Synthesis, structure and emission properties of spirocyclic benzofuranones and dihydroindolones: A domino insertion-coupling-isomerization-Diels-Alder approach to rigid fluorophores

FULL PAPER

DOI: 10.1002/chem.200700759

Synthesis, Structure and Emission Properties ofSpirocyclic Benzouf ranones

and Dihydroindolones: A Domino Insertion–Coupling–Isomerization–

Diels–Alder Approach to Rigid Fluorophores

Daniel M. DꢀSouza,^[a]Alexander Kiel,^[b]Dirk-Peter Herten,^[b]Frank Rominger,^[a]and

Thomas J. J. Müller*^[a]

Dedicated to Professor Peter Hofmann on the occasion of his 60th birthday

Abstract: An alkynoyl ortho-iodo phe-

nolester or alkynoyl ortho-iodo anilides

and propargyl allyl ethers react under

Sonogashira coupling conditions in the

sense of an insertion–coupling–isomeri-

zation–Diels–Alder hetero domino re-

action to furnish (tetrahydroisobenzo-

furan)-spirobenzofuranones and -spiro-

dihydroindolones in good yields. Many

representatives can be crystallized and

single crystal structure analyses display

steric and electronic substituent effects

on the torsional angles of the terminal

(hetero)aryl groups and the central cis,-

trans-butadiene fragment. DFT compu-

tations reveal that in the final pericy-

clic step the Diels–Alder termination is

by far thermodynamically and kineti-

cally favored over a possible Claisen

rearrangement. Compounds of this new

class of spirocyclic compounds possess

large Stokes shifts and fluoresce inten-

sively with blue over green to orange

colors. As a consequence of the spiro-

cyclic rigidity fluorescence lifetimes

and quantum yields are rather high in

some cases.

ꢀ

Keywords:

C C

coupling

·

cycloaddition · domino reactions ·

fluorescence · spiro compounds

Introduction

ing various combinations of elementary organic and organo-

metallic transformations under similar conditions is the

major conceptual challenge in engineering novel types of

uni-, bi- and multimolecular sequences. From a practical

point of view the expansion of diversity oriented synthesis

into combinatorial chemistry^[4]and solid-phase syntheses^[2d,5]

promises manifold opportunities for developing novel lead

structures of pharmaceuticals, catalysts and even novel mol-

ecule based materials.

In the past decade the productive concepts of multicompo-

nent processes, domino reactions and sequential transforma-

tions have considerably stimulated the scientific community

in search for economical and ecological access to biological-

ly active scaffolds and lead structures.^[1,2]In particular, these

diversity oriented syntheses^[3]address the fundamental

issues of preparative efficiency and reaction design. Master-

Generally, domino reactions^[6]are regarded as sequences

of uni- or bimolecular elementary reactions that proceed

without isolation of intermediates or workup. The reactive

functionality of the preceding step has been formed in the

previous transformation. Although, quite remarkable syn-

theses of natural products with polycyclic frameworks have

successfully been achieved by the application of domino re-

actions as key steps, a domino approach to functional mate-

rials, such as chromophores, fluorophores and redox active

molecules, is still in its infancy.^[7]Nevertheless, the prospect

to simultaneously accessing new scaffolds and a large struc-

tural space sets the stage for new innovative synthetic con-

cepts in search for fluorescent materials. In addition, the on-

going quest for high-performance fluorophores in OLED

with peculiar properties is a stimulating challenge.^[8]As part

[a] Dr. D. M. DꢀSouza, Dr. F. Rominger, Prof. Dr. T. J. J. Müller

Organisch-Chemisches Institut

Ruprecht-Karls-Universität Heidelberg

Im Neuenheimer Feld 270, 69120 Heidelberg (Germany)

and

New address: Institut für Organische Chemie und Makromolekulare

Chemie, Heinrich-Heine-Universität Düsseldorf

Universitätsstrasse 1, 40225 Düsseldorf (Germany)

Fax : (+49)211-81-14324

E-mail: ThomasJJ.Mueller@uni-duesseldorf.de

[b] A. Kiel, Dr. D.-P. Herten

Physikalisch-Chemisches Institut

Ruprecht-Karls-Universität Heidelberg

Im Neuenheimer Feld 253, 69120 Heidelberg (Germany)

Supporting information for this article is available on the WWW

under http://www.chemeurj.org/ or from the author.

Chem. Eur. J. 2008, 14, 529 – 547

ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

529

of our program to develop new multicomponent methodolo-

gies for the synthesis of chromophores and fluorophores, we

have recently communicated a domino synthesis of fluores-

cent butadienes that are structurally rigidified by a spirocy-

clic framework.^[9]Here, we report on the synthetic expan-

sion to diversely substituted representatives, computional

studies on the concluding pericyclic step, and photophysical

investigations of this new class of rigidified fluorophores.

Results and Discussion

Domino synthesis ofspirobenzoufranones and spirodihy-

droindolones: In recent years we have developed consecu-

tive multicomponent syntheses of pharmaceutically relevant

heterocycles^[10,11]initiated by a coupling–isomerization reac-

tion^[10,12](CIR) (Scheme 1).

Scheme 2. Mechanistic rationale of the CIR.

Although, the proposed allenol intermediate remains an

elusive and highly reactive intermediate, the major potential

of the CIR clearly lies in selectively addressing allenol deriv-

ative intermediates by thermodynamically and kinetically fa-

vored intramolecular trapping reactions. Furthermore, the

installation of the required conjugation of an electron-with-

drawing functionality by an organometallic elementary step

ꢀ

such as an insertion of an alkyne into a carbon palladium

Scheme 1. Coupling–isomerization reaction (CIR), a novel synthesis of

chalcones and enones.

bond^[14]followed by a CIR would not only represent a meth-

odological extension, but could also provide new access to

hetero domino reactions.^[6,15]As a consequence of an inser-

tion–CIR an electron deficient diene can be readily estab-

lished. Assuming a highly reactive allenol intermediate of

the CIR (see above) in this particular case the transient

should be a vinyl allene, that is, a reactive diene in Diels–

Alder reactions. Hence, we set out to conduct the insertion–

CIR with a propargyl allyl ether, not only shutting off the ir-

reversible allenol–enone tautomerism but also implementing

a tethered dienophile functionality as a trap for an intramo-

lecular [4+2] cycloaddition with inverse electron demand.

Indeed, reaction of alkynoyl ortho-iodo phenolester 1 and

propargyl allyl ethers 2 in presence of catalytic amounts of

The CIR of electron deficient (hetero)aryl halides and

(hetero)aryl propargyl alcohols occurs under the conditions

of the Sonogashira coupling^[13]and represents a mild and ef-

ficient access to enones. Mechanistically, the CIR can be ra-

tionalized as a rapid palladium-copper catalyzed alkynyla-

tion reaction followed by a slow base catalyzed propargyl al-

cohol to enone isomerization (Scheme 2).

Abstract in German: Alkinoyl ortho-iodphenolester oder Al-

kinoyl ortho-iodanilide und Propargylallylether reagieren

unter den Bedingungen der Sonogashira-Kupplung im Sinne

einer Insertions–Kupplungs–Diels–Alder-Hetero-Domino-Re-

aktion zu (Tetrahydroisobenzofuran)-spirobenzofuranonen

bzw. -spirodihydroindolonen in guten Ausbeuten, von denen

viele kristallisiert werden konnten. Die Einkristallstruktur-

analysen offenbaren sterische und elektronische Substituen-

teneffekte auf die Torsionswinkel der terminalen (Hetero)ar-

ylgruppen und des zentralen cis,trans-Butadienfragments.

DFT-Rechnungen zeigen, dass im letzten pericyclischen

Schritt die Diels–Alder-Reaktion gegenüber einer mçglichen

Claisen-Umlagerung bei weitem thermodynamisch und kinet-

isch begünstigt ist. Viele Verbindungen dieser neuen Spirocy-

clenklasse besitzen große Stokes-Verschiebungen und fluores-

zieren intensive mit blauer, grüner oder oranger Farbe. Als

Folge der spirocyclischen Rigidität sind in einigen Fällen die

Fluoreszenzlebensdauern und Quantenausbeuten relative

hoch.

[Pd(PPh₃)₂Cl₂] and CuI in a boiling mixture of toluene and

A

triethylamine gives rise to the formation of the class of (tet-

rahydroisobenzofuran)spirobenzofuranones 3 in moderate

to excellent yields (Scheme 3, Table 1).

Likewise, upon reacting alkynoyl ortho-iodo anilides 4

and propargyl allyl ethers 2 under Sonogashira conditions in

a boiling mixture of butyronitrile and triethylamine (tetrahy-

droisobenzofuran)spiroindolones 5 can be isolated in moder-

ate to excellent yields (Scheme 4, Table 2).

Scheme 3. Insertion–coupling–isomerization–Diels–Alder domino reac-

tion to spirobenzofuranones 3.

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Chem. Eur. J. 2008, 14, 529 – 547

Rigid Fluorophores

FULL PAPER

Table 1. Insertion–coupling–isomerization–Diels–Alder domino reaction

These methine resonances not only show distinct cross-

to spirobenzofuranones 3.^[a]

1

peaks in the H,¹H-COSY spectra to the methylene protons

Entry^[a]Propargyl allyl ether 2

Spirobenzofuranones 3 (yield [%])^[b]

3a: R²=R³=H,

H^1Abut also to the methylene protons H^7A. The methyl

group bound to carbon C⁷, which points in the same hemi-

sphere, can be identified in the NOESY spectra. In some

cases the splitting patterns of the methine and methylene

protons are well resolved and the dihedral angles as derived

from the Karplus curve are in good agreement with the data

obtained from X-ray structure analyses (see below). In the

¹³C NMR spectra the characteristic sp³-hybrized quaternary

spiro carbon resonances of C⁶are found between d 53.1 and

62.4 ppm depending on the lactone or lactam nature of the

benzoannelated ring. Likewise, the carbonyl resonances, in-

dicative for lactams and lactones, range from d 174.6 and

178.5 ppm.

1

2

3

4

5

6

7

8

2a: R²=R³=H,

(het)aryl=p-NCC₆H₄

2b: R²=R³=H,

(het)aryl=o-FC₆H₄

2c: R²=R³=H,

(het)aryl=p-MeOC₆H₄

2d: R²=R³=H,

(het)aryl=p-EtOC₆H₄

2e: R²=R³=H,

(het)aryl=p-Me₂NC₆H₄

2 f: R²=CH₃, R³=H,

(het)aryl=p-EtOC₆H₄

2g: R²=CH₃, R³=H,

(het)aryl=2-thienyl

2h: R²=R³=CH₃,

(het)aryl=p-MeOC₆H₄

N

ACHTREUNG

G

ACHTREUNG

H

ACHTREUNG

U

ACHTREUNG

E

ACHTREUNG

R

ACHTREUNG

H

ACHTREUNG

Additionally, the molecular structure of the spirocyclic

systems 3 and 5 was corroborated by X-ray structure analy-

ses of the benzofuranones 3a–c, e, h, and the dihydroindo-

lones 5d, f–h, l, p–q (Figures 2–13).^[16]

C

ACHTREUNG

[a] Reaction conditions: 1.0 equiv aryl iodide 1, 1.1 equiv propargyl allyl

ether 2 (0.1m in toluene/triethylamine 1:1), 0.05 equiv [Pd(PPh₃)₂Cl₂] and

AHCTREUNG

0.05 equiv CuI were heated to reflux temperature for 72 h. [b] Yields

refer to isolated yields of compounds 3 after flash chromatography on

silica gel and recrystallization to be ꢁ95% pure as determined by NMR

spectroscopy and elemental analysis.

Besides the unambiguous structural assignment of the spi-

rocyclic scaffold the single crystal data disclose more de-

tailed insight into conformational biases exerted by substitu-

tion patterns. Since the central butadiene chromophore is ri-

gidified by its bicyclic nature the appending substituents,

which are predominantly (hetero)aromatic moieties, can

adopt preferred conformations (Figure 14). The mutual ori-

entations of these planar substituents are best described by

the interplanar angles between the (hetero)aromatic sub-

stituents at C³(plane 1) and the butadiene unit (plane 2)

and between plane 2 and the (hetero)aromatic fragment at

C⁵(plane 3) (Table 3).

Scheme 4. Insertion–coupling–isomerization–Diels–Alder domino reac-

tion to spiroindolones 5.

For the benzofuranones 3 the interplanar angles between

planes 1 and 2 lie within the small range of 31.0 and 40.58,

independent both of the electronic nature of the (hetero)ar-

omatic substituents at C³and the methyl substitution at C⁷.

Likewise, the interplanar angles between planes 2 and 3 are

also found in a narrow margin between 42.7 and 50.78. For

the dihydroindolones the substituent variation is broader

and encompasses electronically variable substitution at both

C³and C⁵, and at the indolone nitrogen substituent. The in-

terplanar angles between planes 1 and 2 vary from 7.5 to

43.18, a range that reflects the electronic and steric impact

of the (hetero)aromatic substituents at C³. Expectedly, with

an angle of 15.88 the thienyl substituent (5 f)^[17]is arranged

almost coplanarily with respect to the conformationally

fixed butadienyl system, how-

The structures of spirocycles 3 and 5 were unambiguously

supported by spectroscopic (¹H, ¹³C and DEPT, COSY,

NOESY, HETCOR and HMBC NMR experiments, IR,

UV/Vis, mass spectrometry) and combustion analyses. Most

distinctly, the spirocyclic juncture causes a considerable con-

formational fixation and, therefore, the relative configura-

tion of both series of spirocycles 3 and 5 can be characteris-

tically assigned by examining the NOE contacts of the C^7a

methine multiplet resonances appearing between d 3.52 and

4.02 ppm in the NOESY spectra (Figure 1).

ever, highest planarization is

observed for the p-chlorophen-

yl substituted derivative 5d

(7.58) and the p-formylphenyl

substituted representative 5q

(8.28). In the latter case the

push–pull character of the sub-

stitution pattern is apparently

even responsible for the rather

small interplanar angle be-

tween planes 2 and 3 (30.28).

1

Figure 1. Assignment of selected H NMR resonances of 3 and 5.

Chem. Eur. J. 2008, 14, 529 – 547

ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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531

T. J. J. Müller et al.

Table 2. Insertion–coupling–isomerization–Diels–Alder domino reaction to spiroindolones 5.^[a]

Based upon the product

analysis the hetero domino se-

quence can be interpreted as a

Entry Alkynoyl iodo anilide 4

Propargyl allyl Spiroindolones 5 (yield [%])^[b]

ether 2

1

2

3

4a: R³=Ts, R⁴=Ph

2c

2g

2i:

5a: R²=R³=H,

(het)aryl=p-MeOC₆H₄, R³=Ts, R⁴=Ph (81)

5b: R²=CH₃, R³=H,

(het)aryl=2-thienyl, R³=Ts, R⁴=Ph (72)

5c: R²=R³=CH₃, (het)aryl=p-OHCC₆H₄, R³=Ts,

combination of a transition-

AHCTREUNG

metal-catalyzed insertion cas-

cade that concludes in a peri-

cyclic final step. Intramolecular

Heck reactions^[18]have been

developed to a broad method-

ology and have culminated in

impressive domino sequences

like Negishiꢀs zippers,^[14]how-

ever, the termination of inser-

tion cascades by Sonogashira

alkynylation^[13]has received

only little attention.^[19]Hence,

the hetero domino sequence

can be rationalized as follows

(Scheme 5): as an insertion al-

kynylation followed by a base-

catalyzed isomerization of an

electron poor vinyl propargyl

allyl ether to give an electron

poor vinyl allene that reacts in

an intramolecular [4+2] cyclo-

addition through an anti–exo

transition state to conclude the

sequence by formation of spi-

rocycles 3 or 5 (Table 1, en-

tries 6 and 7, Table 2, entry 2).

Methodologically, upon forma-

4a

AHCTREUNG

R²=R³=CH₃, R⁴=Ph (71)

A

OHCC₆H₄

4

4a

2j:

5d: R²=R³=CH₃, (het)aryl=p-ClC₆H₄, R³=Ts,

R²=R³=CH₃, R⁴=Ph (86)

A

ClC₆H₄

5

6

4a

2k:

5e: R²=R³=CH₃, (het)aryl=Ph, R³=Ts, R⁴=Ph (86)

5 f: R²=R³=CH₃, (het)aryl=2-thienyl, R³=Ts,

R²=R³=CH₃,

AHCTREUNG

thienyl

2h

7

4a

5g: R²=R³=CH₃,

A

8

4b: R³=Ts, R⁴=nBu

2j

5h: R²=R³=CH₃, (het)aryl=p-ClC₆H₄, R³=Ts,

R⁴=nBu (81)

9

4b

2k

2h

2j

5i: R²=R³=CH₃, (het)aryl=Ph, R³=Ts, R⁴=nBu

(79)

10

11

12

13

14

15

16

17

18

19

20

21

4b

5j: R²=R³=CH₃, (het)aryl=p-MeOC₆H₄, R³=Ts,

R⁴=nBu (77)

4c: R³=Ts, R⁴=iPr₃Si

5k: R²=R³=CH₃, (het)aryl=p-ClC₆H₄, R³=Ts,

R⁴=iPr₃Si (79)

4c

2k

2h

2j

5l: R²=R³=CH₃, (het)aryl=Ph, R³=Ts, R⁴=iPr₃Si

(85)

5m: R²=R³=CH₃, (het)aryl=p-MeOC₆H₄, R³=Ts,

R⁴=iPr₃Si (77)

4d: R³=Ms, R⁴=p-

MeOC₆H₄

4d

5n: R²=R³=CH₃, (het)aryl=p-ClC₆H₄, R³=Ms,

R⁴=p-MeOC₆H₄(53)

ꢀ

tion of four new carbon

2k

2h

2i

5o: R²=R³=CH₃, (het)aryl=Ph, R³=Ms, R⁴=p-

MeOC₆H₄(63)

carbon bonds with concomitant

generation of a complex tetra-

cyclic framework in high effi-

ciency this insertion–CI–Diels–

Alder domino reaction fur-

nishes spirocyclic benzofura-

nones 3 and dihydroindolones

4d

5p: R²=R³=CH₃, (het)aryl=p-MeOC₆H₄, R³=Ms,

R⁴=p-MeOC₆H₄(63)

4e: R³=Ts, R⁴=p-

MeOC₆H₄

4e

5q: R²=R³=CH₃, (het)aryl=p-OHCC₆H₄, R³=Ts,

R⁴=p-MeOC₆H₄(66)

2j

5r: R²=R³=CH₃, (het)aryl=p-ClC₆H₄, R³=Ts,

R⁴=p-MeOC₆H₄(87)

4e

2k

5s: R²=R³=CH₃, (het)aryl=Ph, R³=Ts, R⁴=p-

MeOC₆H₄(88)

5

in moderate to excellent

4 f: R³=Ts, R⁴=10-methyl- 2j

5t: R²=R³=CH₃, (het)aryl=p-ClC₆H₄, R³=Ts,

R⁴=10-methylphenothiazin-3-yl (58)

5u: R²=R³=CH₃, (het)aryl=Ph, R³=p-

(AcOCH₂CH₂OC₆H₄SO₂, R⁴=Ph (73)

yields.

phenothiazin-3-yl

4g: R³=p-

2k

Computational studies on the

concluding pericyclic steps of

the domino sequence: In com-

parison with the CIR and most

distinctly, the tautomerism of

the elusive allenol can be shut

off by etherification of the

propargylic alcohol. Hence, the

allenyl intermediate should

react in an intramolecular peri-

cyclic fashion under the ap-

(AcOCH₂CH₂OC₆H₄SO₂,

R⁴=Ph

22

23

4h: R³=Ac, R⁴=Ph

2k

5v: R²=R³=CH₃, (het)aryl=Ph, R³=Ac, R⁴=Ph

(46)

4i: R³=Me, R⁴=Ph

5w: R²=R³=CH₃, (het)aryl=Ph, R³=Me, R⁴=Ph

(38)

[a] Reaction conditions: 1.0 equiv aryl iodide 4, 1.1 equiv propargyl allyl ether 2 (0.1m in butyronitrile/triethyl-

amine 1:1), 0.05 equiv [Pd(PPh₃)₂Cl₂] and 0.05 equiv CuI were heated to reflux temperature for 48–36 h.

AHCTREUNG

[b] Yields refer to isolated yields of compounds 5 after flash chromatography on silica gel and recrystallization

to be ꢁ95% pure as determined by NMR spectroscopy and elemental analysis.

Most significantly, two anisyl substituents cause the inverse

effect and lead to torsions of 32.98 (interplanar angle plane

1 vs 2) and 56.08 (interplanar angle plane 2 vs 3) in com-

pound 5p.

plied reaction conditions. The insertion establishes a conju-

gated electron-withdrawing vinyl carbonyl group that readily

activates the propargylic position. Now, the isomerization of

a coupled vinyl propargyl allyl ether to a vinyl allenyl allyl

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Chem. Eur. J. 2008, 14, 529 – 547

Rigid Fluorophores

FULL PAPER

Figure 4. Molecular structure of 3c (hydrogen atoms are omitted for

clarity).

Figure 2. Molecular structure of 3a (hydrogen atoms are omitted for

clarity).

Figure 5. Molecular structure of 3e (hydrogen atoms are omitted for

clarity).

electron demand^[20]of the vinyl allene with the tethered allyl

dienophile. Experimentally, only the IMDA can be observed

(see above). Hence, the question arises whether the ob-

served cycloaddition is the thermodynamically or kinetically

favored process. As both pathways proceed intramolecularly,

thus, a direct comparison by computational studies lies at

hand.

Therefore, a model system, based upon a reduction on the

required functional features, was designed for quantum

chemical calculations (Scheme 6 and Table 4). Thus, starting

Figure 3. Molecular structure of 3b (hydrogen atoms are omitted for

clarity).

ether opens in principle two reaction pathways: either a

[3,3]-sigmatropic rearrangement in the sense of a allyl–vinyl

Claisen rearrangement or a [4+2] cycloaddition, that is, an

intramolecular Diels–Alder (IMDA) reaction with inverse

Chem. Eur. J. 2008, 14, 529 – 547

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533

T. J. J. Müller et al.

Figure 8. Molecular structure of 5 f (hydrogen atoms are omitted for

clarity).

Figure 6. Molecular structure of 3h (hydrogen atoms are omitted for

clarity).

Figure 9. Molecular structure of 5h (hydrogen atoms are omitted for

clarity).

Figure 7. Molecular structure of 5d (hydrogen atoms are omitted for

clarity).

points of [3,3]-sigmatropic rearrangement or [4+2]-cycload-

dition pathways are the allyloxy enallenes 6 giving rise

either to the allyl substituted oxo dienes 8 or the tetrahydro-

benzofurans 10.

level of theory [RMP2/6-311++G

A

AHCTREUNG

observed exclusive preference of the intramolecular [4+2]

cycloaddition over the Claisen rearrangement but also clear-

ly indicate that the cycloaddition is the favored process both

thermodynamically and kinetically. This result also reprodu-

ces with slightly more expanded systems that emphasize the

actual steric bias at the termini of vinyl allene moieties, still

leading to spirocyclization, that is, the formation of benzo-

The structure optimizations of starting, end and transi-

tion-state geometries were performed by DFT calculations

using the [RB3LYP/6-31+G

(d,p)] functional.^[21]Then, for

A

energy calculations the optimized geometries were entered

to post-HF single point energy calculations on the MP2

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Chem. Eur. J. 2008, 14, 529 – 547

Rigid Fluorophores

FULL PAPER

Figure 12. Molecular structure of 5p (hydrogen atoms are omitted for

clarity).

Figure 10. Molecular structure of 5i (hydrogen atoms are omitted for

clarity).

Figure 13. Molecular structure of 5q (hydrogen atoms are omitted for

clarity).

Figure 11. Molecular structure of 5l (hydrogen atoms are omitted for

clarity).

furanones and dihydroindolones (Scheme 7 and Table 4).

Only if the vinyl allyloxyallene is truncated to an allyloxyal-

lene Claisen rearrangements become the relevant process.^[22]

UV/Vis absorption and emission properties ofspirocyclic

benzofuranones 3 and dihydroindolones 5: Most interesting-

ly, upon irradiation with UV light all members of this new

class of pale yellow to yellow absorbing spirocycles display a

pronounced and intense blue over green to yellow orange

Figure 14. Numbering of the tetrahydrobenzofuran and assignment of

planes of 3 and 5.

Chem. Eur. J. 2008, 14, 529 – 547

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535

T. J. J. Müller et al.

Table 3. Selected interplanar angles [8] of spirocyclic benzofuranones 3

to spiroindolones 5.

Compound

Interplanar angle

planes 1 vs 2

Interplanar angle

planes 2 vs 3

3a

3b

3c

3e

3h

5d

5 f

5h

5i

35.1

31.0

40.5

39.3

35.3

7.5

15.8

25.8

17.1

43.1

32.9

8.2

49.8

52.3

42.7

50.7

44.9

43.7

48.5

–

56.0

30.2

5l

5p

5q

Scheme 6. Energy profile of the modeled pericyclic reactions (energies

are given in kcalmol^ꢀ1).

Scheme 5. Mechanistic rationale for the domino sequence to spirobenzo-

furans 3 and spirodihydroindolones 5.

Scheme 7. Expanded models for the gas-phase computations of conclud-

ing pericyclic step (transition-state energies in italics).^[21]

fluorescence with large Stokes shifts in solution (4300 to

9600 cm^ꢀ1) and in the solid state (Figure 15, Table 5). All

spirocyclic benzofuranones 3 and dihydroindolones 5 were

studied by UV/Vis and fluorescence spectroscopy, and be-

sides absorption and emission also the fluorescence quan-

tum yields and lifetimes of the excited states were deter-

mined for all members of the

the longest wavelength absorption maxima are between 327

to 398 nm with molar extinction coefficients e ranging from

12700 to 35000 mol^ꢀ1dm³cm^ꢀ1. Position and magnitude of

these longest wavelength absorption bands can be therefore

assigned to p–p* transitions, also reflecting S₀–S₁excitation.

series. Albeit the structural re-

lations between spirocyclic

benzofuranones and dihydroin-

dolones are striking, both ab-

sorption and emission proper-

ties are strongly effected by

minute substituent variations

or conformational biases.

Table 4. Relative single point energies of the structures 6, 8 and 10 and the corresponding transititon states 7

and 9 calculated on the MP2 level of theory [RMP2/6-311++G

A

G

given in kcalmol^ꢀ1).^[21]

Allyloxy

Claisen

TS[3,3] 7

Diels–Alder

U

D[[TS

G

enallene 6

product 8

product 10

ꢀTS[3,3] (9)]

ACHTREUNG

0^[a](6a)

0^[a](6b)

0^[a](6c)

0^[a](6d)

ꢀ43.50 (8a)

ꢀ42.60 (8b)

ꢀ41.00 (8c)

ꢀ41.00 (8d)

22.60 (7a)^[b]

23.00 (7b)^[d]

22.60 (7c)^[f]

22.30 (7d)^[h]

ꢀ52.10 (10a)

ꢀ60.00 (10b)

ꢀ58.00 (10c)

ꢀ59.00 (10d)

16.80 (9a)^[c]

8.90 (9b)^[e]

7.00 (9c)^[g]

6.40 (9d)^[i]

ꢀ5.80 [(7a)ꢀ

ꢀ14.10 [(7b)ꢀ

ꢀ15.60 [(7c)ꢀ(9c)]

ꢀ15.90 [(7d)ꢀ(9d)]

ACHTREUNG

All chromophores show ab-

sorptions between near UV

and the edge to visible where

[a] Energies are set to 0 kcalmol^ꢀ1. Imaginary frequencies from the DFT geometry optimizations that verify

transition states: [b] i508.05 cm^ꢀ1

.

[c] i463.57 cm^ꢀ1

.

[d] i508.78 cm^ꢀ1

.

[e] i456.06 cm^ꢀ1

.

[f] i505.64 cm^ꢀ1

.

[g] i456.88 cm^ꢀ1. [h] i503.87 cm^ꢀ1. [i] i455.57 cm^ꢀ1

.

536

www.chemeurj.org

ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Eur. J. 2008, 14, 529 – 547

Rigid Fluorophores

FULL PAPER

sive state. The (hetero)aromatic substituents at C³can be ac-

counted for twisted intramolecular charge transfer (TICT),

most probably going along with a distortion of the molecu-

lar framework as reported for coumarin derivates.^[23]The

latter notion arises because the model trans,cis-1,4-diphenyl

butadiene does not fluoresce at all upon photo excitation,

but rather undergoes a conformational twisting and an effi-

cient internal conversion back to the ground state.^[24]This

deviating peculiar behavior of the spirocyclic 1-(hetero)aryl-

4-(hetero)aryl butadienes 3 and 5 can be unequivocally at-

tributed to structurally fixed

Figure 15. Blue (5e), green (5 f) and orange (5q) fluorescent single crys-

tals (excitation at 370 nm).

conformations in the excited

Table 5. Selected absorption and emission data, fluorescence quantum yields, Stokes shifts and fluorescence

lifetimes of spirocycles 3 and 5 (recorded in CH₂Cl₂, T=298 K).

state.

Time-correlated

single-

Compound Absorption^[a]l_max,abs[nm] (e) Emission^[b]l_max,em

[nm] (F_f)^[c]

Stokes shift Dn˜

Fluorescence lifetimes

photon counting (TCSPC)

measurements have revealed

luminescence lifetimes for spi-

rocycles 3 and 5 that lie be-

tween 0.26 and 4.97 ns with ex-

ception of compound 5h

(0.09 ns). Therefore, the emis-

sion from the excited state can

be attributed to fluorescence

from an excited singlet state.

In most cases a single expo-

nential is not sufficient to

model the measured decay

curves, thus two, and in some

cases even three exponentials

have been used to describe the

data, indicating multiple con-

curring pathways for non-radi-

ative de-excitation.

Further indication of the

concomitant distortion of the

heterocyclic framework is re-

flected by steric substituent ef-

fects. Thus, dimethyl substitu-

tion at C⁷obviously leads to a

more rigid and hence stabi-

lized emissive state, thereby

lowering the Stokes shift by

1000 cm^ꢀ1and increasing excit-

ed state lifetimes. Further pho-

tochemical studies of differen-

ces due to solvent polarity and

in rigid matrices accompanied

by theoretical quantum me-

chanical modeling are necessa-

[c]

[cm^ꢀ1

7200

]

t_1/2[ns]^[e]

3a

368 (12700) 282 (500), 242

(11000)

500 (0.58)

1.50 (0.10) 4.30 (0.90)

3b

3c

3d

3e

3 f

3g

3h

5a

5b

5c

5d

5e

5 f

5g

5h

5i

335 (23200) 282 (7900)

350 (26700) 255 (17500)

347 (23400) 254 (15600)

372 (21200) 284 (11400)

345 (23000) 255 (15100)

359 (21100) 257 (13900)

350 (35000) 254 (17000)

345 (24900) 242 (20000)

360 (20500) 254 sh (20000)

391 (15900) 250 (23800)

353 (22900) 243 sh (27000)

348 (24900) 244 sh (27600)

367 (18600) 253 (19600)

353 (20900) 250 (25500)

327 (22000) 242 sh (20300)

362 (18900) 246 (16900)

333 (20600) 246 (19600)

346 (17700)

487 (0.29)

515 (0.06)

517 (0.07)

522 (0.12)

512 (0.07)

525 (0.08)

502 (0.25)

502 (0.18)

528 (0.09)

532 (0.39)

485 (0.50)

487 (0.44)

515 (0.22)

503 (0.25)

436 (0.04)

433 (0.05)

440 (0.21)

466 (0.45)

466 (0.15)

475 (0.04)

480 (0.62)

9300

9200

9500

7700

9500

8800

8700

9100

8800

6800

7700

8200

7800

8400

7600

4500

7300

7400

4300

8100

7500

1.20 (0.15) 2.70 (0.85)

0.81

2.00 (0.65) 2.70 (0.35)

2.78 (0.03) 1.00 (0.97)

2.00 (0.06) 0.82 (0.94)

0.90 (0.64) 1.8 (0.36)

2.3 (0.93) 0.98 (0.07)

1.77

1.90 (0.41) 0.95 (0.59)

4.97 (0.93) 1.55 (0.07)

3.62 (0.96) 1.44 (0.04)

3.40

1.77 (0.31) 2.90 (0.69)

2.20

0.09 (0.99) 2.22 (0.01)

0.30 (0.98) 1.85 (0.02)

1.05 (0.79) 1.65 (0.21)

1.20 (0.06) 3.00 (0.94)

1.36 (0.41) 0.88 (0.59)

0.26 (0.98) 0.80 (0.02)

3.66

5j

5k

5l

5m

5n

388 (14900) 254 (14000)

343 (11800) 242 sh (16500)

353 (24200) 338 (21200)

247 sh (19200)

5o

347 (21800) 270 (10300)

242 sh

520 (0.58)

9600

3.64 (0.90) 1.49 (0.10)

5p

5q

351 (27400) 256 (21200)

398 (20100) 288 sh (12800)

249 (24200)

488 (0.37)

545 (0.36)

8000

6800

2.74

1.78 (0.10) 4.50 (0.90)

5r

5s

5t

5u

5v

356 (28500) 242 sh (30100)

349 (26600) 246 (26600)

377 (20300) 338 (35500) 225 545 (0.20)

347 (29300) 245 (40200)

348 (21300) 235 sh (24800)

477 (0.53)

475 (0.42)

7100

7600

8200

8300

8100

1.00 (0.26) 3.50 (0.74)

2.60 (0.93) 1.04 (0.07)

4.07 (0.89) 1.67 (0.11)

3.37

488 (0.43)

485 (0.46)

0.70 (0.04) 3.54 (0.96)

[a] Recorded at c=10^ꢀ4m. [b] Recorded at c=10^ꢀ7m. [c] Determined with DPA and with quinine in 0.1m sulfu-

ric acid as standards. [d] Dn˜ =l_max,absꢀl_max,em[cm^ꢀ1]. [e] Determined by time-correlated single-photon counting

(TCSPC) at an excitation wavelength of 370 nm.

Expectedly, aldehyde substitution (compounds 5c, q) leads

to the most pronounced bathochromic shift of absorption

and emission maxima. In the fluorescence spectra, the short-

est wavelength emission maxima range from 433 to 545 nm

and are always accompanied by either a blue- or red-shifted

shoulder. The large Stokes shift can not be explained by

polar solvent relaxation alone but indicates further photo-

chemical mechanisms leading to the formation of the emis-

ry to support this interpretation, and are currently under in-

vestigation.

Electronically, acceptor substitution at C³leads to higher

fluorescence quantum yields with exception of series 5h–j.

On the other hand the structural nature of the spirocyclic

framework by going from benzofuranones (compounds 3c,

h) to dihydroindolones (compounds 5a, g) only affects ab-

sorption maxima to a minor extent. However, dimethyl sub-

Chem. Eur. J. 2008, 14, 529 – 547

ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

537

T. J. J. Müller et al.

60 mesh 230–400 (Macherey-Nagel, Düren). TLC: silica gel plates (60

F₂₅₄Merck, Darmstadt). Melting points (uncorrected values): Büchi Melt-

ing Point B-540. ¹H and ¹³C NMR spectra in CDCl₃: Bruker DRX 300,

Bruker DRX 500 and Bruker AC 300.The assignments of quaternary C

CH, CH₂and CH₃have been made by using DEPT spectra. IR: Bruker

Vector 22 FT-IR. UV/Vis: Perkin Elmer Models Lambda 16 and Hewlett

Packard HP8452A. Fluorescence: Perkin Elmer LS-55. MS: Jeol JMS-

700 and Finnigan TSQ 700. Elemental analyses were carried out in the

Microanalytical Laboratories of the Organisch-Chemisches Institut, Ru-

precht-Karls-Universität Heidelberg (Germany).

stitution increases the fluorescence quantum yield consider-

ably for benzofuranones 3 and only to a minor extent for di-

hydroindolones 5. But dimethyl substitution has no influ-

ence on the emission wavelength of dihydroindolones.

Arylsubstituted p-chlorophenyl butadienes (compounds

5d, n, r) are very similar with respect to absorption and

emission maxima, absorbance and fluorescence quantum

yield, phenothiazine as a substituent (compound 5r) causes

a red-shift of absorption and emission maxima, however,

with a decrease in fluorescence quantum yield. Upon alkyl

and silyl substitution (compounds 5h, k) both absorption

and emission maxima are blue-shifted. Remarkably, silyl

substituents display comparably high fluorescence quantum

yields, whereas the butyl chain causes a dramatic decrease.

Interestingly, variation of the nitrogen substituent in a

consanguineous series of dihydroindolones (compounds 5e,

u, v, w) with a diphenyl substituted butadiene chromophore

neither affects the absorption and emission maxima nor the

fluorescence quantum yields.

X-ray structure determination ofcompounds 3a–c, e, h, 5d, ,f h, i, l, p,

and q: Program SADABS V2.03 for absorption correction as well as soft-

ware package SHELXTL V6.12 for structure solution and refinement:^[26]

The data of the X-ray structure analyses of the compounds are summar-

ized in Tables 6 and 7.

Spectroscopy: Absorption spectra were taken on a Cary 500 UV-Vis-NIR

spectrometer (Varian, Darmstadt, Germany). All spectra were taken in

standard quartz cuvettes (Hellma, Mülheim, Germany) with

length of 0.3 cm in CH₂Cl₂.

a path

Steady-state fluorescence spectra were measured on a Cary Eclipse fluo-

rescence spectrometer (Varian, Darmstadt, Germany) by excitation of

the respective absorption maxima. To avoid re-absorption and re-emis-

sion effects the concentrations were strictly kept below 1 mm.

Ensemble fluorescence lifetime measurements were performed on

a

FluoTime 100 (PicoQuant, Berlin, Germany) using time-correlated

single-photon counting (TCSPC). For excitation we used a pulsed LED

emitting at 370 nm with a pulse width <600 ps (fwhm) operated at

20 MHz. The measurements were done in standard quartz cuvettes (d=

0.3 cm). To exclude polarization effects fluorescence was observed under

magic angle conditions (54.78). Typically 10000 photons were collected in

the maximum channel of a total of 4096 channels. The lifetime was deter-

mined by least-squares deconvolution and their quality judged by the re-

duced c²values and the randomness of the weighted residuals.

Conclusion

In conclusion, we have developed a new insertion–coupling–

isomerization–Diels–Alder domino reaction that furnishes

spirocyclic benzofuranones 3 and dihydroindolones 5 in

moderate to excellent yields. DFT and MP2 calculations

show that in the product forming step the Diels–Alder reac-

tion is thermodynamically and kinetically favored over a

Claisen rearrangement. The solid-state structure of these

poly(hetero)cyclic frameworks reveals considerable substitu-

ent effects on the torsional angles between the central buta-

diene chromophore and the terminal (hetero)aryl substitu-

We estimated the quantum yields of our compounds by comparison with

the known quantum yields of 9,10-diphenylanthracence and quinine sul-

fate at an excitation wavelength of 366 nm. According to Equation (1)

the fluorescence emission I_iof standards R and samples S at five differ-

ent optical densities OD_i, that is, concentrations, were determined and

corrected for the refractive index n_iof the respective solutions i. The pre-

sented quantum yields Q were obtained in each case by averaging of five

measurements yielding a respective standard deviation <0.1%.^[27]

G

ents. In addition, these new poly(hetero)cyclic entities estab-

G

lish a new class of fluorophores with tuneable absorption

and emission properties. As the fluorescence colors can

range from blue over green to orange and as emission shows

a high Stokes shift both in solution and in solid state they

are promising candidates for solution and solid state applica-

tions both in biolabeling (e.g. with side chain functionalized

representatives such as compound 5u) and OLED devices.

Furthermore, the complex structural framework in conjunc-

tion with a diversity oriented domino approach opens new

opportunities towards multifluorophore systems.

2

I_SOD_Rn_S

ð1Þ

Q_S¼ Q

^RI_ROD_Sn_R

2

General procedure for the insertion–coupling–isomerization–cycloaddi-

tion sequence to spirobenzofuranones 3: In a heat gun dried and nitrogen

filled Schlenk crew cap vessel phenylpropynoic acid 2-iodophenyl ester

(1) (348 mg, 1.00 mmol) and propargyl allyl ether 2 (1.10 mmol) were dis-

solved in toluene (3 mL) and triethylamine (3 mL) (for experimental de-

tails see Table 8). The solution was deaerated with a weak stream of ni-

trogen through

a

cannula for 5 min. Then, [PdCl₂(PPh₃)₂] (35 mg,

G

0.05 mmol) and CuI (10 mg, 0.05 mmol) were added and the mixture was

stirred for 1 h at RT. The vessel was placed in the reactor^[28]and the reac-

tion mixture was heated to reflux temperature for 72 h. Then, the reac-

tion mixture was cooled to room temp, the solvents were removed in

vacuo and the residue was purified by chromatography on silica gel (hex-

anes/ethyl acetate). Further purification was achieved by recrystallization

from pentane/ether and the spirobenzofuranones 3 were obtained as ana-

lytically pure crystalline solids.

Experimental Section

General considerations: All reactions involving palladium/copper cataly-

sis were performed in degassed oxygen free solvents under a nitrogen at-

mosphere using Schlenk and syringe techniques. The catalysts [Pd-

3H-Benzofuran-2-one-3-spiro-5’-4’-(6’-phenyl-3’,3a’,4’,5’-tetrahydroisoben-

zofuran-1’-yl)-benzonitrile (3a): According to the general procedure after

chromatography on silica gel (hexanes/ethyl acetate 5:1) and recrystalli-

zation from diethyl ether/pentane spirobenzofuranone 3a was obtained

as intensively yellow-blue fluorescent crystals. M.p. 2418C; ¹H NMR

(CDCl₃, 500 MHz): d=2.19 (dd, J=12.2 Hz, 1H), 2.37 (t, J=12.3 Hz,

1H), 3.93 (m, 1H), 4.01 (dd, J=8.1, 13.0 Hz, 1H), 4.78 (t, J=8.3 Hz,

1H), 6.85–6.87 (m, 2H), 7.11 (s, 1H), 7.15–7.20 (m, 4H), 7.33 (dd, J=0.8,

A

drich, Fluka or Merck and used without further purification. Triethyla-

mine, toluene and butyronitrile were dried and distilled according to

standard procedures.^[25]Detailed preparative procedures including full

analytics and ¹H, ¹³C and 135DEPT NMR spectra of ortho-iodo pheno-

lester 1, propargyl allyl ethers 2 and ortho-iodo phenolamides 4 can be

found in the Supporting Information. Column chromatography: silica gel

538

www.chemeurj.org

ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Eur. J. 2008, 14, 529 – 547

Rigid Fluorophores

FULL PAPER

Table 6. Crystal data and structure refinements for 3a–c, e, and h.

C₂₈H₁₉NO₃·0.2C₄H₉O (417.5 + 14.8):

C 80.02, H 4.90, N 3.24; found: C

79.96, H 4.56, N 3.50.

Compound

3a

3b

3c

C₂₈H₂₂O₄

3e

3h

C₃₀H₂₆O₄

Empirical

formula

F_w

C₂₈H₁₉NO₃

C₂₇H₁₉FO₃

C₂₉H₂₅NO₃

3H-Benzofuran-2-one-3-spiro-6’-3’-

(2’-fluorophenyl)-5’-phenyl-1’,6’,7’,7a’-

tetrahydroisobenzofuran (3b): Ac-

cording to the general procedure

after chromatography on silica gel

(hexanes/ethyl acetate 5:1) and re-

crystallization from diethyl ether/pen-

tane spirobenzofuranone 3b was ob-

tained as intensively yellow fluores-

cent crystals. M.p. 1898C; ¹H NMR

(CDCl₃, 500 MHz): d=2.18 (dd, J=

4.4, 12.0 Hz, 1H), 2.38 (t, J=12.4 Hz,

1H), 3.92 (m, 1H), 4.04 (dd, J=8.4,

12.8 Hz, 1H), 4.77 (t, J=8.5 Hz, 1H),

6.83–6.85 (m, 2H), 6.94 (d, J=2.4 Hz,

1H), 7.13–7.17 (m, 4H), 7.20 (dt, J=

1.0, 7.6 Hz, 2H), 7.24 (dd, J=1.0,

5.7 Hz, 1H), 7.40 (dq, J=1.3, 7.8 Hz,

2H), 7.44 (dd, J=1.1, 7.6 Hz, 1H),

7.61 ppm (dt, J=1.8, 7.4 Hz, 1H);

¹³C NMR (CDCl₃, 125 MHz): d=37.9

(CH), 39.1 (CH₂), 53.3 (C_quat), 74.9

(CH₂), 111.2 (CH), 113.0 (C_quat), 116.2

(CH), 116.4 (CH), 118.4 (C_quat), 118.5

(C_quat), 123.4 (CH), 123.4 (CH), 124.2

(CH), 124.5 (CH), 124.9 (CH), 126.5

(CH), 126.7 (CH), 127.5 (CH), 128.1

(C_quat), 128.5 (CH), 129.3 (CH), 130.2

(CH), 130.2 (CH), 130.9 (CH), 131.0

(CH), 132.4 (CH), 132.8 (C_quat), 140.0

(C_quat), 147.4 (C_quat), 152.4 (C_quat),

158.4 (C_quat), 160.4 (C_quat), 178.2 ppm

(C_quat); EI MS (70 eV): m/z (%): 410

(100) [M⁺], 381 (12), 305 (12), 289

(14), 259 (6), 123 (22); HRMS: m/z:

calcd for C₂₇H₁₉FO₃: 410.1318; found:

410.1326; IR (KBr): n˜ =3058 (w),

2989 (w), 2935 (w), 2876 (w), 1902

(s), 1615 (m), 1596 (w), 1492 (m),

1461 (m), 1230 (m), 1051 (s), 758 (s),

590 cm^ꢀ1(w); UV/Vis (CH₂Cl₂): l_max

417.44

410.42

422.46

435.50

100(2)

450.51

200(2)

0.71073

triclinic

T [K]

200(2)

l []

crystal

system

0.71073

monoclinic

0.71073

monoclinic

0.71073

monoclinic

0.71073

monoclinic

¯

space group P2₁/n

P2₁/n

P2₁/c

4

P1

Z

4

2

unit cell di-

mensions

a []

b []

c []

12.1661(8)

11.5630(7)

14.5855(10)

90

11.9124(2)

14.3534(2)

12.6520(2)

90

12.5638(3)

11.8966(2)

14.2975(3)

90

12.2819(15)

12.2233(15)

15.0269(19)

90

92.821(2)

90

7.1775(1)

8.0619(1)

20.0116(1)

81.414(1)

84.705(1)

81.149(1)

1128.49(2)

1.33

a [8]

b [8]

g [8]

92.381(1)

90

050.1(2)

1.35

112.350(1)

90

2000.77(5)

1.36

92.121(1)

90

2135.53(8)

1.31

V [³]

1_calcd[gcm^ꢀ3

2253.2(5)

1.28

]

m [mm^ꢀ1

]

0.09

0.08

0.09

crystal size

0.400.340.29 0.320.260.23 0.400.300.26 0.300.300.16 0.500.240.22

[mm³]

q range for

data collec-

tion [8]

2.1 to 27.5

2.0 to 27.5

2.2 to 27.5

2.1 to 28.3

1.0 to 27.5

index ranges ꢀ11ꢂhꢂ15

ꢀ15ꢂhꢂ25

ꢀ18ꢂkꢂ18

ꢀ16ꢂlꢂ16

20352

ꢀ16ꢂhꢂ16

ꢀ15ꢂkꢂ15

ꢀ18ꢂlꢂ18

21703

ꢀ16ꢂhꢂ13

ꢀ14ꢂkꢂ16

ꢀ19ꢂlꢂ20

16528

ꢀ9ꢂhꢂ9

ꢀ10ꢂk ꢂ10

ꢀ25ꢂlꢂ25

10926

ꢀ11ꢂkꢂ13

ꢀ14ꢂlꢂ18

reflections

collected

6776

independent 4418 (R-

4585 (R-

4877 (R-

5596 (R-

(int)=0.0316)

5115 (R-

reflections

obsd reflec-

tions

C

(int)=0.0330)

A

G

A

absorption

correction

max. and

min. trans-

mission

semiempirical from equivalents

0.97 and 0.97

0.98 and 0.97

0.99 and 0.98

0.98 and 0.96

refinement

method

full-matrix least-squares on F²

data/re-

4418/0/289

1.03

4585/3/289

1.02

4877/0/290

1.02

5596/0/398

5115/0/310

1.01

(e)=282

(7900),

334 nm

elemental

straints/pa-

rameters

GoF on F²

final R indi-

ces (I

(23200 mol^ꢀ1dm³cm^ꢀ1);

analysis calcd (%) for C₂₇H₁₉FO₃

(422.5): C 79.01, H 4.67; found: C

78.86, H 4.74.

1.03

3H-Benzofuran-2-one-3-spiro-6’-3’-

(4’-methoxyphenyl)-5’-phenyl-

1’,6’,7’,7a’-tetrahydroisobenzofuran

(3c): According to the general proce-

dure after chromatography on silica

gel (hexanes/ethyl acetate 5:1) and

>2s(I))

R1

wR2

0.040

0.090

0.043

0.098

0.037

0.088

0.041

0.108

0.040

0.096

recrystallization from diethyl ether/pentane spirobenzofuranone 3c was

obtained as intensively yellow-blue fluorescent crystals. M.p. 2088C;

¹H NMR (CDCl₃, 500 MHz): d=2.16 (dd, J=4.4, 12.0 Hz, 1H), 2.32 (t,

J=12.2 Hz, 1H), 3.86 (s, 3H), 3.89 (m, 1H), 3.97 (dd, J=8.1, 12.8 Hz,

1H), 4.73 (t, J=8.3 Hz, 1H), 6.85–6.87 (m, 2H), 6.95 (d, J=8.9 Hz, 2H),

7.15–7.16 (m, 4H), 7.20 (d, J=8.0 Hz, 1H), 7.24 (dt, J=0.6, 7.6 Hz, 1H),

7.39 (dd, J=1.3, 7.9 Hz, Hz, 1H), 7.43 (d, J=7.6 Hz, 1H), 7.64 ppm (d,

=8.9 Hz, 1H); ¹³C NMR (CDCl₃, 125 MHz): d=38.0 (CH), 38.8 (CH₂),

53.2 (C_quat), 55.3 (CH₃), 74.5 (CH₂), 108.9 (C_quat), 111.2 (CH), 114.0 (CH),

123.2 (C_quat), 123.7 (CH), 124.4 (CH), 124.8 (CH), 126.4 (CH), 127.3

(CH), 128.5 (CH), 128.8 (CH), 129.2 (CH), 131.5 (C_quat), 133.1 (C_quat),

140.3 (C_quat), 150.4 (C_quat), 152.4 (C_quat), 160.3 (C_quat), 178.3 ppm (C_quat);

EI MS (70eV): m/z (%): 422 (100) [M⁺], 393 (29), 369 (6), 301 (31), 267

(26), 162 (32), 113 (52); HRMS: m/z: calcd for C₂₈H₂₂O₄: 422.1518;

7.6 Hz, 1H), 7.40–7.43 (m, 2H), 7.69 (d, J=8.4 Hz, 2H), 7.78 ppm (d, J=

8.5 Hz, 2H); ¹³C NMR (CDCl₃, 125 MHz): d=38.3 (CH), 38.6 (CH₂),

53.3 (C_quat), 74.6 (CH₂), 111.4 (CH), 112.1 (C_quat), 113.7 (C_quat), 118.6

(C_quat), 122.6 (CH), 124.6 (CH), 124.7 (CH), 126.6 (CH), 127.5 (CH),

127.9 (CH), 128.6 (CH), 129.5 (CH), 132.3 (CH), 132.3 (C_quat), 134.8

(C_quat), 135.2 (C_quat), 139.7 (C_quat), 149.8 (C_quat), 152.4 (C_quat), 177.8 ppm

(C_quat); EI MS (70 eV): m/z (%): 417 (100) [M⁺], 388 (9), 312 (10), 296

(9), 259 (7), 162 (7), 130 (11); HRMS: m/z: calcd for C₂₈H₁₉NO₃:

417.1365; found: 417.1351; IR (KBr): n˜ =3056 (w), 2934 (w), 2877 (w),

2226 (s), 1805 (s), 1607 (s), 1520 (m), 1474 (s), 1230 (m), 1078 (s), 1051

(s), 762 cm^ꢀ1(m); UV/Vis (CH₂Cl₂): l_max(e)=246 (11000), 282 (500),

368 nm (12700 mol^ꢀ1dm³cm^ꢀ1); elemental analysis calcd (%) for

Chem. Eur. J. 2008, 14, 529 – 547

ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

539

T. J. J. Müller et al.

Table 7. Crystal data and structure refinements for 5d, f, h, i, l, p, and q.

Compound

5d

5 f5h

5i

5l

5p

5q

empirical formula

F_w

C₃₆H₃₀ClNO₄S

608.12

C₃₄H₂₉NO₄S₂

579.70

C₃₄H₃₄ClNO₄S

588.13

C₃₄H₃₅NO₄S

553.69

C₃₉H₄₇NO₄SSi

653.93

C₃₂H₃₁NO₆S

557.64

C₃₈H₃₃NO₆S

631.71

T [K]

200(2)

l []

crystal system

space group

0.71073

monoclinic

P2₁/n

0.71073

monoclinic

P2₁/n

0.71073

triclinic

P1

0.71073

monoclinic

P2₁/c

0.71073

monoclinic

P2₁/c

0.71073

triclinic

P1

triclinic

¯

P1

Z

4

2

4

2

unit cell dimensions

a []

b []

c []

a [8]

11.2088(2)

19.9746(3)

13.8293(2)

90

99.168(1)

90

3056.71(8)

1.32

0.23

11.424(1)

18.584(2)

13.719(1)

90

101.869(3)

90

2850.1

1.35

0.23

9.1393(3)

11.7505(4)

14.4395(4)

104.341(1)

94.156(1)

94.205(1)

1491.71(8)

1.31

9.8926(3)

10.5896(3)

14.8590(4)

70.728(1)

79.595(1)

73.190(1)

1400.33(7)

1.31

10.7040(3)

11.8527(4)

27.9972(9)

90

95.053(1)

90

3538.24(19)

1.23

0.17

10.1932(3)

10.4287(3)

25.6579(8)

90

95.436(1)

90

2715.22(14)

1.36

0.17

9.170(1)

12.481(2)

14.435(2)

103.203(3)

93.917(3)

98.107(3)

1583.7(5)

1.33

b [8]

g [8]

V [³]

1_calcd[gcm^ꢀ3

]

m [mm^ꢀ1

crystal size [mm³]

]

0.24

0.16

0.15

0.320.300.20 0.140.120.08 0.240.180.14 0.300.160.10 0.240.160.10 0.220.180.12 0.310.150.12

q range for data collec- 1.8 to 27.5

tion [8]

1.9 to 23.3

1.8 to 27.5

2.1 to 27.5

1.5 to 24.4

1.6 to 25.4

1.5 to 24.1

index ranges

ꢀ14ꢂhꢂ14

ꢀ25ꢂkꢂ25

ꢀ17ꢂlꢂ17

31600

ꢀ12ꢂhꢂ12

ꢀ20ꢂkꢂ20

ꢀ15ꢂlꢂ15

19052

ꢀ11ꢂhꢂ11

ꢀ15ꢂkꢂ15

ꢀ18ꢂlꢂ18

15673

ꢀ12ꢂhꢂ12

ꢀ13ꢂkꢂ13

ꢀ19ꢂlꢂ19

14660

ꢀ12ꢂh 12

ꢀ13ꢂkꢂ13

ꢀ32ꢂlꢂ32

28571

ꢀ12ꢂhꢂ12

ꢀ12ꢂkꢂ12

ꢀ30ꢂlꢂ30

23583

ꢀ10ꢂhꢂ10

ꢀ14ꢂkꢂ14

ꢀ16ꢂlꢂ16

11956

reflns collected

independent reflns

7008 (R-

4057 (R-

6786 (R-

6372 (R-

5842 (R-

4979 (R-

5038 (R-

A

(int)=0.0807)

(int)=0.0406)

U

(int)=0.0638)

U

G

obsd reflns

2138 (I >2s(I)) 3697 (I >2s(I)) 4376 (I >2s(I)) 4392 (I >2s(I)) 3955 (I >2s(I)) 3401 (I >2s(I)) 3861 (I >2s(I))

absorption correction

semiempirical from equivalents

max. and min. transmis- 0.95 and 0.93

0.98 and 0.97

0.97 and 0.95

0.98 and 0.95

0.98 and 0.96

0.98 and 0.95

sion

refinement method

full-matrix least-squares on F²

data/restraints/parame- 7008/0/391

ters

4057/0/368

1.34

6786/2/383

1.00

6372/0/365

1.01

5842/0/424

1.01

4979/0/367

1.01

5038/0/419

1.03

GoF on F²

final R indices (I

>2s(I))

R1

1.01

0.038

0.112

0.044

0.042

0.041

0.039

0.040

wR2

0.094

0.199

0.094

0.093

0.082

0.097

largest diff. peak and

0.25 and ꢀ0.38

0.68 and ꢀ0.50

0.35 and ꢀ0.36

0.24 and ꢀ0.42

0.25 and ꢀ0.36

0.22 and ꢀ0.27

0.22 and ꢀ0.23

ꢀ3

hole [e

]

500 MHz): d=1.44 (t, J=7.9 Hz, 3H), 2.15 (dd, J=4.3, 12.0 Hz, 1H),

2.32 (t, J=12.1 Hz, 1H), 3.87 (m, 1H), 3.96 (dd, J=8.2, 12.8 Hz, 1H),

4.08 (q, J=6.9 Hz, 2H), 4.72 (t, J=8.2 Hz, 1H), 6.85–6.87 (m, 2H), 6.94

(d, J=8.9 Hz, 2H), 7.15–7.16 (m, 4H), 7.20 (d, J=8.0 Hz, 1H), 7.24 (dt,

J=0.7, 7.6 Hz, 1H), 7.39 (dd, J=1.1, 7.8 Hz, 1H), 7.42 (d, J=7.8 Hz,

1H), 7.63 ppm (d, J=8.9 Hz, 2H); ¹³C NMR (CDCl₃, 125 MHz): d=14.8

(CH₃), 38.0 (CH), 38.8 (CH₂), 53.2 (C_quat), 63.5 (CH₂), 74.4 (CH₂), 108.9

(C_quat), 111.2 (CH), 114.6 (CH), 123.0 (C_quat), 123.8 (CH), 124.4 (CH),

124.9 (CH), 162.4 (CH), 127.3 (CH), 128.5 (CH), 128.8 (CH), 129.2

(CH), 131.4 (C_quat), 133.1 (C_quat), 140.3 (C_quat), 152.3 (C_quat), 152.5 (C_quat),

159.7 (C_quat), 178.3 ppm (C_quat); EI MS (70eV): m/z (%): 436 (100) [M⁺],

408 (8), 407 (18), 311 (11), 315 (17), 287 (8), 149(13); HRMS: m/z: calcd

for C₂₉H₂₄O₄: 436.1675; found: 436.1660; IR (KBr): n˜ =3053 (w), 2981

(w), 2934 (w), 2873 (w), 1803 (s), 1610 (s), 1509 (m), 1474 (m), 1252 (m),

1231 (w), 1078 (w), 1049 (s), 756 cm^ꢀ1(m); UV/Vis (CH₂Cl₂): l_max(e)=

256 (15600), 348 nm (23400 mol^ꢀ1dm³cm^ꢀ1); elemental analysis calcd

(%) for C₂₉H₂₄O₄(436.5): C 79.80, H 5.54; found: C 79.76, H 5.55.

Table 8. Experimental details of the synthesis of spirobenzofuranones 3.

Entry

Propargyl allyl ether 2 [mg]

([mmol])

Spirobenzofuranones 3

(Yield [%])

A

ACHTREUNG

1

2

3

4

5

6

7

8

217 (1.10) of 2a

209 (1.10) of 2b

222 (1.10) of 2c

194 (1.10) of 2d

237 (1.10) of 2e

253 (1.10) of 2 f

212 (1.10) of 2g

253 (1.10) of 2h

213 (51) of 3a

211 (50) of 3b

279 (66) of 3c

201 (46) of 3d

139 (32) of 3e

131 (29) of 3 f

202 (49) of 3g

149 (33) of 3h

found: 422.1532; IR (KBr): n˜ =3053 (w), 2933 (w), 2872 (w), 1803 (s),

1612 (s), 1510 (m), 1474 (m), 1254 (m), 1078 (w), 1050 (s), 755 (m),

600 cm^ꢀ1(w); UV/Vis (CH₂Cl₂): l_max(e)=256 (17500), 348 nm

(26700 mol^ꢀ1dm³cm^ꢀ1); elemental analysis calcd (%) for C₂₈H₂₂O₄

(422.5): C 79.60, H 5.25; found: C 79.28, H 5.23.

3H-Benzofuran-2-one-3-spiro-5’-dimethyl-[4’-(6’-phenyl-3’,3a’,4’,5’-tetra-

hydroisobenzofuran-1’-yl)phenyl]amine (3e): According to the general

procedure after chromatography on silica gel (hexanes/ethyl acetate 5:1)

and recrystallization from diethyl ether/pentane spirobenzofuranone 3e

was obtained as intensive yellow crystals. M.p. 2058C; ¹H NMR (CDCl₃,

500 MHz): d=2.14 (dd, J=12.0 Hz, 1H), 2.30 (t, J=12.1 Hz, 1H), 3.03

(s, 6H), 3.68 (m, J=4.4 Hz, 1H), 3.94 (dd, J=8.0, 12.7 Hz, 1H), 4.70 (t,

3H-Benzofuran-2-one-3-spiro-6’-3’-(4’-ethoxyphenyl)-5’-phenyl-1’,6’,7’,7a’-

tetrahydroisobenzofuran (3d): According to the general procedure after

chromatography on silica gel (hexanes/ethyl acetate 5:1) and recrystalli-

zation from diethyl ether/pentane spirobenzofuranone 3d was obtained

as intensively yellow fluorescent crystals. M.p. 1988C; ¹H NMR (CDCl₃,

540

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ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Eur. J. 2008, 14, 529 – 547

Rigid Fluorophores

FULL PAPER

J=8.1 Hz, 1H), 6.74 (d, J=8.4 Hz, 2H), 6.82–6.88 (m, 2H), 7.13–7.16 (m,

3H), 7.19–7.21 (m, 2H), 7.23 (dt, J=1.0, 7.6 Hz, J=1.0 Hz, 1H), 7.40 (dt,

J=1.4, 7.8 Hz, 2H), 7.43 ppm (dd, J=1.0, 7.6 Hz, 2H); ¹³C NMR

(CDCl₃, 125 MHz): d=37.9 (CH₃), 38.9 (CH₂), 40.2 (CH), 53.1 (C_quat),

74.3 (CH₂), 107.5 (C_quat), 111.1 (CH), 111.8 (CH), 124.3 (CH), 124.4

(CH), 124.9 (CH), 126.3 (CH), 127.1 (CH), 128.5 (CH), 128.5 (CH),

129.1 (CH), 130.0 (C_quat), 133.4 (C_quat), 140.6 (C_quat), 150.8 (C_quat), 152.3

(C_quat), 153.4 (C_quat), 178.5 ppm (C_quat); EI MS (70eV): m/z (%): 435

(100) [M⁺], 407 (11), 406 (32), 330 (7), 314 (9), 267 (8), 236 (8), 217 (10),

162 (21), 113 (15); HRMS: m/z: calcd for C₂₉H₂₅NO₃: 435.1834; found:

435.1830; IR (KBr): n˜ =3054 (w), 2985 (w), 2931 (w), 2875 (w), 1803 (s),

1610 (s), 1512 (m), 1475 (m), 1373 (m), 1230 (w), 1053 (m), 760 cm^ꢀ1(w);

UV/Vis (CH₂Cl₂): l_max(e)=286 (11400), 374 nm (21200 mol^ꢀ1dm³cm^ꢀ1);

elemental analysis calcd (%) for C₂₉H₂₅NO₃·0.2C₄H₉O (435.5 + 14.9): C

79.48, H 6.04, N 3.11; found: C 79.18, H 5.73, N 3.34.

(m), 704 cm^ꢀ1(w); UV/Vis (CH₂Cl₂): l_max(e)=260 (13900), 358 nm

(21100 mol^ꢀ1dm³cm^ꢀ1); elemental analysis calcd (%) for C₂₆H₂₀O₃S

(412.5): C 75.70, H 4.89, S 7.77; found: C 75.77, H 4.91, S 7.74.

3H-Benzofuran-2-one-3-spiro-6’-3’-(4’-methoxyphenyl)-7’,7’-dimethyl-5’-

phenyl-1’,6’,7’,7a’-tetrahydroisobenzofuran (3h): According to the general

procedure after chromatography on silica gel (hexanes/ethyl acetate 5:1)

and recrystallization from diethyl ether/pentane spirobenzofuranone 3h

was obtained as yellow-blue fluorescent crystals. M.p. 1998C; ¹H NMR

(CDCl₃, 500 MHz): d=0.72 (s, 3H), 1.28 (s, 3H), 3.86 (s, 3H), 3.94 (dd,

J=8.7, 12.4 Hz, 1H), 4.23 (dd, J=8.7, 12.4 Hz, 1H), 4.51 (dd, J=8.9,

9.6 Hz, 1H), 6.83–6.85 (m, 2H), 6.96 (d, J=9.0 Hz, 2H), 7.05 (s, 1H),

7.16–7.19 (m, 4H), 7.23 (dt, J=1.0, 7.6 Hz, 1H), 7.34 (dd, J=1.3, 7.6 Hz,

1H), 7.40 (dt, J=1.3, 7.6 Hz, 1H), 7.66 ppm (d, J=8.9 Hz, 2H);

¹³C NMR (CDCl₃, 125 MHz): d=16.6 (CH₃), 22.5 (CH₃), 39.4 (C_quat), 47.7

(CH), 55.3 (CH₃), 61.8 (C_quat), 70.1 (CH₂), 108.1 (C_quat), 110.5 (CH), 114.0

(CH), 122.6 (CH), 123.3 (C_quat), 124.1 (CH), 126.0 (CH), 126.2 (CH),

127.2 (CH), 128.5 (CH), 128.8 (CH), 129.2 (CH), 131.7 (C_quat), 132.9

(C_quat), 141.2 (C_quat), 153.0 (C_quat), 160.3 (C_quat), 175.6 ppm (C_quat); EI MS

(70eV): m/z (%): 450 (100) [M⁺], 381 (5), 369 (5), 315 (11), 267 (6), 247

(10), 162 (11), 135 (24), 113 (10); HRMS: m/z: calcd for C₃₀H₂₆O₄:

450.1831; found: 450.1824. IR (KBr): n˜ =3053 (w), 2954 (w), 2894 (w),

2837 (w), 1803 (s), 1609 (s), 1595 (w), 1511 (m), 1474 (m), 1255 (s), 1080

(m), 1046 (s), 757 (m), 699 cm^ꢀ1(w); UV/Vis (CH₂Cl₂): l_max(e)=256

(17000), 350 nm (35000 mol^ꢀ1dm³cm^ꢀ1); elemental analysis calcd (%)

for C₃₀H₂₆O₄(450.5): C 79.98, H 5.82; found: C 79.70, H 5.72.

3H-Benzofuran-2-one-3-spiro-6’-3’-(4’-ethoxyphenyl)-7’-methyl-5’-phenyl-

1’,6’,7’,7a’-tetrahydroisobenzofuran (3 f): According to the general proce-

dure after chromatography on silica gel (hexanes/ethyl acetate 5:1) and

recrystallization from diethyl ether/pentane spirobenzofuranone 3 f was

obtained as yellow fluorescent crystals. M.p. 2068C; ¹H NMR (CDCl₃,

300 MHz): d=0.68 (d, J=6.6 Hz, 3H), 1.44 (t, J=7.1 Hz, 3H), 2.49 (dq,

J=6.9, 12.5 Hz, 1H), 3.57 (dt, J=8.9, 12.4 Hz, 1H), 3.97 (dd, J=8.4,

12.5 Hz, 1H), 4.07 (q, J=6.8 Hz, 2H), 4.70 (t, J=8.5 Hz, 1H), 6.82–6.86

(m, 2H), 6.93 (d, J=8.8 Hz, 2H), 7.15–7.22 (m, 5H), 7.25–7.28 (m, 1H),

7.35–7.44 (m, 2H), 7.61 pppm (d, J=8.8 Hz, 2H); ¹³C NMR (CDCl₃,

75 MHz): d=14.0 (CH₃), 14.7 (CH₃), 42.5 (CH), 44.1 (CH), 58.6 (C_quat),

63.5 (CH₂), 74.0 (CH₂), 109.1 (C_quat), 110.8 (CH), 114.5 (CH), 114.5 (CH),

123.1 (C_quat), 123.4 (CH), 124.5 (CH), 125.5 (CH), 126.8 (CH), 127.3

(CH), 128.4 (CH), 128.7 (CH), 129.3 (CH), 130.0 (C_quat), 133.4 (C_quat),

140.7 (C_quat), 152.3 (C_quat), 153.1 (C_quat), 159.6 (C_quat), 178.1 ppm (C_quat);

EI MS (70eV): m/z (%): 450 (100) [M⁺], 407 (9), 301 (17), 194 (8), 149

(21), 121 (21); IR (KBr): n˜ =3053 (w), 2981 (w), 2934 (w), 2872 (w), 1803

(s), 1610 (s), 1596 (w), 1509 (m), 1475 (m), 1252 (m), 1231 (m), 1078 (m),

1049 (s), 755 cm^ꢀ1(m); UV/Vis (CH₂Cl₂): l_max(e)=256 (15100), 348 nm

(23000 mol^ꢀ1dm³cm^ꢀ1); elemental analysis calcd (%) for C₃₀H₂₆O₄

(450.5): C 79.98, H 5.82; found: C 79.80, H 5.54.

General procedure for the insertion–coupling–isomerization–cycloaddi-

tion sequence to spiroindolones 5: In an heat gun dried and nitrogen

filled Schlenk crew cap vessel alkynyoyl iodo anilide 4 (1.50 mmol) and

propargyl allyl ether

2 (1.65 mmol) were dissolved in butyronitrile

(6 mL) and triethylamine (6 mL) (for experimental details see Table 9).

The solution was deaerated with a weak stream of nitrogen through a

cannula for 5 min. Then, [PdCl₂(PPh₃)₂] (53 mg, 0.08 mmol) and CuI

G

(8 mg, 0.04 mmol) were added and the mixture was stirred for 1 h at RT.

The vessel was placed in the reactor^[28]and the reaction mixture was

heated to reflux temperature for 16 or 72 h. Then, the reaction mixture

was cooled to RT, the solvents were removed in vacuo and the residue

was purified by chromatography on silica gel (hexanes/ethyl acetate).

Further purification was achieved by recrystallization from pentane/ether

3H-Benzofuran-2-one-3-spiro-6’-7’-methyl-5’-phenyl-3’-thien-2’-yl-

1’,6’,7’,7a’-tetrahydroisobenzofuran (3g): According to the general proce-

dure after chromatography on silica gel (hexanes/ethyl acetate 5:1) and

recrystallization from diethyl ether/

pentane spirobenzofuranone 3g was

Table 9. Experimental details of the synthesis of spiroindolones 5.

obtained as deep yellow fluorescent

crystals. M.p. 2048C; ¹H NMR

(CDCl₃, 500 MHz): d=0.68 (d, J=

6.7 Hz, 1H), 2.52 (dq, J=6.9, 12.3 Hz,

1H), 3.56 (dt, J=8.7, 12.4 Hz, 1H),

3.99 (dd, J=8.5, 12.6 Hz, 1H), 4.71 (t,

J=8.5 Hz, 1H), 6.85–6.87 (m, 2H),

7.10 (dd, J=3.7, 5.0 Hz, 1H), 7.14–

7.17 (m, 5H), 7.24 (dd, J=0.8, 7.6 Hz,

1H), 7.33 (dd, J=1.1, 7.5 Hz, 1H),

7.39–7.41 ppm (m, 3H); ¹³C NMR

(CDCl₃, 125 MHz): d=14.0 (CH),

42.6 (CH), 44.0 (CH), 58.7 (C_quat),

74.4 (CH₂), 110.3 (C_quat), 110.9 (CH),

122.7 (CH), 124.6 (CH), 125.4 (CH),

126.4 (CH), 126.7 (CH), 126.8 (CH),

127.5 (CH), 127.5 (CH), 128.5 (CH),

129.5 (CH), 129.7 (C_quat), 132.6

(C_quat), 134.6 (C_quat), 140.4 (C_quat),

146.8 (C_quat), 153.1 (C_quat), 177.9 ppm

(C_quat); EI MS (70eV): m/z (%): 412

(100) [M⁺], 369 (7), 317 (5), 301 (16),

291 (5), 194 (7), 150 (11), 113 (10),

111 (23); HRMS: m/z: calcd for

Entry

Alkynoyl iodo anilide 4 [mg]

([mmol])

Propargyl allyl ether 2 [mg]

([mmol])

Spiroindolones 5 [mg]

(Yield [%])^[b]

G

E

ACHTREUNG

1^[a]

752 (1.50) of 4a

722 (1.50) of 4b

872 (1.50) of 4c

683 (1.50) of 4d

797 (1.50) of 4e

955 (1.50) of 4 f

884 (1.50) of 4g

584 (1.50) of 4h

542 (1.50) of 4i

334 (1.65) of 2c

317 (1.65) of 2g

499 (1.65) of 2i

387 (1.65) of 2j

330 (1.65) of 2k

340 (1.65) of 2l

380 (1.65) of 2h

387 (1.65) of 2j

330 (1.65) of 2k

380 (1.65) of 2h

387 (1.65) of 2j

330 (1.65) of 2k

380 (1.65) of 2h

387 (1.65) of 2j

330 (1.65) of 2k

380 (1.65) of 2h

499 (1.65) of 2i

387 (1.65) of 2j

330 (1.65) of 2k

387 (1.65) of 2j

330 (1.65) of 2k

698 (81%) of 5a

612 (72) of 5b

641 (71) of 5c

785 (86) of 5d

740 (86) of 5e

627 (72) of 5 f

712 (79) of 5g

715 (81) of 5h

658 (79) of 5i

673 (77) of 5j

811 (79) of 5k

831 (85) of 5l

789 (77) of 5m

450 (53) of 5n

500 (63) of 5o

510 (63) of 5p

625 (66) of 5q

833 (87) of 5r

797 (88) of 5s

647 (58) of 5t

725 (73) of 5u

318 (46) of 5v

247 (38) of 5w

2^[a]

3^[b]

4^[a]

5^[a]

6^[a]

7^[a]

8^[a]

9^[a]

10^[a]

11^[a]

12^[a]

13^[a]

14^[b]

15^[b]

16^[b]

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23^[a]

C₂₆H₂₀O₃S:

412.1133;

found:

412.1119; IR (KBr): n˜ =2963 (w),

2871 (w), 1803 (s), 1617 (s), 1460 (m),

1229 (w), 1054 (m), 1031 (w), 759

[a] Heating for 72 h. [b]Heating for 16 h.

Chem. Eur. J. 2008, 14, 529 – 547

ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

541

T. J. J. Müller et al.

and the spiroindolones 5 were obtained as analytically pure, yellow fluo-

rescent solids.

C₃₃H₂₇NO₄S₂: 565.1381; found: 565.1390; IR (KBr): n˜ =3125 (w), 3015

(w), 1758 (s), 1599 (s), 1460 (s), 1377 (s), 1234 (m), 1212 (w), 1190 (w),

1178 (m), 1092 (s), 759 (s), 702 (s), 569 cm^ꢀ1(s); UV/Vis (CH₂Cl₂): l_max

(e)=256 (20000), 358 nm (20500 mol^ꢀ1dm³cm^ꢀ1); elemental analysis

calcd (%) for C₃₃H₂₇NO₄S₂(565.7): C 70.06, H 4.81, N 2.48; found: C

69.60, H 4.81, N 2.60.

1-Tosyl-1,3-dihydroindol-2-one-3-spiro-6’-3’-(4’-methoxyphenyl)-5’-

phenyl-1’,6’,7’,7a’-tetrahydroisobenzofuran (5a): According to the general

procedure after chromatography on silica gel (hexanes/ethyl acetate 3:1)

and recrystallization from diethyl ether/pentane spiroindolone 5a was ob-

tained as a yellow fluorescent solid. M.p. 1798C; ¹H NMR (500 MHz,

CDCl₃): d = 2.00 (dd, J=4.4, 11.8 Hz, 1H), 2.17 (t, J=12.1 Hz, 1H),

2.43 (s, 3H), 3.79 (m, 1H), 3.84 (s, 3H), 3.89 (m, 1H), 4.67 (t, J=8.1 Hz,

1H), 6.51 (d, J=8.1 Hz, 2H), 6.75 (t, J=7.4 Hz, 2H), 6.93 (dd, J=2.2,

8.8 Hz, 3H), 7.10 (s, 1H), 7.19 (d, J=8.5 Hz, 2H), 7.24 (d, J=7.7 Hz,

1H), 7.35 (d, J=7.4 Hz, 1H), 7.43 (td, J=0.8, 8.1 Hz, 2H), 7.60 (d, J=

8.5 Hz, 2H), 8.02 ppm (d, J=8.1 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃):

d = 21.7 (CH₃), 37.9 (CH), 38.8 (CH₂), 54.6 (C_quat), 55.3 (CH₃), 74.5

(CH₂), 109.1 (C_quat), 113.8 (CH), 114.0 (CH), 123.3 (C_quat), 123.9 (CH),

124.6 (CH), 124.9 (CH), 125.7 (CH), 126.2 (CH), 127.5 (CH), 127.9

(CH), 128.5 (CH), 128.8 (CH), 129.4 (CH), 131.8 (C_quat), 133.3 (C_quat),

135.0 (C_quat), 137.9 (C_quat), 140.2 (C_quat), 145.2 (C_quat), 152.3 (C_quat), 160.2

(C_quat), 177.1 ppm (C_quat); EI MS (70eV): m/z (%): 575 (100) [M⁺], 420

(28) [M⁺ꢀSO₂C₆H₄CH₃], 369 (11), 317 (9); HRMS: m/z: calcd for

C₃₅H₂₉NO₅S: 575.1766; found: 575.1755; IR (KBr): n˜ =2934 (w), 1763 (s),

1604 (s), 1510 (m), 1376 (m), 1175 (s), 1070 (s), 759 (m), 581 (m),

566 cm^ꢀ1(w); UV/Vis (CH₂Cl₂): l_max(e)=242 (20000), 350 nm

1-Tosyl-1,3-dihydroindol-2-one-3-spiro-6’-3’-(4’-chlorophenyl)-7’,7’-di-

methyl-5’-phenyl-1’,6’,7’,7a’-tetrahydroisobenzofuran (5d): According to

the general procedure after chromatography on silica gel (hexanes/ethyl

acetate 3:1) and recrystallization from THF spiroindolone 5d was ob-

tained as yellow fluorescent crystals. M.p. 2548C: ¹H NMR (500 MHz,

CDCl₃): d = 0.72 (s, 3H), 1.20 (s, 3H), 2.43 (s, 3H), 3.90 (dd, J=9.0,

12.4 Hz, 1H), 4.21 (dd, J=9.0, 12.4 Hz, 1H), 4.52 (m, 1H), 6.43 (m, 2H),

6.68 (dd, J=7.7, 8.0 Hz, 2H), 6.90 (t, J=7.4 Hz, 1H), 6.94 (s, 1H), 7.19

(d, J=8.4 Hz, 2H), 7.22 (dd, J=1.0, 7.4 Hz, 1H), 7.26 (m, 1H), 7.37 (d,

J=8.4 Hz, 2H), 7.43 (m, 1H), 7.60 (d, J=8.7 Hz, 2H), 7.84 (d, J=8.4 Hz,

2H), 8.03 ppm (d, J=8.0 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃): d=16.8

(CH₃), 21.7 (CH₃), 21.9 (CH₃), 40.0 (C_quat), 47.8 (CH), 62.3 (C_quat), 70.2

(CH₂), 110.1 (C_quat), 112.9 (CH), 122.4 (CH), 124.5 (CH), 125.9 (CH),

126.2 (CH), 126.3 (CH), 127.9 (CH), 128.1 (CH), 128.5 (CH), 128.8

(CH), 129.2 (CH), 129.6 (CH), 131.5 (C_quat), 134.8 (C_quat), 134.9 (C_quat),

134.9 (C_quat), 139.0 (C_quat), 141.0 (C_quat), 145.2 (C_quat), 151.6 (C_quat),

37

174.8 ppm (C_quat); EI MS (70eV): m/z (%): 609 (45) [M⁺ꢀ Cl], 607

(24900 mol^ꢀ1dm³cm^ꢀ1);

elemental

analysis

calcd

(%)

for

(100) [M⁺ꢀ Cl], 454 (11) [M⁺ꢀ ClꢀSO₂C₆H₄CH₃], 452 (29) [M⁺

35

37

ꢀ ClꢀSO₂C₆H₄CH₃]; HRMS: m/z: calcd for C₃₆H₃₀³⁵ClNO₄S: 607.1584;

35

C₃₅H₂₉NO₅S·0.5H₂O (575.7 + 9.0): C 71.90, H 5.17, N 2.40; found: C

72.10, H 5.31, N 2.47.

found: 607.1552; IR (KBr): n˜ =3048 (w), 2974 (m), 2895 (w), 1759 (s),

1598 (s), 1490 (s), 1460 (s), 1374 (s), 1237 (s), 1190 (m), 1178 (s), 1162 (s),

1093 (s), 1068 (s), 760 (s), 702 (m), 691 (m), 659 (m), 573 cm^ꢀ1(s); UV/

Vis (CH₂Cl₂): l_max(e)=242 (27000), 350 nm (22900 mol^ꢀ1dm³cm^ꢀ1); ele-

mental analysis calcd (%) for C₃₆H₃₀ClNO₄S (608.2): C 71.10, H 4.97, N

2.30, Cl 5.83, S 5.2.7; found: C 71.07, H 5.02, N 2.37, Cl 5.84, S 5.27.

1-Tosyl-1,3-dihydroindol-2-one-3-spiro-6’-3’-(4’-methoxyphenyl)-7’-

methyl-5’-phenyl-1’,6’,7’,7a’-tetrahydroisobenzofuran (5b): According to

the general procedure after chromatography on silica gel (hexanes/ethyl

acetate 3:1) and recrystallization from diethyl ether/pentane spiroindo-

1

lone 5b was obtained as a yellow fluorescent solid. M.p. 1848C; H NMR

(500 MHz, CDCl₃): d=0.53 (d, J=6.7 Hz, 3H), 2.42 (s, 3H), 2.40–2.44

(m, 1H), 3.52 (dt, J=8.7, 12.4 Hz, 1H), 3.93 (dd, J=8.5, 12.8 Hz, 1H),

4.65 (t, J=8.5 Hz, 1H), 6.55 (m, 2H), 6.80 (dd, J=7.7, 8.1 Hz, 2H), 6.96

(m, 1H), 7.04 (s, 1H), 7.07 (dd, J=3.8, 5.0 Hz, 1H), 7.17 (m, 1H), 7.19

(m, 1H), 7.25 (dd, J=1.0, 7.4 Hz, 1H), 7.28 (m, 1H), 7.36 (m, 2H), 7.43

(m, 1H), 7.78 (d, J=8.4 Hz, 2H), 8.00 ppm (d, J=8.3 Hz, 1H); ¹³C NMR

(125 MHz, CDCl₃): d = 13.3 (CH₃), 21.7 (CH₃), 43.0 (CH), 43.9 (CH),

59.3 (C_quat), 74.5 (CH₂), 110.3 (C_quat), 113.4 (CH), 123.0 (CH), 124.9

(CH), 125.8 (CH), 126.3 (CH), 126.6 (CH), 126.6 (CH), 126.7 (CH),

127.4 (CH), 127.8 (CH), 128.1 (CH), 129.2 (CH), 129.6 (CH), 130.0

(C_quat), 132.7 (C_quat), 134.9 (C_quat), 135.2 (C_quat), 139.3 (C_quat), 140.3 (C_quat),

145.2 (C_quat), 146. 6 (C_quat), 176.7 ppm (C_quat); EI MS (70eV): m/z (%):

565 (100) [M⁺], 411 (28) [M⁺ꢀSO₂C₆H₄CH₃]; HRMS: m/z: calcd for

C₃₃H₂₇NO₄S₂: 565.1381; found: 565.1390; IR (KBr): n˜ =3125 (w), 3015

(w), 1758 (s), 1599 (s), 1460 (s), 1377 (s), 1234 (m), 1212 (w), 1190 (w),

1178 (m), 1092 (s), 759 (s), 702 (s), 569 cm^ꢀ1(s); UV/Vis (CH₂Cl₂): l_max

(e)=256 (20000), 358 nm (20500 mol^ꢀ1dm³cm^ꢀ1); elemental analysis

calcd (%) for C₃₃H₂₇NO₄S₂(565.7): C 70.06, H 4.81, N 2.48; found: C

69.60, H 4.81, N 2.60.

1-Tosyl-1,3-dihydroindol-2-one-3-spiro-6’-3’,5’-diphenyl-7’,7’-dimethyl-

1’,6’,7’,7a’-tetrahydroisobenzofuran (5e): According to the general proce-

dure after chromatography on silica gel (hexanes/ethyl acetate 3:1) and

recrystallization from THF spiroindolone 5e was obtained as yellow fluo-

rescent crystals. M.p. 2198C; ¹H NMR (500 MHz, CDCl₃): d = 0.73 (s,

3H), 1.21 (s, 3H), 2.44 (s, 3H), 3.91 (dd, J=10.0, 12.4 Hz, 1H), 4.23 (dd,

J=8.7, 12.4 Hz, 1H), 4.53 (dd, J=8.7, 9.7 Hz, 1H), 6.44 (dd, J=1.2,

8.3 Hz, 2H), 6.68 (dd, J=7.5, 8.2 Hz, 2H), 6.90 (tt, J=1.1, 7.4 Hz, 2H),

7.01 (s, 1H), 7.19 (m, 2H), 7.23 (dd, J=1.0, 7.6 Hz, 1H), 7.29 (dd, J=1.3,

7.6 Hz, 1H), 7.34–7.45 (m, 4H), 7.67 (m, 2H), 7.85 (d, J=8.4 Hz, 2H),

8.04 ppm (d, J=8.2 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃): d=16.8

(CH₃), 21.6 (CH₃), 21.9 (CH₃), 39.9 (C_quat), 47.7 (CH), 62.3 (C_quat), 70.2

(CH₂), 109.5 (C_quat), 112.8 (CH), 122.8 (CH), 124.4 (CH), 126.1 (CH),

126.2 (CH), 127.2 (CH), 127.9 (CH), 128.0 (CH), 128.5 (CH), 129.0

(CH), 129.1 (CH), 129.5 (CH), 129.6 (CH), 130.7 (C_quat), 131.6 (C_quat),

134.1 (C_quat), 134.9 (C_quat), 139.0 (C_quat), 141.1 (C_quat), 145.1 (C_quat), 152.8

(C_quat), 174.9 ppm (C_quat); EI MS (70eV): m/z (%): 573 (100) [M⁺], 418

(32) [M⁺ꢀSO₂C₆H₄CH₃], 267 (10), 201 (10); HRMS: m/z: calcd for

C₃₆H₃₁NO₄S: 573.1974; found: 573.1957; IR (KBr): n˜ =3054 (w), 2974

(w), 1758 (s), 1598 (m), 1492 (w), 1460 (s), 1376 (s), 1190 (m), 1064 (s),

760 cm^ꢀ1(s); UV/Vis (CH₂Cl₂): l_max(e)=244 (27600), 348 nm

(24900 mol^ꢀ1dm³cm^ꢀ1); elemental analysis calcd (%) for C₃₆H₃₁NO₄S

(573.7): C 75.37, H 5.45, N 2.44, S 5.59; found: C 75.04, H 5.33, N 2.65, S

5.63.

1-Tosyl-1,3-dihydroindol-2-one-3-spiro-6’-3’-(4’-formylphenyl)-7’-methyl-

5’-phenyl-1’,6’,7’,7a’-tetrahydroisobenzofuran (5c): According to the gen-

eral procedure after chromatography on silica gel (hexanes/ethyl acetate

3:1) and recrystallization from diethyl ether/pentane spiroindolone 5c

was obtained as

a

yellow fluorescent solid. M.p. 1998C; ¹H NMR