, 167.1 ppm. MS (ES⁺): m/z (%) = 601.9

138.0, 143.1, 143.2, 150.0, 165.8, 168.0 ppm. MS (ES⁺): m/z (%) = (80) [M + H]⁺. HRMS (EI): calcd. for C₂₉H₂₃Cl₄N₃O₃601.04935;

568.0 (100) [M + H]⁺. C₂₉H₂₄Cl₃N₃O₃(exact mass: 567.0883):

calcd. C 61.23, H 4.25, N 7.39; found C 61.46, H 4.10, N 7.47.

found 601.05116.

Ethyl 1-(4-Chlorophenyl)-10-(2,6-dichlorophenyl)-8-methyl-3-(4-

methylphenyl)-6-oxo-1,2,7-triazaspiro[4.5]deca-2,8-diene-9-carboxyl-

ate (19d): Yield 36% (0.06 g from 0.10 g) as a white solid, m.p.

Ethyl 1,10-Bis(4-chlorophenyl)-8-methyl-6-oxo-3-(4-methylphenyl)-

1,2,7-triazaspiro[4.5]deca-2,8-diene-9-carboxylate (18d): Yield 49%

(0.18 g from 0.20 g) as a white solid, m.p. 223–225 °C. R_f= 0.41

228–230 °C. R = 0.50 (80:20, hexane/EtOAc). IR (KBr): ν = 1635

˜

f

(CONH), 1700 (CO₂Et) cm^–1. ¹H NMR (300 MHz, CDCl₃): δ =

1.09 (t, J = 7.1 Hz, 3 H, OCH₂CH₃), 1.99 (s, 3 H, CH₃), 2.35 (s, 3

H, CH₃), 2.72 (d, J = 16.6 Hz, 1 H, CHH), 3.76 (d, J = 16.6 Hz,

1 H, CHH), 4.00 (q, J = 7.1 Hz, 2 H, OCH₂CH₃), 5.76 (d, J =

1.2 Hz, 1 H, CH), 6.99 (s, 1 H, ArH), 7.14 (t, J = 7.7 Hz, 3 H,

ArH), 7.25–7.29 (m, 5 H, ArH and NH), 7.33–7.37 (m, 1 H, ArH),

7.48 (d, J = 8.1 Hz, 2 H, ArH) ppm. ¹³C NMR (75 MHz, CDCl₃):

δ = 14.1, 19.2, 21.6, 41.5, 46.4, 60.3, 73.1, 102.7, 125.8, 126.3, 128.3,

128.7, 129.0, 129.3, 129.8, 131.4, 135.1, 136.6, 138.4, 139.5, 143.6,

145.8, 152.2, 166.0, 167.5 ppm. MS (ES⁺): m/z (%) = 582.0 (100)

[M + H]⁺. C₃₀H₂₆Cl₃N₃O₃(exact mass: 581.1040): calcd. C 61.81,

H 4.50, N 7.21; found C 61.66, H 4.63, N 7.08.

(80:20, hexane/EtOAc). IR (KBr): ν = 1677 (CONH), 1706

˜

(CO₂Et) cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 1.17 (t, J =

7.1 Hz, 3 H, OCH₂CH₃), 1.95 (s, 3 H, CH₃), 2.36 (s, 3 H, ArCH₃),

2.99 (d, J = 16.9 Hz, 1 H, CHH), 3.57 (d, J = 16.9 Hz, 1 H, CHH),

4.05 (q, J = 7.1 Hz, 2 H, OCH₂CH₃), 4.51 (s, 1 H, CH), 7.05 (d, J

= 8.2 Hz, 2 H, ArH), 7.14–7.26 (m, 9 H, NH merged with ArH),

7.47 (d, J = 7.8 Hz, 2 H, ArH) ppm. ¹³C NMR (50 MHz, CDCl₃):

δ = 14.3, 18.9, 21.5, 41.6, 47.8, 60.6, 74.3, 108.5, 126.0, 126.2, 128.4,

128.9, 129.2, 129.4, 129.8, 131.4, 133.6, 138.2, 139.7, 143.3, 143.5,

151.4, 165.9, 168.4 ppm. MS (FAB⁺) m/z (%) = 548.1 (100) [M +

H]⁺. C₃₀H₂₇Cl₂N₃O₃(exact mass: 547.1429): calcd. C 65.70, H

4.96, N 7.66; found C 65.89, H 5.14, N 7.87.

Ethyl 1-(4-Chlorophenyl)-10-(2,6-dichlorophenyl)-8-methyl-6-oxo-3-

9-Acetyl-1-(4-chlorophenyl)-8-methyl-10-(4-methylphenyl)-3-phenyl-

1,2,7-triazaspiro[4.5]deca-2,8-dien-6-one (20a): Yield 58% (0.38 g

from 0.35 g) as a white solid, m.p. 203–205 °C. R_f= 0.27 (80:20,

phenyl-1,2,7-triazaspiro[4.5]deca-2,8-diene-9-carboxylate

(19a):

Yield 34% (0.14 g from 0.25 g) as a white solid, m.p. 250–251 °C.

R = 0.49 (80:20, hexane/EtOAc). IR (KBr): ν = 1635 (CONH),

˜

f

hexane/EtOAc). IR (KBr): ν = 1681 (CONH), 1701 (COCH ) cm^–1.

˜

3

1700 (CO₂Et) cm^–1. H NMR (300 MHz, CDCl₃): δ = 1.08 (t, J =

1

¹H NMR (300 MHz, CDCl₃): δ = 1.93 (s, 3 H, CH₃), 1.94 (s, 3 H,

CH₃), 2.28 (s, 3 H, ArCH₃), 3.26 (d, J = 17.0 Hz, 1 H, CHH), 3.53

(d, J = 17.1 Hz, 1 H, CHH), 4.47 (s, 1 H, CH), 6.97 (d, J = 8.0 Hz,

2 H, ArH), 7.05 (d, J = 8.0 Hz, 2 H, ArH), 7.16 (d, J = 6.8 Hz, 2

H, ArH), 7.24 (d, J = 6.5 Hz, 2 H, ArH), 7.33 (d, J = 6.8 Hz, 3 H,

ArH), 7.54–7.57 (m, 2 H, ArH), 7.92 (s, 1 H, NH) ppm. ¹³C NMR

(75 MHz, CDCl₃): δ = 19.3, 21.1, 41.4, 48.3, 74.6, 117.3, 124.9,

126.2, 128.6, 129.4, 130.0, 130.6, 131.7, 134.9, 137.9, 141.6, 143.3,

150.7, 168.5, 197.9 ppm. MS (ES⁺): m/z (%) = 484.2 (100) [M +

H]⁺DART-HRMS: calcd. for C₂₉H_{2 7}Cl₁N₃O₂[M + H]⁺

484.17918; found 484.17656.

7.1 Hz, 3 H, OCH₂CH₃), 1.95 (s, 3 H, CH₃), 2.80 (d, J = 16.4 Hz,

1 H, CHH), 3.71 (d, J = 16.4 Hz, 1 H, CHH), 4.00 (q, J = 7.1 Hz,

2 H, OCH₂CH₃), 5.77 (s, 1 H, CH), 7.04 (d, J = 9.5 Hz, 1 H, ArH),

7.16 (d, J = 8.0 Hz, 1 H, ArH), 7.23–7.26 (m, 5 H, ArH), 7.32–

7.43 (m, 3 H, ArH), 7.43 (d, J = 8.0 Hz, 1 H, ArH), 7.58–7.60 (m,

2 H, NH and ArH) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 14.1,

19.2, 40.3, 45.4, 60.2, 74.7, 102.7, 125.8, 126.4, 127.4, 128.6, 129.0,

129.5, 129.8, 131.3, 133.6, 136.6, 146.0, 153.1, 166.1 ppm. MS

(ES⁺) m/z (%) = 568.0 (100) [M + H]⁺. C₂₉H₂₄Cl₃N₃O₃(exact mass:

567.0883): calcd. C 61.23, H 4.25, N 7.39; found C 60.98, H 4.37,

N 7.51.

9-Acetyl-1-(4-chlorophenyl)-3-(2-fluorophenyl)-8-methyl-10-(4-meth-

ylphenyl)-1,2,7-triazaspiro[4.5]deca-2,8-dien-6-one (20b): Yield 44%

(0.13 g from 0.15 g) as a white solid, m.p. 197–199 °C. R_f= 0.19

Ethyl 1-(4-Chlorophenyl)-10-(2,6-dichlorophenyl)-3-(2-fluorophenyl)-

8-methyl-6-oxo-1,2,7-triazaspiro[4.5]deca-2,8-diene-9-carboxylate

(19b): Yield 45% (0.19 g from 0.25 g) as a white solid, m.p. 223–

(80:20, hexane/EtOAc). IR (KBr): ν = 1661 (CONH), 1702

˜

225 °C. R = 0.49 (80:20, hexane/EtOAc). IR (KBr): ν = 1646

˜

f

(COCH₃) cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 1.94 (s, 3 H,

CH₃), 1.98 (s, 3 H, COCH₃), 2.27 (s, 3 H, ArCH₃), 3.50 (d, J =

17.7 Hz, 1 H, CHH), 3.59 (d, J = 17.7 Hz, 1 H, CHH), 4.58 (s, 1

H, CH), 6.96–7.12 (m, 5 H, ArH), 7.16 (d, J = 6.8 Hz, 2 H, ArH),

7.24–7.33 (m, 5 H, ArH and NH), 7.67–7.73 (m, 1 H, ArH) ppm.

¹³C NMR (75 MHz, CDCl₃): δ = 19.1, 21.1, 30.2, 43.5, 47.5, 74.4,

116.1, 116.4, 117.4, 123.6, 124.3, 128.7, 128.8, 129.8, 130.7, 130.8,

134.4, 137.9, 141.1, 142.7, 146.5, 168.8, 198.4 ppm. MS (ES+): m/z

(%) = 502.1 (100) [M + H]⁺, 504.1 (33) [M + 3]⁺. C₂₉H₂₅ClFN₃O₂

(exact mass: 501.1619): calcd. C 69.39, H 5.02, N 8.37; found C

69.52, H 4.86, N 8.49.

(CONH), 1703 (CO₂Et) cm^–1. ¹H NMR (300 MHz, CDCl₃): δ =

1.08 (t, J = 7.1 Hz, 3 H, OCH₂CH₃), 2.01 (s, 3 H, CH₃), 2.85, 2.88

1

2

1

(dd, J = 17.4, J = 1.8 Hz, 1 H, CHH), 3.86, 3.90 (dd, J = 17.4,

²J = 1.8 Hz, 1 H, CHH), 4.01 (q, J = 7.1 Hz, 2 H, OCH₂CH₃),

5.73 (d, J = 1.1 Hz, 1 H, CH), 6.98–7.04 (m, 1 H, ArH), 7.09–7.16

(m, 3 H, ArH), 7.33–7.37 (m, 7 H, ArH and NH), 7.81–7.86 (m, 1

H, ArH) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 14.1, 19.2, 43.3,

46.2, 60.3, 73.4, 102.8, 116.5, 119.9, 124.3, 125.7, 128.4, 128.7,

129.1, 129.8, 131.5, 135.2, 136.4, 138.3, 143.1, 145.7, 148.4, 165.9,

167.6 ppm. MS (ES⁺): m/z (%) = 586.0 (100) [M + H]⁺.

C₂₉H₂₃Cl₃FN₃O₃(exact mass: 585.0789): calcd. C 59.35, H 3.95,

N 7.16; found C 59.13, H 4.11, N 7.19.

9-Acetyl-1,3-bis(4-chlorophenyl)-8-methyl-10-(4-methylphenyl)-

1,2,7-triazaspiro[4.5]deca-2,8-dien-6-one (20c): Yield 56% (0.17 g

from 0.15 g) as a white solid, m.p. 203–205 °C. R_f= 0.25 (80:20,

Ethyl 1,3-Bis(4-chlorophenyl)-10-(2,6-dichlorophenyl)-8-methyl-6-

oxo-1,2,7-triazaspiro[4.5]deca-2,8-diene-9-carboxylate (19c): Yield

5454

www.eurjoc.org

Eur. J. Org. Chem. 2008, 5446–5460

Spiro-Fused Quinolin-2-ones from Baylis–Hillman Adducts

hexane/EtOAc). IR (KBr): ν = 1671 (CONH), 1699 (COCH ) cm^–1.

1 H, CHH), 4.71 (d, J = 4.8 Hz, 1 H, CHOH), 6.14 (d, J = 4.8 Hz,

1 H, CHOH), 6.94 (d, J = 7.8 Hz, 1 H, ArH), 7.04 (t, J = 7.4 Hz,

˜

3

¹H NMR (200 MHz, CDCl₃): δ = 1.93 (s, 3 H, CH₃), 1.97 (s, 3 H,

CH₃), 2.29 (s, 3 H, ArCH₃), 3.21 (d, J = 16.9 Hz, 1 H, CHH), 3.45 1 H, ArH), 7.28 (t, J = 7.7 Hz, 1 H, ArH), 7.36 (d, J = 7.4 Hz, 1

(d, J = 16.9 Hz, 1 H, CHH), 4.48 (s, 1 H, CH), 6.96 (d, J = 7.9 Hz,

2 H, ArH), 7.06 (d, J = 7.9 Hz, 2 H, ArH), 7.14 (d, J = 8.5 Hz, 2

H, ArH), 7.24–7.31 (m, 5 H, ArH and NH), 7.47 (d, J = 8.4 Hz, 2

H, ArH) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 19.3, 21.1, 30.2,

41.4, 48.3, 74.8, 117.4, 124.8, 127.3, 128.6, 128.9, 130.0, 130.7,

134.9, 135.2, 138.0, 141.3, 143.0, 149.4, 168.3, 197.9 ppm. MS

(ES+): m/z (%) = 517.1 (100) [M + H]⁺. C₂₉H₂₅Cl₂N₃O₂(exact

mass: 517.1324): calcd. C 67.19, H 4.86, N 8.11; found C 67.38, H

4.70, N 8.18.

H, ArH), 7.52 (d, J = 8.5 Hz, 2 H, ArH), 7.71–7.75 (m, 1 H, ArH),

10.55 (s, 1 H. NH) ppm. ¹³C NMR (75 MHz, [D₆]DMSO): δ =

37.8, 69.3, 87.4, 115.4, 122.6, 125.0, 127.7, 128.6, 128.7, 129.0,

129.1,135.0, 136.4, 155.7, 166.7 ppm. MS (ES+): m/z (%) = 329.4

(100) [M + H]⁺. C₁₇H₁₃ClN₂O₃(exact mass: 328.0615): calcd. C

62.11, H 3.99, N 8.52; found C 61.94, H 4.15, N 8.72.

4Ј-Hydroxy-3-(4-methylphenyl)-1ЈH,4H-spiro[isoxazole-5,3Ј-quin-

olin]-2Ј(4ЈH)-one (5d): Yield 69% (0.22 g from 0.40 g) as a white

solid, m.p. Ͼ250 °C. R = 0.34 (94:6, CHCl /MeOH). IR (KBr): ν

˜

f

3

General Procedure for the Synthesis of 5a–d, 6a–d, 33a–d, 35a–d,

40a–d, and 41, as Exemplified for 5a: A two-neck flask charged

with a suspension of 3a (0.5 g, 1.35 mmol) in THF (5 mL) was

heated at 70 °C. When the compound was properly dissolved, water

(3.0 mL) and indium powder (0.621 g, 5.40 mmol) were added

whilst stirring. Concentrated HCl (0.88 mL, 8.10 mmol) was added

dropwise, and the reaction was continued for 5 min. The reaction

was quenched with 10 % aqueous NaHCO₃whilst stirring, and

EtOAc (50 mL) was added. The mixture was passed thorough a bed

of Celite with EtOAc, and the resulting mixture was partitioned in

a separating funnel. The aqueous layer was separated and further

extracted with EtOAc (2ϫ20 mL). The organic layers were com-

bined, washed with brine (50 mL), dried (anhydrous Na₂SO₄), and

concentrated in vacuo to afford a residue, which upon column

chromatography on deactivated silica gel (60–120 mesh) (25 mL of

water was added to 100 g of silica gel and thoroughly mixed) with

CHCl₃/MeOH (99.5:0.5, v/v) as the eluent, furnished 0.26 g (66%)

of 9a as a white solid.

= 1668 (CONH), 3402 (OH) cm^–1

.

¹H NMR (300 MHz, [D₆]-

DMSO): δ = 2.37 (s, 3 H, ArCH₃), 3.60 (d, J = 16.9 Hz, 1 H,

CHH), 3.81 (d, J = 16.9 Hz, 1 H, CHH), 4.70 (s, 1 H, CHOH),

6.13 (s, 1 H, CHOH), 6.96 (d, J = 7.4 Hz, 2 H, ArH), 7.30–7.52

(m, 5 H, ArH), 7.62 (d, J = 7.4 Hz, 1 H, ArH), 10.53 (s, 1 H, NH)

ppm. ¹³C NMR (50 MHz, [D₆]DMSO): δ = 21.0, 38.0, 69.4, 86.9,

115.3, 122.5, 125.0, 126.0, 126.7, 128.7, 129.0, 129.5, 136.5, 140.2,

156.2, 166.8 ppm. MS (ES+): m/z (%) = 309.0 (100) [M + H]⁺.

C₁₈H₁₆N₂O₃(exact mass: 308.1161): calcd. C 70.12, H 5.23, N 9.09;

found C 69.93, H 5.11, N 9.21.

4Ј-Hydroxy-6Ј,7Ј-dimethoxy-3-phenyl-1ЈH,4H-spiro[isoxazole-5,3Ј-

quinolin]-2Ј(4ЈH)-one (6a): Yield 56 % (0.18 g from 0.40 g) as a

white solid, m.p. 240–242 °C. R_f= 0.36 (94:6, CHCl₃/MeOH). IR

1

(KBr): ν = 1678 (CONH), 3469 (OH) cm^–1. H NMR (300 MHz,

˜

[D₆]DMSO): δ = 3.61 (d, J = 17.5 Hz, 1 H, CHH), 3.73 (s, 3 H,

OCH₃), 3.74 (s, 3 H, OCH₃), 3.79 (d, J = 17.5 Hz, 1 H, CHH),

4.61 (d, J = 4.8 Hz, 1 H, CHOH), 5.98 (d, J = 4.8 Hz, 1 H,

CHOH), 6.59 (s, 1 H, ArH), 6.97 (s, 1 H, ArH), 7.46–7.48 (m, 3

H, ArH), 7.70–7.73 (m, 2 H, ArH), 10.28 (s, 1 H, CONH) ppm.

¹³C NMR (75 MHz, [D₆]DMSO): δ = 37.9, 55.6, 56.0, 69.2, 87.2,

100.6, 113.0, 116.3, 126.7, 128.8, 129.9, 130.3, 144.2, 149.3, 156.2,

166.4 ppm. MS (ES+): m/z (%) = 354.9 (100) [M + H]⁺DART-

HRMS: calcd. for C₁₉H₁₉N₂O₅[M + H]⁺355.1294; found

355.12797.

4Ј-Hydroxy-3-phenyl-1ЈH,4H-spiro[isoxazole-5,3Ј-quinolin]-2Ј(4ЈH)-

one (5a): M.p. 258–260 °C. R_f= 0.39 (94:6, CHCl₃/MeOH). IR

1

(KBr): ν = 1672 (CONH), 3405 (OH) cm^–1. H NMR (300 MHz,

˜

[D₆]DMSO): δ = 3.62 (d, J = 17.4 Hz, 1 H, CHH), 3.82 (d, J =

17.4 Hz, 1 H, CHH), 4.70 (d, J = 4.5 Hz, 1 H, CHOH), 6.12 (d, J

= 4.5 Hz, 1 H, CHOH), 6.95 (d, J = 7.8 Hz, 1 H, ArH), 7.04 (t, J

= 7.3 Hz, 1 H, ArH), 7.28 (t, J = 7.4 Hz, 1 H, ArH), 7.36 (d, J =

7.4 Hz, 1 H, ArH), 7.46–7.48 (m, 3 H, ArH), 7.70–7.72 (m, 2 H,

ArH), 10.53 (s, 1 H, CONH) ppm. ¹³C NMR (75 MHz, [D₆]-

DMSO): δ = 37.9, 69.3, 87.0, 115.3, 122.4, 124.9, 126.7, 128.6,

128.7, 128.8, 128.9, 130.3, 136.4, 156.3, 166.7 ppm. MS (ES+): m/z

(%) = 295.0 (100) [M + H]⁺. C₁₇H₁₄N₂O₃(exact mass: 294.1004):

calcd. C 69.38, H 4.79, N 9.52; found C 69.26, H 4.88, N 9.39.

3-(2-Fluorophenyl)-4Ј-hydroxy-6Ј,7Ј-dimethoxy-1ЈH,4H-spiro[isox-

azole-5,3Ј-quinolin]-2Ј(4ЈH)-one (6b): Yield 59 % (0.20 g from

0.40 g) as a white solid, m.p. 236–238 °C. R_f= 0.38 (94:6, CHCl₃/

1

MeOH). IR (KBr): ν = 1681 (CONH), 3373 (OH) cm^–1. H NMR

˜

(300 MHz, [D₆]DMSO): δ = 3.65 (d, J = 17.2 Hz, 1 H, CHH), 3.74

(s, 6 H, 2ϫOCH₃), 3.82 (d, J = 17.2 Hz, 1 H, CHH), 4.62 (d, J =

4.8 Hz, 1 H, CHOH), 6.02 (d, J = 4.8 Hz, 1 H, CHOH), 6.58 (s 1

H, ArH), 6.97 (s, 1 H, ArH), 7.27–7.38 (m, 2 H, ArH), 7.51–7.57

(m, 1 H, ArH), 7.77 (t, J = 7.5 Hz, 1 H, ArH), 10.32 (s, 1 H, NH)

ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 38.3, 55.7, 56.1, 69.2, 87.0,

3-(2-Fluorophenyl)-4Ј-hydroxy-1ЈH,4H-spiro[isoxazole-5,3Ј-quinol-

in]-2Ј(4ЈH)-one (5b): Yield 64% (0.06 g from 0.12 g) as a white so-

lid, m.p. 183–185 °C. R = 0.40 (94:6, CHCl /MeOH). IR (KBr): ν

˜

f

3

= 1672 (CONH), 3399 (OH) cm^–1

.

¹H NMR (300 MHz, [D₆]- 100.5, 113.1, 116.2, 116.8, 124.9, 129.4, 130.0, 132.3, 132.4, 144.3,

DMSO): δ = 3.65 (d, J = 16.8 Hz, 1 H, CHH), 3.84 (d, J = 16.8 Hz,

149.4, 152.7, 166.3 ppm. MS (ES+): m/z (%) = 373.0 (100) [M +

1 H, CHH), 4.71 (s, 1 H, CHOH), 6.15 (br. s, 1 H, CHOH), 6.94 H]⁺. C₁₉H₁₇FN₂O₅(exact mass: 372.1122): calcd. C 61.29, H 4.60,

(d, J = 7.8 Hz, 1 H, ArH), 7.01–7.06 (m, 1 H, ArH), 7.26–7.43 (m, N 7.52; found C 60.95, H 4.73, N 7.58.

4 H, ArH), 7.51–7.58 (m, 1 H, ArH), 7.77–7.80 (m, 1 H, ArH),

3-(4-Chlorophenyl)-4Ј-hydroxy-6Ј,7Ј-dimethoxy-1ЈH,4H-spiro[isox-

10.55 (s, 1 H, NH) ppm. ¹³C NMR (50 MHz, [D₆]DMSO): δ =

azole-5,3Ј-quinolin]-2Ј(4ЈH)-one (6c): Yield 55% (0.46 g from 1.0 g)

69.3, 86.8, 115.4, 116.5, 116.8, 122.5, 124.9, 125.0, 128.8, 129.1,

as a white solid, m.p. 243–245 °C. R_f= 0.37 (94:6, CHCl₃/MeOH).

129.4, 132.5, 136.4, 138.1, 152.9, 158.0, 161.3, 166.6 ppm. MS

IR (KBr): ν = 1689 (CONH), 3276 (OH) cm^{–1 1}H NMR

.

˜

(ES+): m/z (%) = 313.0 (100) [M + H]⁺. C₁₇H₁₃FN₂O₃(exact mass:

312.0910): calcd. C 65.38, H 4.20, N 8.97; found C 65.50, H 4.33,

N 9.10.

(300 MHz, [D₆]DMSO): δ = 3.59 (d, 1 H, J = 17.3 Hz, CHH), 3.73

(s, 6 H, 2ϫOCH₃), 3.76 (d, J = 17.3 Hz, 1 H, CHH), 4.63 (d, J =

4.8 Hz, 1 H, CHOH), 6.00 (d, J = 4.8 Hz, 1 H, CHOH), 6.60 (s, 1

H, ArH), 6.98 (s, 1 H, ArH), 7.53 (d, J = 8.4 Hz, 2 H, ArH), 7.74

(d, J = 8.4 Hz, 2 H, ArH), 10.29 (s, 1 H, CONH) ppm. ¹³C NMR

3-(4-Chlorophenyl)-4Ј-hydroxy-1ЈH,4H-spiro[isoxazole-5,3Ј-quin-

olin]-2Ј(4ЈH)-one (5c): Yield 79% (0.24 g from 0.37 g) as a white

solid, m.p. Ͼ250 °C. R = 0.38 (94:6, CHCl /MeOH). IR (KBr): ν (75 MHz, [D₆]DMSO): δ = 37.8, 55.7, 56.0, 69.2, 87.6, 100.6, 112.9,

˜

f

3

= 1672 (CONH), 3399 (OH) cm^–1

.

¹H NMR (300 MHz, [D₆]- 116.3, 127.7, 128.5, 129.0, 129.9, 135.0, 144.3, 149.3, 155.6,

DMSO): δ = 3.60 (d, J = 17.5 Hz, 1 H, CHH), 3.80 (d, J = 17.5 Hz,

166.4 ppm. MS (ES+): m/z (%) = 388.9 (100) [M + H]⁺.

Eur. J. Org. Chem. 2008, 5446–5460

www.eurjoc.org

5455

V. Singh, V. Singh, S. Batra

FULL PAPER

C₁₉H₁₇ClN₂O₅(exact mass: 388.0826): calcd. C 58.69, H 4.41, N

7.21; found C 58.83, H 4.29, N 7.03.

7.18–7.29 (m, 4 H, ArH), 7.55–7.60 (m, 3 H, ArH), 10.58 (s, 1 H,

CONH) ppm. ¹³C NMR (75 MHz, [D₆]DMSO): δ = 21.0, 36.6,

41.2, 83.5, 115.1, 121.3, 122.4, 127.4, 128.5, 129.4, 137.1, 140.1,

156.5, 166.3 ppm. MS (ES+): m/z (%) = 293.0 (100) [M + H]⁺.

C₁₈H₁₆N₂O₂(exact mass: 292.1212): calcd. C 73.95, H 5.52, N 9.58;

found C 74.12, H 5.72, N 9.45.

4Ј-Hydroxy-6Ј,7Ј-dimethoxy-3-(4-methylphenyl)-1ЈH,4H-spiro[isox-

azole-5,3Ј-quinolin]-2Ј(4ЈH)-one (6d): Yield 58 % (0.16 g from

0.34 g) as a white solid, m.p. 247–248 °C. R_f= 0.65 (94:6, CHCl₃/

1

MeOH): IR (KBr): ν = 1676 (CONH), 3438 (OH) cm^–1. H NMR

˜

(300 MHz, [D₆]DMSO): δ = 2.34 (s, 3 H, ArCH₃), 3.58 (d, J = 6Ј,7Ј-Dimethoxy-3-phenyl-1ЈH,4H-spiro[isoxazole-5,3Ј-quinolin]-

17.4 Hz, 1 H, CHH), 3.72 (s, 3 H, OCH₃), 3.73 (s, 3 H, OCH₃), 2Ј(4ЈH)-one (34a): Yield 63% (0.083 g from 0.155 g) as a white so-

3.78 (d, J = 17.4 Hz, 1 H, CHH), 4.58 (d, J = 4.8 Hz, 1 H, CHOH), lid, m.p. 225–227 °C. R = 0.62 (94:6, CHCl /MeOH). IR (KBr): ν

˜

f

3

1

5.96 (d, J = 4.8 Hz, 1 H, CHOH), 6.58 (s, 1 H, ArH), 6.96 (s, 1 H,

ArH), 7.26 (d, J = 8.0 Hz, 2 H, ArH), 7.59 (d, J = 8.0 Hz, 2 H,

= 1683 (CONH) cm^–1. H NMR (300 MHz, CDCl₃): δ = 3.22 (s,

2 H, CH₂), 3.34 (s, 1 H, CHH), 3.73 (s, 6 H, 2ϫOCH₃), 3.99 (d,

ArH), 10.24 (s, 1 H, CONH) ppm. ¹³C NMR (75 MHz, [D₆]- J = 17.2 Hz, 1 H, CHH), 6.61 (s, 1 H, ArH), 6.87 (s, 1 H, ArH),

DMSO): δ = 21.1, 38.7, 55.7, 56.0, 69.3, 87.1, 100.5, 113.0, 116.4,

126.1, 126.8, 129.6, 130.0, 140.3, 144.3, 149.3, 156.3, 166.6 ppm.

MS (ES+): m/z (%) = 368.9 (100) [M + H]⁺. C₂₀H₂₀N₂O₅(exact

mass: 368.1372): calcd. C 65.21, H 5.47, N 7.60; found C 65.21, H

5.47, N 7.60.

7.48–7.50 (m, 3 H, ArH), 7.69–7.72 (m, 2 H, ArH), 10.35 (s, 1 H,

CONH) ppm. ¹³C NMR (75 MHz, [D₆]DMSO): δ = 36.3, 41.3,

55.7, 56.0, 83.9, 100.6, 112.6, 113.0, 126.7, 128.9, 130.3, 130.5,

144.3, 148.2, 156.6, 165.9 ppm. MS (ES+): m/z (%) = 339.0 (100)

[M + H]⁺. C₁₉H₁₈N₂O₄(exact mass: 338.1267): calcd. C 67.44, H

5.36, N 8.28; found C 67.69, H 5.24, N 8.32.

3-Phenyl-1ЈH,4H-spiro[isoxazole-5,3Ј-quinolin]-2Ј(4ЈH)-one (33a):

Yield 65% (0.11 g from 0.20 g) as a white solid, m.p. 240–242 °C.

3-(2-Fluorophenyl)-6Ј,7Ј-dimethoxy-1ЈH,4H-spiro[isoxazole-5,3Ј-quin-

R = 0.71 (94:6, CHCl /MeOH). IR (KBr): ν = 1687 (CONH) cm^–1. olin]-2Ј(4ЈH)-one (34b): Yield 53% (0.18 g from 0.40 g) as a white

˜

f

3

¹H NMR (300 MHz, CDCl₃): δ = 3.21 (d, J = 16.8 Hz, 2 H, CH₂),

solid, m.p. 230–232 °C. R_f= 0.59 (94:6, CHCl₃/MeOH). IR (KBr):

3.42 (d, J = 16.4 Hz, 1 H, CHH), 4.17 (d, J = 16.4 Hz, 1 H, CHH), ν = 1684 (CONH) cm^–1. H NMR (300 MHz, CDCl ): δ = 2.76–

1

˜

3

6.84 (d, J = 7.8 Hz, 1 H, ArH), 7.04 (t, J = 7.4 Hz, 1 H, ArH), 2.94 (m, 3 H, 3ϫCHH), 3.33 (s, 6 H, 2ϫOCH₃), 3.66 (d, J =

7.21 (t, J = 7.1 Hz, 2 H, ArH), 7.40–7.42 (m, 2 H, ArH), 7.67–7.70 16.8 Hz, 1 H, CHH), 6.21 (s, 1 H, ArH), 6.47 (s, 1 H, ArH), 6.89–

(m, 3 H, ArH), 8.20 (s, 1 H, CONH) ppm. ¹³C NMR (75 MHz, 7.00 (m, 2 H, ArH), 7.13–7.19 (m, 1 H, ArH), 7.36–7.40 (m, 1 H,

[D₆]DMSO): δ = 36.6, 41.1, 83.7, 115.1, 121.3, 122.4, 126.7, 127.4,

ArH), 10.01 (s, 1 H, CONH) ppm. ¹³C NMR (75 MHz, [D₆]-

128.5, 128.9, 130.3, 137.1, 156.7, 166.2 ppm. MS (ES+): m/z (%) = DMSO): δ = 36.1, 42.8, 55.6, 56.0, 83.8, 100.6, 112.5, 113.0, 116.4,

279.1 (100) [M + H]⁺. DART-HRMS: calcd. for C₁₇H₁₅N₂O₂[M

+ H]⁺279.1134; found 279.1187.

116.7, 124.9, 129.2, 130.4, 132.3, 132.4, 144.3, 148.2, 153.1,

165.7 ppm. MS (ES+): m/z (%) = 357.0 (100) [M + H]⁺.

C₁₉H₁₇FN₂O₄(exact mass: 356.1172): calcd. C 64.04, H 4.81, N

7.86; found C 63.87, H 4.96, N 7.61.

3-(2-Fluorophenyl)-1ЈH,4H-spiro[isoxazole-5,3Ј-quinolin]-2Ј(4ЈH)-

one (33b): Yield 50% (0.21 g from 0.50 g) as a white solid, m.p.

218–220 °C. R = 0.70 (94:6, CHCl /MeOH). IR (KBr): ν = 1692 3-(4-Chlorophenyl)-6Ј,7Ј-dimethoxy-1ЈH,4H-spiro[isoxazole-5,3Ј-quin-

˜

f

3

(CONH) cm^–1

.

¹H NMR (300 MHz, CDCl₃): δ = 3.22 (d, J = olin]-2Ј(4ЈH)-one (34c): Yield 60% (0.18 g from 0.35 g) as a white

16.4 Hz, 1 H, CHH), 3.33 (dd, ¹J = 17.5, J = 2.1 Hz, 1 H, CHH),

solid, m.p. 228–230 °C. R_f= 0.75 (94:6, CHCl₃/MeOH). IR (KBr):

2

3.43 (d, J = 16.4 Hz, 1 H, CHH), 4.20 (dd, J = 17.5, J = 2.1 Hz, ν = 1683 (CONH) cm^–1. ¹H NMR (300 MHz, CDCl ): δ = 3.21 (d,

1

2

˜

3

1 H, CHH), 7.03 (d, J = 7.5 Hz, 1 H, ArH), 7.07–7.12 (m, 2 H,

ArH), 7.15–7.23 (m, 3 H, ArH), 7.37–7.44 (m, 1 H, ArH), 7.87–

7.92 (m, 1 H, ArH), 8.17 (s, 1 H, CONH) ppm. ¹³C NMR

(75 MHz, CDCl₃+ [D₆]DMSO): δ = 37.4, 43.7, 43.8, 83.7, 83.8,

115.6, 116.1, 116.4, 116.9, 117.0, 120.5, 122.9, 124.2, 124.3, 127.7,

128.4, 128.9, 130.0, 131.7, 131.8, 136.7, 152.7, 152.8, 167.0 ppm.

J = 17.1 Hz, 1 H, CHH), 3.33 (d, J = 2.1 Hz, 2 H, CH₂), 3.71 (s,

3 H, OCH₃), 3.72 (s, 3 H, OCH₃), 4.02 (d, J = 17.1 Hz, 1 H, CHH),

6.59 (s, 1 H, ArH), 6.85 (s, 1 H, ArH), 7.28–7.38 (m, 2 H, ArH),

7.51–7.58 (m, 1 H, ArH), 7.74–7.79 (m, 1 H, ArH), 10.38 (s, 1 H,

CONH) ppm. ¹³C NMR (75 MHz, [D₆]DMSO): δ = 36.2, 42.8,

55.6, 56.0, 83.8, 100.5, 112.5, 112.9, 116.5, 116.8, 125.0, 129.3,

MS (ES+): m/z (%) = 297.0 (100) [M + H]⁺. C₁₇H₁₃FN₂O₂(exact 130.4, 132.4, 144.3, 148.1, 153.14, 165.8 ppm. MS (ES+): m/z (%)

mass: 296.0961): calcd. C 68.91, H 4.42, N 9.45; found C 69.19, H

4.25, N 9.31.

= 373.1 (100) [M + H]⁺. C₁₉H₁₇ClN₂O₄(exact mass: 372.0877):

calcd. C 61.21, H 4.60, N 7.51; found C 61.47, H 4.46, N 7.68.

3-(4-Chlorophenyl)-1ЈH,4H-spiro[isoxazole-5,3Ј-quinolin]-2Ј(4ЈH)-

one (33c): Yield 65% (0.16 g from 0.30 g) as a white solid, m.p.

6Ј,7Ј-Dimethoxy-3-(4-methylphenyl)-1ЈH,4H-spiro[isoxazole-5,3Ј-

quinolin]-2Ј(4ЈH)-one (34d): Yield 67 % (0.17 g from 0.30 g) as a

200–202 °C. R = 0.72 (94:6, CHCl /MeOH). IR (KBr): ν = 1676 white solid, m.p. 230–232 °C. R_f= 0.75 (94:6, CHCl₃/MeOH). IR

˜

f

3

(CONH), 3446 (OH) cm^–1. H NMR (300 MHz, CDCl₃): δ = 3.31

(s, 2 H, CH₂), 3.99 (d, J = 16.5 Hz, 1 H, CHH), 4.07 (d, J =

16.5 Hz, 1 H, CHH), 6.96 (d, J = 7.8 Hz, 2 H, ArH), 7.21–7.32 (m,

(KBr): ν = 1683 (CONH) cm^–1. H NMR (300 MHz, CDCl ): δ =

1

˜

3

2.34 (s, 3 H, ArCH₃), 3.15 (d, J = 17.1 Hz, 1 H, CHH), 3.27 (d, J

= 2.2 Hz, 2 H, CH₂), 3.71 (s, 3 H, OCH₃), 3.72 (s, 3 H, OCH₃),

2 H, ArH), 7.50–7.55 (m, 2 H, ArH), 7.71–7.73 (m, 2 H, ArH), 3.97 (d, J = 17.1 Hz, 1 H, CHH), 6.59 (s, 1 H, ArH), 6.85 (s, 1 H,

10.62 (s, 1 H, CONH) ppm. ¹³C NMR (75 MHz, [D₆]DMSO): δ =

36.5, 41.0, 84.1, 115.1, 121.2, 122.5, 127.4, 127.8, 128.4, 128.5,

128.9, 134.9, 137.1, 155.9, 166.1 ppm. MS (ES+): m/z (%) = 313.1

(100) [M + H]⁺. C₁₇H₁₃ClN₂O₂(exact mass: 312.0666): calcd. C

69.57, H 4.86, N 9.01; found C 69.28, H 4.98, N 9.12.

ArH), 7.27 (d, J = 7.8 Hz, 2 H, ArH), 7.58 (d, J = 7.8 Hz, 2 H,

ArH), 10.35 (s, 1 H, CONH) ppm. ¹³C NMR (75 MHz, [D₆]

DMSO): δ = 21.0, 36.3, 41.4, 55.7, 56.0, 83.7, 100.5, 112.6, 112.9,

126.2, 130.5, 140.2, 144.3, 148.2, 156.5, 166.0 ppm. MS (ES+): m/z

(%) = 353.1 (100) [M + H]⁺. C₂₀H₂₀N₂O₄(exact mass: 352.1423):

calcd. C 68.17, H 5.72, N 7.95; found C 67.96, H 5.76, N 7.88.

3-(4-Methylphenyl)-1ЈH,4H-spiro[isoxazole-5,3Ј-quinolin]-2Ј(4ЈH)-

one (33d): Yield 65% (0.16 g from 0.30 g) as a white solid, m.p.

3Ј-Phenyl-5,8-dihydro-4ЈH,6H-spiro[1,3-dioxolo[4,5-g]quinoline-

207–209 °C. R = 0.75 (94:6, CHCl /MeOH). IR (KBr): ν = 1687 7,5Ј-isoxazol]-6-one (35a): Yield 56% (0.09 g from 0.20 g) as a white

˜

f

3

(CONH), 3460 f (OH) cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 2.35 solid, m.p. 218–220 °C. R_f= 0.70 (94:6, CHCl₃/MeOH). IR (KBr):

(s, 3 H, ArCH₃), 3.30 (s, 2 H, CH₂), 3.33 (d, J = 17.0 Hz, 1 H,

CHH), 4.00 (d, J = 17.0 Hz, 1 H, CHH), 6.93–7.18 (m, 1 H, ArH),

ν = 1687 (CONH) cm^–1. ¹H NMR (300 MHz, CDCl ): δ = 3.15 (d,

J = 16.6 Hz, 1 H, CHH), 3.25 (d, J = 16.9 Hz, 1 H, CHH), 3.33

˜

3

5456

www.eurjoc.org

Eur. J. Org. Chem. 2008, 5446–5460

Spiro-Fused Quinolin-2-ones from Baylis–Hillman Adducts

(d, J = 16.6 Hz, 1 H, CHH), 4.10 (d, J = 16.9 Hz, 1 H, CHH), 5.97 (C=N), 3321 (OH) cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 2.73 (s,

(d, J = 2.0 Hz, 2 H, OCH₂O), 6.49 (s, 1 H, ArH), 6.68 (s, 1 H, 3 H, CH₃), 4.35 (s, 2 H, CH₂), 6.97–7.08 (m, 2 H, ArH), 7.26 (d,

ArH), 7.30–7.45 (m, 3 H, ArH), 7.65–7.68 (m, 2 H, ArH), 9.45 (s,

1 H, CONH) ppm. ¹³C NMR (75 MHz, CDCl₃+ TFA): δ = 37.1, (m, 2 H, ArH), 7.88 (s, 1 H, ArH), 7.99 (d, J = 7.4 Hz, 1 H, ArH),

42.8, 83.6, 98.6, 98.7, 101.8, 109.0, 113.5, 113.6, 127.2, 127.9, 128.6,

9.38 (s, 1 H, NOH) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 23.2,

J = 5.7 Hz, 2 H, ArH), 7.43 (d, J = 6.3 Hz, 2 H, ArH), 7.60–7.68

128.7, 129.1, 131.3, 145.1, 147.9, 157.3 ppm. MS (ES+): m/z (%) = 31.8, 116.1, 116.4, 124.0, 124.1, 124.4, 124.5, 126.0, 127.3, 128.1,

323.0 (100) [M + H]⁺DART-HRMS: calcd. for C₁₈H₁₅N₂O₄[M +

H]⁺323.1032; found 323.1020.

128.8, 129.1, 130.1, 131.0, 131.1, 135.8, 146.4, 154.2, 158.6 ppm.

MS (ES+): m/z (%) = 295.2 (100) [M + H]⁺. C₁₈H₁₅FN₂O (exact

mass: 294.1168): calcd. C 73.45, H 5.14, N 9.52; found C 73.64, H

5.02, N 9.47.

3Ј-(2-Fluorophenyl)-5,8-dihydro-4ЈH,5H-spiro[1,3-dioxolo[4,5-g]quin-

oline-7,5Ј-isoxazol]-6-one (35b): Yield 77% (0.19 g from 0.30 g) as

a white solid, m.p. 238–240 °C. R_f= 0.60 (94:6, CHCl₃/MeOH). IR

1-(4-Chlorophenyl)-2-(2-methylquinolin-3-yl)ethan-1-one Oxime

(KBr): ν = 1687 (CONH) cm^–1. ¹H NMR (300 MHz, [D ]DMSO): (40c): Yield 65% (0.16 g from 0.30 g) as a white solid, m.p. 202–

˜

6

δ = 3.47 (d, J = 6.9 Hz, 2 H, CH₂), 4.08–4.18 (m, 2 H, CH₂), 6.09

204 °C. R = 0.36 (94:6, CHCl /MeOH). IR (KBr): ν = 1610

˜

f 3

(d, J = 1.6 Hz, 2 H, OCH₂O), 6.67 (s, 1 H, ArH), 6.85 (s, 1 H, (C=N), 3389 (OH) cm^–1. ¹H NMR (300 MHz, [D₆]DMSO): δ =

ArH), 7.40–7.51 (m, 2 H, ArH), 7.63–7.70 (m, 1 H, ArH), 7.86–

2.71 (s, 3 H, CH₃), 4.25 (s, 2 H, CH₂), 7.40 (d, J = 8.7 Hz, 2 H,

ArH), 7.45 (d, J = 7.1 Hz, 1 H, ArH), 7.60–7.65 (m, 1 H, ArH),

7.91 (m, 1 H, ArH), 10.58 (s, 1 H, CONH) ppm. ¹³C NMR

(75 MHz, [D₆]DMSO): δ = 36.3, 42.6, 42.7, 83.4, 97.2, 101.0, 108.7, 7.69 (d, J = 8.7 Hz, 2 H, ArH), 7.77 (d, J = 7.8 Hz, 1 H, ArH),

113.5, 116.4, 116.7, 124.8, 124.9, 129.2, 131.0, 131.1, 132.3, 132.4,

142.6, 146.3, 153.0, 153.1, 165.7 ppm. MS (ES+): m/z (%) = 341.0

(100) [M + H]⁺. C₁₈H₁₃ClN₂O₄(exact mass: 340.0859): calcd. C

63.53, H 3.85, N 8.23; found C 63.81, H 3.70, N 8.03.

7.87 (d, J = 8.3 Hz, 1 H, ArH), 11.70 (s, 1 H, NOH) ppm. ¹³C

NMR (75 MHz, CDCl₃): δ = 23.2, 28.5, 125.8, 126.7, 127.2, 127.8,

128.5, 128.7, 129.1, 133.3, 134.6, 145.8, 153.0, 158.3 ppm. MS

(ES+): m/z (%) = 311.2 (100) [M + H]⁺. C₁₈H₁₅ClN₂O (exact mass:

310.0873): calcd. C 69.57, H 4.86, N 9.01; found C 69.34, H 5.03,

N 9.12.

3Ј-(4-Chlorophenyl)-5,8-dihydro-4ЈH,5H-spiro[1,3-dioxolo[4,5-g]quin-

oline-7,5Ј-isoxazol]-6-one (35c): Yield 58% (0.22 g from 0.38 g) as

a white solid, m.p. Ͼ254 °C. R_f= 0.73 (94:6, CHCl₃/MeOH). IR 1-(4-Methylphenyl)-2-(2-methylquinolin-3-yl)ethan-1-one Oxime

(KBr): ν = 1680 (CONH) cm^–1. ¹H NMR (300 MHz, [D ]DMSO): (40d): Yield 67% (0.33 g from 0.60 g) as a white solid, m.p. 188–

˜

6

δ = 3.21 (s, 2 H, CH₂), 3.35 (d, J = 17.1 Hz, 1 H, CHH), 3.98 (d,

J = 17.1 Hz, 1 H, CHH), 5.98 (d, J = 1.3 Hz, 2 H, OCH₂O), 6.57

(s, 1 H, ArH), 6.85 (s, 1 H, ArH), 7.55 (d, J = 8.5 Hz, 2 H, ArH),

7.73 (d, J = 8.5 Hz, 2 H, ArH), 10.44 (s, 1 H, CONH) ppm. ¹³C

189 °C. R = 0.34 (94:6, CHCl /MeOH). IR (KBr): ν = 1607

˜

f 3

(C=N), 3417 (OH) cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 2.33 (s,

3 H, ArCH₃), 2.84 (s, 3 H, CH₃), 4.28 (s, 2 H, CH₂), 7.13 (d, J =

8.1 Hz, 1 H, ArH), 7.39–7.44 (m, 1 H, ArH), 7.52 (d, J = 8.1 Hz,

NMR (75 MHz, [D₆]DMSO): δ = 36.4, 41.0, 83.9, 97.2, 101.0, 2 H, ArH), 7.61–7.64 (m, 2 H, ArH), 7.77 (s, 1 H, ArH), 8.03 (d, J

108.7, 113.5, 127.8, 128.4, 128.9, 131.1, 134.9, 142.6, 146.4, 155.9,

= 8.2 Hz, 1 H, ArH), 9.24 (s, 1 H, NOH) ppm. ¹³C NMR (75 MHz,

165.8 ppm. MS (ES+): m/z (%) = 356.9 (100) [M + H]⁺. CDCl₃): δ = 20.7, 23.2, 28.6, 125.8, 126.0, 126.7, 127.2, 127.9,

C₁₈H₁₃ClN₂O₄(exact mass: 356.0564): calcd. C 60.60, H 3.67, N

7.85; found C 60.35, H 3.79, N 7.98.

128.7, 129.1, 129.5, 133.0, 133.3, 138.3, 145.8, 153.8, 158.3 ppm.

MS (ES+): m/z (%) = 291.2 (100) [M + H]⁺. C₁₉H₁₈N₂O (exact

mass: 290.1419): calcd. C 78.59, H 6.25, N 9.65; found C 78.41, H

6.11, N 9.76.

3Ј-(4-Methylphenyl)-5,8-dihydro-4ЈH,5H-spiro[1,3-dioxolo[4,5-g]quin-

oline-7,5Ј-isoxazol]-6-one (35d): Yield 61% (0.26 g from 0.40 g) as

a white solid, m.p. Ͼ250 °C. R_f= 0.61 (94:6, CHCl₃/MeOH). IR 2-(2-Methylquinolin-3-yl)-1-phenylethan-1-one (41a): Yield 14 %

1

(KBr): ν = 1683 (CONH) cm^–1. H NMR (300 MHz, CDCl ): δ = (0.13 g from 1.20 g) as a white solid, m.p. 111–113 °C, R_f= 0.80

˜

3

2.50 (s, 3 H, ArCH₃), 2.66 (s, 1 H, CH), 3.33 (s, 1 H, CH), 3.49 (d,

(94:6, CHCl /MeOH). IR (KBr): ν = 1687 (CO) cm^–1. ¹H NMR

˜

3

J = 17.1 Hz, 1 H, CHH), 4.11 (d, J = 17.1 Hz, 1 H, CHH), 6.12

(300 MHz, CDCl₃): δ = 2.69 (s, 3 H, CH₃), 4.49 (s, 2 H, CH₂),

(d, J = 1.4 Hz, 2 H, OCH₂O), 6.70 (s, 1 H, ArH), 6.99 (s, 1 H, 7.25–7.28 (m, 1 H, ArH), 7.44–7.54 (m, 3 H, ArH), 7.60–7.73 (m,

ArH), 7.43 (d, J = 8.0 Hz, 2 H, ArH), 7.73 (d, J = 8.0 Hz, 2 H,

3 H, ArH), 7.88 (s, 1 H, ArH), 8.01–8.08 (m, 3 H, ArH) ppm. ¹³C

ArH), 10.58 (s, 1 H, CONH) ppm. ¹³C NMR (75 MHz, CDCl₃+ NMR (75 MHz, CDCl₃): δ = 23.6, 43.1, 126.0, 127.2, 127.5, 128.4,

TFA): δ = 21.0, 36.4, 41.3, 83.3, 97.2, 100.9, 108.7, 113.6, 126.1,

128.5, 128.9, 129.2, 133.7, 136.6, 137.2, 147.1, 158.6, 196.7 ppm.

126.6, 129.4, 131.2, 140.1, 142.5, 146.3, 156.4, 165.9 ppm. MS

MS (ES+) m/z (%) = 262.2 (100) [M + H]⁺. C₁₉H₁₆O₂(exact mass:

(ES+): m/z (%) = 337.0 (100) [M + H]⁺. DART-HRMS: calcd. for 261.1154): calcd. C 82.58, H 5.84; found C 82.58, H 5.84.

C₁₉H₁₇N₂O₄[M + H]⁺337.1188; found 337.1168.

1-(4-Chlorophenyl)-2-(2-methylquinolin-3-yl)ethan-1-one (41c):

2-(2-Methylquinolin-3-yl)-1-phenylethan-1-one Oxime (40a): Yield: Yield 95% (0.18g from 0.20 g) as a white solid, m.p. 148–149 °C,

52% (0.48 g from 1.20 g) as a shiny white solid, m.p. 233–235 °C.

R = 0.81 (94:6, CHCl /MeOH). IR (KBr): ν = 1679 (CO) cm^–1.

˜

f 3

R = 0.65 (94:6, CHCl /MeOH). IR (KBr): ν = 1719 (COCH ), ¹H NMR (300 MHz, CDCl₃): δ = 2.65 (s, 3 H, CH₃), 4.46 (s, 2 H,

˜

f

3

3424 (OH) cm^–1. H NMR (300 MHz, [D₆]DMSO): δ = 2.50 (s, 3

CH₂), 7.48–7.51 (m, 3 H, ArH), 7.64–7.74 (m, 2 H, ArH), 7.87 (s,

1

H, CH₃), 4.04 (s, 2 H, CH₂), 7.08–7.15 (m, 3 H, ArH), 7.18–7.23 1 H, ArH), 7.99–8.04 (m, 3 H, ArH) ppm. ¹³C NMR (75 MHz,

(m, 1 H, ArH), 7.36–7.42 (m, 2 H, ArH), 7.44–7.48 (m, 2 H, ArH), CDCl₃): δ = 23.6, 29.8. 43.0, 126.1, 127.2, 128.1, 128.4, 129.2,

7.52 (d, J = 7.5 Hz, 1 H, ArH), 7.66 (d, J = 8.4 Hz, 1 H, ArH),

11.40 (s, 1 H, NOH) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 23.2,

28.7, 125.7, 126.0, 126.7, 127.2, 127.8, 128.4, 128.6, 128.8, 129.3,

133.3, 135.8, 145.8, 153.9, 158.2 ppm. MS (ES+): m/z (%) = 277.2

(100) [M + H]⁺. HRMS (EI): calcd. for C₁₈H₁₆N₂O [M]⁺276.1263;

found 276.1267.

129.3, 129.4, 129.8, 134.9, 137.3, 140.2, 147.1, 158.5, 195.5 ppm.

MS (ES+): m/z (%) = 296.2 (100) [M + H]⁺. C₁₈H₁₄ClNO (exact

mass: 295.0764): calcd. C 73.10; H, 4.77; N, 4.74; found C 73.03,

H 4.44, N, 4.83.

General Procedure for the Synthesis of 41a,c from 40a,c, as Exem-

plified for 41a: To a stirred solution of 40a (0.05 g, 0.18 mmol) in

THF/H₂O (3.0 mL, 1:1) was added aqueous HCl (1.0 mL, 35% v/

v), and the mixture was refluxed for 1 h. After completion of the

1-(2-Fluorophenyl)-2-(2-methylquinolin-3-yl)ethan-1-one Oxime

(40b): Yield 65% (0.27 g from 0.50 g) as a white solid, m.p. 165–

166 °C. R = 0.64 (94:6, CHCl /MeOH). IR (KBr): ν = 1610 reaction, the THF was evaporated, the reaction mixture was

˜

f

3

Eur. J. Org. Chem. 2008, 5446–5460

www.eurjoc.org

5457

V. Singh, V. Singh, S. Batra

FULL PAPER

poured into 10% NaHCO₃, and the resulting mixture was extracted

with EtOAc (2ϫ20 mL). The combined organic layers were dried

with anhydrous Na₂SO₄and concentrated to afford a white solid

residue. The crude product was recrystallized from EtOAc/hexanes

to afford 0.042 g (89%) of 41a as a white solid.

(75 MHz, CDCl₃): δ = 64.9, 73.7, 115.1, 116.1, 122.3, 123.0, 126.2,

126.6, 127.3, 128.5, 128.7, 130.7, 133.1, 135.1, 141.3, 144.9,

168.4 ppm. MS (FAB+) m/z (%) = 437 (100) [M + H]⁺.

C₂₃H₁₇Cl₂N₃O₂(exact mass: 437.0698): calcd. C 63.03, H 3.91, N

9.59; found C 63.27, H 4.11, N 9.41.

General Procedure for the Synthesis of 40a,c from 41a,c, as Exem-

2-(4-Chlorophenyl)-4Ј-hydroxy-5-(4-methylphenyl)-2,4-dihydro-1ЈH-

spiro[pyrazole-3,3Ј-quinolin]-2Ј(4ЈH)-one (9d): M.p. Ͼ250 °C. R_f=

plified for 40a: A reaction mixture containing 41a (0.05 g,

0.19 mmol), NH₂OH·HCl (0.02 g, 0.28 mmol), and CH₃CO₂Na 0.27 (80:20, hexane/EtOAc). IR (KBr): ν = 1673 (CONH) cm^–1. ¹H

˜

(0.02 g, 0.28 mmol) in MeOH (3.0 mL) was refluxed for 1 h. Excess

MeOH was then evaporated from the reaction mixture, cold water

(10 mL) was added, and the mixture was extracted with EtOAc

(2ϫ20 mL). The combined organic layers were dried with anhy-

drous Na₂SO₄and concentrated to furnish a white solid residue.

The crude product was recrystallized from EtOAc/hexanes to af-

ford 0.05 g (94%) of 40a as a white solid.

NMR (300 MHz, CDCl₃): δ = 2.34 (s, 3 H, ArCH₃), 3.11 (d, J =

17.1 Hz, 1 H, CHH), 3.80 (d, J = 17.1 Hz, 1 H, CHH), 5.49 (d, J

= 5.7 Hz, 1 H, CHOH), 5.66 (s, 1 H, CHOH), 6.97 (d, J = 7.5 Hz,

1 H, ArH), 7.08–7.23 (m, 7 H, ArH), 7.50–7.56 (m, 4 H, ArH),

10.09 (s, 1 H, NH) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 21.0,

64.8, 73.2, 115.0, 115.8, 121.8, 122.9, 125.6, 126.2, 126.5, 128.4,

128.6, 129.0, 129.2, 135.1, 138.3, 141.6, 146.0, 168.5 ppm. MS

(ES+): m/z (%) = 418.0 (100) [M + H]⁺. C₂₄H₂₀ClN₃O₂(exact

mass: 417.1244): calcd. C 68.98, H 4.82, N 10.06; found C 69.13,

H 4.72, N 10.18.

General Procedure for the Synthesis of 9a–e, 10a, 37a,c–e, as Exem-

plified for 9d: To a stirred solution of 7d (0.13 g, 0.35 mmol) in

glacial acetic acid (10 mL) iron powder (0.12 g, 2.11 mmol) was

added, and the reaction mixture was refluxed at 120 °C under nitro-

gen for 3 h. Upon completion of the reaction, the reaction mixture

was poured into ice-cold water whilst stirring to yield a solid, which

was filtered and washed with 10% NaHCO₃, followed by water.

The product was recrystallized from EtOAc to furnish 0.10 g (73%)

of 9d as a white solid.

2-(4-Chlorophenyl)-4Ј-hydroxy-5-(thiophen-2-yl)-2,4-dihydro-1ЈH-

spiro[pyrazole-3,3Ј-quinolin]-2Ј(4ЈH)-one (9e): Yield 80% (0.14 g

from 0.18 g) as a white solid, m.p. Ͼ250 °C. R_f= 0.21 (80:20, hex-

ane/EtOAc). IR (KBr): ν = 1681 (CONH) cm^–1¹H NMR

.

˜

(300 MHz, CDCl₃): δ = 3.16 (d, J = 17.3 Hz, 1 H, CHH), 3.61 (d,

J = 17.3 Hz, 1 H, CHH), 5.56 (d, J = 5.8 Hz, 1 H, CHOH), 6.24

(d, J = 5.8 Hz, 1 H, CHOH), 6.95 (d, J = 7.6 Hz, 1 H, ArH), 7.04–

7.07 (m, 4 H, ArH), 7.18–7.25 (m, 4 H, ArH), 7.41 (d, J = 7.2 Hz,

1 H, ArH), 7.55 (d, J = 7.2 Hz, 1 H, ArH), 10.63 (s, 1 H, NH)

ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 59.8, 64.8, 73.5, 115.1,

115.9, 122.1, 122.9, 126.1, 126.5, 127.5, 127.8, 128.5, 135.0, 141.2,

142.4, 168.2 ppm. MS (ES+): m/z (%) = 410.1 (100) [M + H]⁺.

C₂₁H₁₆ClN₃O₂S (exact mass: 409.0652): calcd. C 61.53, H 3.93, N

10.25; found C 61.40, H 4.12, N 10.14.

2-(4-Chlorophenyl)-4Ј-hydroxy-5-phenyl-2,4-dihydro-1ЈH-spiro[pyr-

azole-3,3Ј-quinolin]-2Ј(4ЈH)-one (9a): Yield 95 % (0.24 g from

0.30 g) as a white solid, m.p. Ͼ250 °C. R_f= 0.25 (80:20, hexane/

1

EtOAc). IR (KBr): ν = 1670 (CONH) cm^–1. H NMR (300 MHz,

˜

[D₆]DMSO): δ = 3.18 (d, J = 17.4 Hz, 1 H, CHH), 3.63 (d, J =

17.4 Hz, 1 H, CHH), 5.59 (d, J = 4.9 Hz, 1 H, CHOH), 6.21 (d, J

= 4.9 Hz, 1 H, CHOH), 6.99 (d, J = 7.6 Hz, 1 H, ArH), 7.09 (t, J

= 7.3 Hz, 1 H, ArH), 7.16 (d, J = 9.0 Hz, 2 H, ArH), 7.25–7.31

(m, 2 H, ArH), 7.34–7.45 (m, 5 H, ArH), 7.67 (d, J = 7.6 Hz, 2 H, 2-(4-Chlorophenyl)-4Ј-hydroxy-6Ј,7Ј-dimethoxy-5-phenyl-2,4-dihy-

ArH), 10.63 (s, 1 H, NH) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = dro-1ЈH-spiro[pyrazole-3,3Ј-quinolin]-2Ј(4ЈH)-one (10a): Yield 50%

64.8, 73.4, 115.1, 115.9, 122.0, 122.9, 125.6, 126.2, 126.6, 128.4,

128.5, 128.6, 131.8, 135.1, 141.5, 145.9, 168.5 ppm. MS (ES+): m/z

(%) = 404.1 (100) [M + H]⁺, 406.1 (33%) [M + 3]⁺. C₂₃H₁₈ClN₃O₂

(exact mass: 403.1088): calcd. C 68.40, H 4.49, N 10.40; found C

68.67, H 4.26, N 10.49.

(0.44 g from 0.50 g) as a pale yellow solid, m.p. 107–108 °C. R_f=

0.80 (80:20, hexane/EtOAc). IR (KBr): ν = 1685 (CONH) cm^–1. ¹H

˜

NMR (300 MHz, [D₆]DMSO): δ = 3.15 (d, J = 17.4 Hz, 1 H,

CHH), 3.66 (d, J = 17.4 Hz, 1 H, CHH), 3.74 (s, 3 H, OCH₃), 3.78

(s, 3 H, OCH₃), 5.51 (d, J = 6.0 Hz, 1 H, CHOH), 6.15 (d, J =

6.0 Hz, 1 H, CHOH), 6.64 (s, 1 H, ArH), 6.99 (s, 1 H, ArH), 7.13

(d, J = 8.9 Hz, 2 H, ArH), 7.36 (d, J = 8.9 Hz, 2 H, ArH), 7.36–

7.41 (m, 3 H, ArH), 7.66 (d, J = 6.6 Hz, 2 H, ArH), 10.37 (s, 1 H,

NH) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 55.7, 55.9, 64.8, 73.6,

100.4, 110.6, 115.8, 117.3, 121.9, 125.5, 125.6, 128.3, 128.5, 128.7,

141.5, 144.7, 145.9, 148.9, 168.4 ppm. MS (ES+): m/z (%) = 464.1

(50) [M + H]⁺. HRMS (EI): calcd. for C₂₅H₂₂ClN₃O₄463.1299;

found 463.1313.

2-(4-Chlorophenyl)-5-(2-fluorophenyl)-4Ј-hydroxy-2,4-dihydro-1ЈH-

spiro[pyrazole-3,3Ј-quinolin]-2Ј(4ЈH)-one (9b): Yield 96% (0.37 g

from 0.45 g) as a white solid, m.p. Ͼ250 °C. R_f= 0.23 (80:20, hex-

ane/EtOAc). IR (KBr): ν = 1676 (CONH) cm^–1¹H NMR

.

˜

(300 MHz, CDCl₃): δ = 3.18 (d, J = 17.5 Hz, 1 H, CHH), 3.69 (d,

J = 17.5 Hz, 1 H, CHH), 5.58 (d, J = 6.1 Hz, 1 H, CHOH), 6.23

(d, J = 6.1 Hz, 1 H, CHOH), 6.97 (d, J = 7.3 Hz, 1 H, ArH), 7.09

(d, J = 7.3 Hz, 1 H, ArH), 7.15–7.18 (m, 2 H, ArH), 7.22–7.28 (m,

5 H, ArH), 7.37–7.43 (m, 2 H, ArH), 7.83 (t, J = 7.3 Hz, 1 H, 2-(4-Chlorophenyl)-5-phenyl-2,4-dihydro-1ЈH-spiro[pyrazole-3,3Ј-quin-

ArH), 10.63 (s, 1 H, NH) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = olin]-2Ј(4ЈH)-one (37a): Yield 94% (0.16 g from 0.20 g) as a white

64.9, 73.2, 115.1, 116.1, 116.3, 122.5, 122.9, 124.7, 126.1, 126.6,

128.3, 128.5, 128.6, 128.8, 130.5, 135.0, 141.2, 168.4 ppm. MS

solid, m.p. Ͼ250 °C. R_f= 0.51 (70:30, hexane/EtOAc). IR (KBr):

ν = 1685 (CONH) cm^–1. ¹H NMR (300 MHz, [D₆]DMSO): δ =

˜

(ES+) m/z (%) = 422.0 (30) [M + H]⁺. C₂₃H₁₇ClFN₃O₂(exact mass: 2.93 (d, J = 15.8 Hz, 1 H, CHH), 3.40 (s, 2 H, CH₂), 3.61 (d, J =

421.0993): calcd. C 65.48, H 4.06, N 9.96; found C 65.63, H 4.19,

N 10.6.

15.8 Hz, 1 H, CHH), 6.96 (d, J = 7.0 Hz, 2 H, ArH), 7.11 (d, J =

8.6 Hz, 2 H, ArH), 7.17–7.28 (m, 4 H, ArH), 7.36 (d, J = 6.3 Hz,

3 H, ArH), 7.67 (d, J = 6.3 Hz, 2 H, ArH), 10.62 (s, 1 H, NH)

ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 32.7, 44.8, 68.1, 115.2,

116.3, 120.7, 122.8, 125.8, 127.9, 128.6, 129.0, 129.5, 131.7, 137.2,

141.3, 146.0, 168.7 ppm. MS (ES+): m/z (%) = 388.1 (33) [M +

H]⁺. C₂₃H₁₈ClN₃O (exact mass: 387.1138): calcd. C 71.22, H 4.68,

N 10.83; found C 71.47, H 4.79, N 10.77.

2,5-Bis(4-chlorophenyl)-4Ј-hydroxy-2,4-dihydro-1ЈH-spiro[pyrazole-

3,3Ј-quinolin]-2Ј(4ЈH)-one (9c): Yield 77% (0.12 g from 0.18 g) as a

white solid, m.p. Ͼ250 °C. R_f= 0.26 (80:20, hexane/EtOAc). IR

1

(KBr): ν = 1672 (CONH) cm^–1. H NMR (300 MHz, CDCl ): δ =

˜

3

2.59 (s, 1 H, CHOH), 3.10 (d, J = 17.1 Hz, 1 H, CHH), 3.80 (d, J

= 17.1 Hz, 1 H, CHH), 5.67 (s, 1 H, CHOH), 6.97 (d, J = 7.5 Hz,

1 H, ArH), 7.06–7.11 (m, 1 H, ArH), 7.20–7.31 (m, 6 H, ArH), 2,5-Bis(4-chlorophenyl)-2,4-dihydro-1ЈH-spiro[pyrazole-3,3Ј-quin-

7.46–7.58 (m, 4 H, ArH), 10.19 (s, 1 H, NH) ppm. ¹³C NMR olin]-2Ј(4ЈH)-one (37c): Yield 71% (0.31 g from 0.50 g) as a white

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Eur. J. Org. Chem. 2008, 5446–5460

Spiro-Fused Quinolin-2-ones from Baylis–Hillman Adducts

[4] R. Pathak, S. Madapa, S. Batra, Tetrahedron 2007, 63, 451–

460.

solid, m.p. Ͼ250 °C. R_f= 0.53 (70:30, hexane/EtOAc). IR (KBr):

ν = 1688 (CONH) cm^–1. ¹H NMR (300 MHz, CDCl ): δ = 2.95 (d,

˜

3

[5] For examples, see a) P. B. Hurley, G. R. Dake, J. Org. Chem.

2008, 73, 4131–4138; b) A. Sy Arlene, D. C. Swenson, J. B.

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1062; n) R. Pradhan, M. Patra, A. K. Behera, B. K. Mishra,

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cited therein; o) J. Yang, H. Song, X. Xiao, J. Wang, Y. Qin,

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din, C. J. O’Donnell, T. Oh, D. W. Old, L. E. Overman, M. J.

Sharp, J. Am. Chem. Soc. 2005, 127, 18054–18065.

J = 16.0 Hz, 1 H, CHH), 3.41 (d, J = 2.2 Hz, 2 H, CH₂), 3.65 (d,

J = 16.0 Hz, 1 H, CHH), 6.97–6.99 (m, 2 H, ArH), 7.13 (d, J =

9.0 Hz, 2 H, ArH), 7.19–7.26 (m, 2 H, ArH), 7.28 (d, J = 9.0 Hz,

2 H, ArH), 7.43 (d, J = 8.5 Hz, 2 H, ArH), 7.71 (d, J = 8.5 Hz, 2

H, ArH), 10.61 (s, 1 H, NH) ppm. MS (ES+): m/z (%) = 422.1

(100) [M + H]⁺. C₂₃H₁₇Cl₂N₃O (exact mass: 421.0749): calcd. C

65.41, H 4.06, N 9.95; found C 65.22, H 4.19, N 10.14.

2-(4-Chlorophenyl)-5-(4-methylphenyl)-2,4-dihydro-1ЈH-spiro[pyr-

azole-3,3Ј-quinolin]-2Ј(4ЈH)-one (37d): Yield 81 % (0.18 g from

0.22 g) as a light brown solid, m.p. Ͼ250 °C. R_f= 0.54 (70:30, hex-

ane/EtOAc). IR (KBr): ν = 1690 (CONH) cm^{–1 1}H NMR

.

˜

(300 MHz, [D₆]DMSO): δ = 2.32 (s, 3 H, ArCH₃), 2.93 (d, J =

15.6 Hz, 1 H, CHH), 3.39 (s, 2 H, CH₂), 3.65 (d, J = 15.6 Hz, 1

H, CHH), 6.98 (s, J = 6.9 Hz, 1 H, ArH), 7.12 (d, J = 8.6 Hz, 4

H, ArH), 7.19–7.29 (m, 6 H, ArH), 7.58 (d, J = 7.6 Hz, 2 H, ArH),

10.61 (s, 1 H, NH) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 22.0,

33.6, 45.5, 69.2, 116.1, 117.0, 121.6, 123.4, 123.6, 126.7, 128.8,

129.5, 129.8, 130.1, 130.4, 138.3, 139.5, 142.3, 147.1, 170.0 ppm.

MS (ES+): m/z (%) = 402.1 (100) [M + H]⁺. C₂₄H₂₀ClN₃O (exact

mass: 401.1295): calcd. C 71.73, H 5.02, N 10.46; found C 71.87,

H 5.23, N 10.27.

2-(4-Chlorophenyl)-5-(thiophen-2-yl)-2,4-dihydro-1ЈH-spiro[pyrazole-

3,3Ј-quinolin]-2Ј(4ЈH)-one (37e): Yield: 85% (0.17 g from 0.20 g) as

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Colovray, C. Cleva, J.-F. Arrighi, J. Atherall, J. Macritchie, T.

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a light blue solid, m.p. Ͼ250 °C. R_f= 0.50 (70:30, hexane/EtOAc).

1

IR (KBr): ν = 1685 (CONH) cm^–1. H NMR (300 MHz, CDCl ):

˜

3

δ = 2.75 (d, J = 15.9 Hz, 1 H, CHH), 3.39 (s, 2 H, CH₂), 3.68 (d,

J = 15.9 Hz, 1 H, CHH), 6.98–7.01 (m, 4 H, ArH), 7.10–7.24 (m,

5 H, ArH), 7.32–7.34 (m, 1 H, ArH), 7.43 (s, 1 H, ArH), 10.16 (s,

1 H, NH) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 32.7, 45.5, 68.2,

115.2, 116.2, 120.7, 122.8, 127.9, 128.1, 128.7, 129.5, 134.9, 137.1,

141.1, 142.6, 168.4 ppm. MS (ES+): m/z (%) = 394.1 (100) [M +

H]⁺. C₂₁H₁₆ClN₃OS (exact mass: 393.0703): calcd. C 64.03, H 4.09,

N 10.67; found C 64.21, H 3.86, N 10.75.

Supporting Information (see footnote on the first page of this arti-

cle): Spectroscopic data for all the starting substrates and copies of

NMR spectra for all the compounds.

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Acknowledgments

V. S. and V. S. gratefully acknowledge financial support from the

Council of Scientific and Industrial Research (CSIR), New Delhi

in the form of fellowships. This work was also supported by a grant

from the Department of Science and Technology (DST), New

Delhi (SR/SI/OC-16/2006). The help extended by Prof. Sandeep

Verma, IIT, Kanpur and one of his PhD students, Mr. C. Purohit,

in analyzing the crystal data included in this paper is gratefully

acknowledged.

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Eur. J. Org. Chem. 2008, 5446–5460

www.eurjoc.org

5459

V. Singh, V. Singh, S. Batra

FULL PAPER

¯

H. R. Bijanzadeh, S. Balalaie, Tetrahedron Lett. 2008, 49,

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= P1, a = 9.367(2), b = 9.858(2), c = 14.818(4) Å, α = 90.982(4),

β = 106.384(4), γ = 91.166(5)°, V = 1312.1(5) Å³, Z = 2, D =

1.347 mg/m³, µ(Mo-K_α) = 0.190 mm^–1, F(000) = 556, colorless

block, size 0.2ϫ0.2ϫ0.2 mm, 8535 reflections collected, R(int)

= 0.0327, unique reflections = 6183, final R indices [I Ͼ 2σ(I)]

on F²: R1 = 0.0897, wR2 = 0.2376, GoF = 1.014; R indices (all

data): R1 = 0.1701, wR2 = 0.3080. Data were collected with a

Bruker SMART CCD4 X-ray diffraction instrument with

graphite-monochromated Mo-K_αradiation (λ = 0.710 Å) at

room temp. The structure was solved by direct methods with

the SIR92 programme and refined with full-matrix least

squares on F²(SHELX97). The structure was expanded with

the Fourier technique. All non-hydrogen atoms were refined

anisotropically. Hydrogen atoms were placed at geometrically

idealized positions. All the software packages were integrated

into the WINGX software package. CCDC-699461 (17d) con-

tains the supplementary crystallographic data for this paper.

These data can be obtained free of charge from The Cambridge

Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_

request/cif.

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[16]

Crystal data for 19c (crystallized from CHCl₃): Empirical for-

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¯

298(2) K, wavelength = 0.71073 Å, triclinic, space group = P1,

a = 9.367(2), b = 9.858(2), c = 14.818(4) Å, α = 90.982(4), β =

106.384(4), γ = 91.166(5)°, V = 1312.1(5) Å³, Z = 2, D =

1.347 mg/m³, µ(Mo-K_α) = 0.190 mm^–1, F(000) = 556, colorless

block, size 0.2ϫ0.2ϫ0.2 mm, 8535 reflections collected, R(int)

= 0.0327, unique reflections = 6183, final R indices [I Ͼ 2σ(I)]

on F²: R1 = 0.0897, wR2 = 0.2376, GoF = 1.014; R indices (all

data): R1 = 0.1603, wR2 = 0.2679. Data were collected with a

Bruker SMART CCD4 X-ray diffraction instrument with

graphite-monochromated Mo-K_αradiation (λ = 0.710 Å) at

room temp. The structure was solved by direct methods with

the SIR92 programme and refined with full-matrix least

squares on F²(SHELX97). The structure was expanded with

the Fourier technique. All non-hydrogen atoms were refined

anisotropically. Hydrogen atoms were placed at geometrically

idealized positions. All the software packages were integrated

into the WINGX software package. CCDC-699462 (19c) con-

tains the supplementary crystallographic data for this paper.

These data can be obtained free of charge from The Cambridge

Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_

request/cif.

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[17] All the spirocyclic derivatives were evaluated as antimalarials

in a chloroquine-sensitive P. falciparum strain (3D-7), but none

of them displayed any significant activity.

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[15] Crystal data for 17d (crystallized from CHCl₃/EtOAc): Empiri-

cal formula: C₃₀H₂₇Cl₁F₁N₃O₃, formula mass = 532.00 g/mol,

T = 298(2) K, wavelength = 0.71073 Å, triclinic, space group

Received: July 28, 2008

Published Online: September 30, 2008

5460

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Eur. J. Org. Chem. 2008, 5446–5460

Article Doi

Straightforward strategy for the stereoselective synthesis of spiro-fused (C-5)isoxazolino- or (C-3)pyrazolino-(C-3)quinolin-2-ones from Baylis-Hillman adducts by 1,3-dipolar cycloaddition and reductive cyclization

DOI: 10.1002/ejoc.200800746

Source and publish data:

Authors:

Article abstract of DOI:10.1002/ejoc.200800746

Full text of DOI:10.1002/ejoc.200800746

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