Coupling-isomerization-Stetter and coupling-isomerization-Stetter-Paal- Knorr sequences - A multicomponent approach to furans and pyrroles

FEATURE ARTICLE

2391

Coupling-Isomerization-Stetter and Coupling-Isomerization-Stetter–Paal–

Knorr Sequences – A Multicomponent Approach to Furans and Pyrroles

A

M

ulticompone

o

l

to

F

ura

a

ns and Pyr

n

roles d U. Braun, Thomas J. J. Müller*

Organisch-Chemisches Institut , Ruprecht-Karls-Universität Heidelberg, Im Neuenheimer Feld 270, 69120 Heidelberg, Germany

Fax +49(6221)546579; E-mail: Thomas_J.J.Mueller@urz.uni-heidelberg.de

Received 16 March 2004

Abstract: 2,3,5-Trisubstituted furans 6 and 1,2,3,5-tetrasubstituted

pyrroles 8 can be synthesized in good yields in a one-pot three-step

three- or four-component process by a coupling-isomerization-Stet-

ter–Paal–Knorr sequence of an electron-poor (hetero)aryl halide 1,

a terminal propargyl alcohol 2, an aldehyde 3, and, in the case of

pyrroles, a primary amine 7. All novel furans and pyrroles exhibit a

strong blue fluorescence with considerable Stokes shifts.

Key words: catalysis, cross-couplings, diketones, furans, pyrroles

Introduction

Sequential one-pot multicomponent processes have a con-

siderable and steadily increasing academic, economic and

ecological interest since they address very fundamental

principles of synthetic efficiency and reaction design.^1,2In

addition, the prospect of extending one-pot reactions into

combinatorial and solid phase syntheses^1c,3opens mani-

fold opportunities for developing novel lead structures of

pharmaceuticals, catalysts and even novel molecule-

based materials. Recently, based upon a palladium-cop-

per-catalyzed domino coupling-isomerization (CI) se-

quence of electron-poor halogen substituted p-systems

and 1-(hetero)aryl prop-2-yn-1-ols furnishing 1,3-di(hete-

ro)aryl enones (i.e. chalcones)⁴and considering the mild

reaction conditions, quite a number of generic structures

of pharmaceutically relevant heterocyclic classes can be

readily accessed. Therefore, we have recently introduced

a very efficient entry to three-component one-pot synthe-

ses of pyrazolines,⁴pyrimidines,⁵and 1,5-

benzoheteroazepines⁶and four-component one-pot syn-

theses of pyrroles,⁷pyrindines, and tetrahydroquinolines⁸

(Scheme 1).

Scheme 1 One-pot syntheses of pyrazolines, pyrimidines, benzo-

heteroazepines, pyrroles, pyrindines, and tetrahydroquinolines based

upon a coupling-isomerization sequence.

Thus, applying our concept of coupling-isomerization re-

action towards the synthesis of furans and pyrroles, it can

be readily deduced that 2,3,5-trisubstituted furans and

1,2,3,5-tetrasubstituted pyrroles should be accessible by

combining a Stetter reaction, furnishing the 1,4-dike-

tones,¹⁶and a subsequent Paal–Knorr cyclocondensation

(Scheme 2).^9a,b,dHere, we report on synthetic studies of

the CIR-Stetter access to 1,4-diketones, and on CI-Stet-

ter–Paal–Knorr sequences to furans and pyrroles, as well

as their absorption and emission properties.

Among numerous heterocycles, furans and pyrroles have

always been the most prominent ones since they constitute

important classes of natural products,⁹synthetic pharma-

ceuticals,^6,9cand of electrically conducting materials such

as polypyrroles.¹⁰In particular, 2,3,5-trisubstituted furans

and 1,2,3,5-tetrasubstituted pyrroles are highly biologi-

cally active and have proven to display antibacterial,¹¹an-

tiviral (also anti-HIV-1),¹²anti-inflammatory¹³and

antioxidant¹⁴activity as well as inhibition of cytokine-me-

diated diseases.¹⁵

Scheme 2 Retrosynthetic concept for a three-component furan and

four-component pyrrole synthesis.

SYNTHESIS 2004, No. 14, pp 2391–2406

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Advanced online publication: 23.08.2004

DOI: 10.1055/s-2004-831192; Art ID: Z05304SS

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R. U. Braun, T. J. J. Müller

FEATURE ARTICLE

plying the Karplus correlation of coupling constants and

dihedral angles suggests that a thermodynamically fa-

CI-Stetter Sequence to 1,4-Diketones

First, we had to test the compatibility of the Stetter addi- vored staggered orientation minimizing the gauche inter-

tion of (hetero)aromatic and aliphatic aldehydes with re- actions of the bulky EWG-p- and (hetero)aryl-

gard to the CIR formed chalcone functionality. Thus, substituents is strongly populated in solution. Further-

upon reacting electron-poor (hetero)aryl halides 1, (hete- more, the appearance of vicinal coupling constants

3

ro)aryl propynols 2, and after some reaction time, alde- (³J = 3.7–5.1 Hz, J = 9.1–10.1 Hz) for the signals at d

hydes 3, in the presence of a thiazolium salt 4 under the 4.41–5.32 completes the assignment of the methine reso-

conditions of the Sonogashira coupling in a boiling mix- nances. In this series of 1,4-diketones, compound 5k is the

ture of triethylamine and a solvent or neat triethylamine, only one bearing an additional center of chirality. There-

beige to yellow 1,2,4-trisubstituted 1,4-diketones 5 were fore, the formation of a mixture of diastereomers could be

obtained in 34–88% yield (Scheme 3, Table 1).

expected. The diastereomeric ratio of 1:1 indicates the ab-

sence of any 1,4-facial diastereoselection in the course of

the Stetter reaction. Furthermore, the resonances of the

(hetero)aromatic and aliphatic protons can be detected

with expected chemical shifts.

The structures of the 1,4-diketones 5 were unambiguously

assigned by ¹H, ¹³C and NOESY NMR experiments. As a

consequence of the Michael addition of aldehydes to the

transient enone functionality, three distinct aliphatic pro-

ton resonances, a methine and two diastereotopic methyl- Most revealing, in the carbon NMR spectra, two quaterna-

1

ene protons, appear most characteristically in the H ry carbonyl resonances are found between d 184.9–198.0

spectra as splitting patterns (doublets of doublets) of for alkyl (hetero)aryl ketones and/or d 207.6–212.4 for di-

ABM spin systems. Therefore, due to the characteristic alkyl ketones. The methine and methylene carbon nuclei

geminal and vicinal coupling constants (²J = 17.7–18.1 resulting from the Stetter reaction appear at d 46.9–53.6

3

Hz, ³J = 3.7–5.1 Hz, J = 9.1–10.1 Hz), the signals at d and d 40.5–44.1, respectively. Another strong spectro-

3.13–3.39 and d 3.98–4.21 can be assigned to the diaste- scopic support of the 1,4-dicarbonyl functionality can be

reotopic methylene protons. Conformational analyses ap- derived from the mass spectra, revealing that an a-cleav-

Biographical Sketches

Roland U. Braun was born in Würzburg, Germany, in thetic and mechanistic investigations of the coupling-

1974 and studied chemistry at the Ludwig-Maximilians- isomerization reaction and the development of novel mul-

Universität München from 1994 to 2000. He obtained his ticomponent syntheses of heterocycles. His research inter-

Diploma in 2000 under the supervision of Prof. H. Mayr ests encompass synthetic heterocyclic chemistry and

and completed his Ph.D. in 2004 at the Ruprecht-Karls- transition metal catalysis.

Universität Heidelberg with Prof. T. J. J. Müller on syn-

Thomas J. J. Müller was born in Würzburg, Germany, in search at the Technical University Darmstadt, moved to

1964 and studied chemistry at the Ludwig-Maximilians- LMU as a DFG scholar in 1997, to obtain his habilitation

Universität München (LMU) from 1984 to 1989. He ob- and was appointed to Privatdozent in 2000. In 1999/2000

tained his Diploma in 1989 and completed his Ph.D. in he was acting professor at the University of Stuttgart. In

1992 with Prof. R. Gompper on novel cyanine systems as 2002 he became a professor of organic chemistry at the

models for optical switches and molecular metals. After a Ruprecht-Karls-Universität Heidelberg. His research in-

post-doctoral stay with Prof. B. M. Trost at Stanford Uni- terests encompass synthetic heterocyclic chemistry, its

versity (USA) in 1993 and 1994 working on ruthenium- implication for developing novel tailor-made chro-

catalyzed Alder–Ene reactions, he returned to Germany. mophores, nanometer-sized redox active molecules, and

In 1994, as a Liebig scholar, he began his independent re- the design of novel multicomponent reactions.

Synthesis 2004, No. 14, 2391–2406 © Thieme Stuttgart · New York

FEATURE ARTICLE

A Multicomponent Approach to Furans and Pyrroles

2393

(5i, 5j, 5k, and 5l) two significant carbonyl vibrations are

detected at 1705–1716 and 1676–1685 cm^–1.

The applicability of this one-pot CI-Stetter sequence to

the synthesis of 1,4-diketones 5 is fairly broad, and occurs

under mild conditions and with excellent chemoselectivi-

ty. Conceptually, this sequence is highly intriguing since

two catalytic processes, the CIR and the Stetter reaction,

are highly compatible and can be sequentially performed

in the same reaction medium. In particular, the scope of

the Stetter reaction in this sequence encompasses elec-

tron-poor to electron-rich aromatic aldehydes (entries 1–

8), aliphatic aldehydes (entries 9–12), and even polar

functional groups (entry 12) are compatible with the con-

ditions of the CI-Stetter sequence. In agreement with the

Stetter reaction,¹⁶3,4-dimethyl-5-(2-hydroxyethyl) thiaz-

olium iodide (4a) is the catalyst of choice for aromatic al-

dehydes, whereas 3-benzyl-4-methyl-5-(2- hydroxyethyl)

thiazolium chloride (4b) is used for the addition of ali-

phatic aldehydes to enones.

Scheme 3 CI-Stetter sequence to 1,4-diketones 5

age of the carbonyl fragments is by far the most important

initial fragmentation step. In the IR spectra, typical CO-

valence vibrations of (hetero)aryl ketones are found be-

tween 1673 and 1683 cm^–1. In the case of aliphatic ketones

Table 1 Coupling-Isomerization-Stetter Synthesis of 1,4-Diketones 5

Entry (Hetero)aryl

Propargyl

Aldehyde 3

Thiazolium

1,4-Diketone 5 (Yield)

Halide 1

Alcohol 2

Salt 4

1

(het)aryl = Ph (2a)

R¹= p-NCC₆H₄(3a)

R¢ = CH₃(4a)

1a

5a (88%)

2^a

1a

2a

R¹= Ph (3b)

4a

5b (84%)

5c (81%)

3

4

1a

2a

R¹= 2-furyl (3c)

4a

R¹= p-MeOC₆H₄(3d)

5d (75%)

5

1a

2a

R¹= 10-methyl phenothiazin- 4a

3-yl (3e)

5e (82%)

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R. U. Braun, T. J. J. Müller

FEATURE ARTICLE

Table 1 Coupling-Isomerization-Stetter Synthesis of 1,4-Diketones 5 (continued)

Entry (Hetero)aryl

Propargyl

Aldehyde 3

Thiazolium

1,4-Diketone 5 (Yield)

Halide 1

Alcohol 2

Salt 4

6

7

1a

2a

R¹= 2-pyrryl (3f)

4a

5f (34%)

1a

2a

R¹= p-OHCC₆H₄(3g)

4a

5g (69%)

5h (70%)

8

(het)aryl = 3-furyl (2b) 3d

4a

1b

1a

9

2a

R¹= i-Pr (3h)

R¢ = CH₂Ph

(4b)

5i (54%)

5j (76%)

10

11

1a

2a

R¹= n-pentyl (3i)

4b

R¹=

(3j)

5k (66%)

5l (59%)

12

1a

2a

R¹= (CH₂)₅OH (3l)

4b

^aTHF.

consecutive combination of modern cross-coupling meth-

odology and classic Michael addition cyclocondensation,

the latter still being of significant importance in the indus-

CI-Stetter–Paal–Knorr Sequences to Furans and

Pyrroles

Encouraged by the excellent coupling-isomerization-Stet- trial processes of numerous heterocyclic pharmaceuticals.

ter sequence, we set out to extend and combine this one-

pot three-component reaction with a third and fourth step,

i.e. a Paal–Knorr reaction for designing novel three-com-

ponent furan and four-component pyrrole synthesis. This

Thus, the CI-Stetter–Paal–Knorr synthesis of furans be-

gins with the CI-Stetter synthesis of 1,4-diketones 5 start-

ing from electron-deficient (hetero)aryl halides 1, 1-

phenylpropyn-1-ol (2a), and aromatic or aliphatic alde-

approach is particularly intriguing since it represents a

hydes 3. After complete conversion of the intermediate

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FEATURE ARTICLE

A Multicomponent Approach to Furans and Pyrroles

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Table 2 Coupling-Isomerization-Stetter–Paal–Knorr Synthesis of Furans 6

Entry

1

(Hetero)aryl Halide 1

Aldehyde 3

Thiazolium Salt 4

Furan 6 (Yield)

1a

3b

4a

6a (79%)

2

1a

3c

4a

6b (74%)

3^a

R¹= p-FC₆H₄(3m)

1c

6c (46%)

6d (42%)

4

5

3b

3i

4a

4b

1d

1a

6e (64%)

^aIn CH₃CN.

enones to 1,4-diketones 5 (as monitored by TLC), concen- ro)aryl halides 1, 1-phenyl propyn-1-ol (2a), followed by

trated hydrochloric acid and acetic acid were successively the thiazolium salt-catalyzed Stetter reaction with aromat-

added to the reaction mixture. Subsequent to heating for

5–28 hours, the furans 6 were obtained as beige solids

(6a–d) or as a yellow resin (6e) in moderate to good yields

(Scheme 4, Table 2).

The formation of the furan core is unambiguously sup-

ported by the spectroscopic and analytical data. In the ¹H

NMR spectra of the 2,3,5-trisubstituted furans 6, the dis-

tinct furyl C⁴protons can be readily assigned by the char-

acteristic singlets at d 6.75–7.12. In comparison to

unsubstituted furan (d 6.37),¹⁷these methine resonances

are shifted downfield as a consequence of the anisotropic

ring current of the adjacent (hetero)aromatic substituents

at C³and C⁵. Accordingly, in the ¹³C NMR spectra, the C³

(quaternary) and C⁴(methine) furyl carbon nuclei are

characteristically shifted upfield and can be detected at d

118.3–122.6 (C³_quat) and d 105.4–108.4 (C⁴H).

Furthermore, the CIR-Stetter–Paal–Knorr synthesis of

pyrroles starts with the CIR of electron-deficient (hete-

Scheme 4 CI-Stetter–Paal–Knorr synthesis of furans 6.

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FEATURE ARTICLE

ic or aliphatic aldehydes 3. After complete conversion of to unsubstituted pyrrole (d 6.05)¹⁷as a consequence of the

the intermediate enones to 1,4-diketones 5 (as monitored anisotropic ring current of the adjacent (hetero)aromatic

by TLC), primary amines 7 or ammonium chloride (7a) substituents at C³and C⁵. For 2,3,5-trisubstituted pyrroles

and acetic acid were successively added to the reaction 8a–e, the N-H resonances can be detected as broad sin-

mixture. Subsequent heating for 24–33 hours led to the glets at d 8.51–8.57. The a-methylene and methine pro-

pyrroles 8, which were obtained as colorless to light yel- tons in direct proximity to the pyrryl nitrogen atom are

low or beige solids in moderate to good yields (Scheme 5, shifted to lower field and appear at d 5.08 and 5.14 for

Table 3).

benzyl derivatives 8f and 8g, whereas those of nonaromat-

ic substituents can be found shifted to higher field at d

4.22–4.61. In the ¹³C NMR spectra, the C³(quaternary)

and C⁴(methine) pyrryl carbon nuclei are characteristical-

ly shifted upfield and can be detected at d 119.7–122.8

(C³_quat) and d 105.8–110.1 (C⁴H).

The successful pyrrole formation is unambiguously sup-

ported by the spectroscopic and analytical data. In the ¹H

NMR spectra of the 2,3,5-trisubstituted and 1,2,3,5-tetra-

substituted pyrroles 8, the characteristic pyrryl C⁴methine

resonances can be clearly assigned by the appearance of

singlets at d 6.18–6.95. As in the case of the furans 6, these

methine resonances are shifted downfield in comparison

Table 3 Coupling-Isomerization-Stetter–Paal–Knorr Synthesis of Pyrroles 8

Entry

1

(Hetero)aryl Halide 1 Aldehyde 3

Thiazolium Salt 4 Amine 7

Pyrrole 8 (Yield)

1a

3b

4a

R²= H (as NH₄Cl)

(7a)

8a (70%)

8a (59%)

2

1a

3b

3d

4a

R²= (CO)CH₂NH₂

(7b)

3^a

7a

8b (60%)

8c (54%)

4

5

1c

1a

3m

4a

4b

7a

3i

8d (59%)

6

1a

3l

4b

7a

8e (53%)

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FEATURE ARTICLE

A Multicomponent Approach to Furans and Pyrroles

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Table 3 Coupling-Isomerization-Stetter–Paal–Knorr Synthesis of Pyrroles 8 (continued)

Entry

7

(Hetero)aryl Halide 1 Aldehyde 3

1a 3b

Thiazolium Salt 4 Amine 7

4a

R²= CH₂Ph

Pyrrole 8 (Yield)

(7c)

8f (60%)

8

1a

3c

4a

7c

8g (55%)

9

1a

3b

4a

R²= CH₂CO₂Et

(7d)

8h (54%)

10

1a

3j

4b

7b

8i (56%)

11

1a

3b

4a

R²= CH₂CH₂OH

(7e)

8j (57%)

12

1a

3i

4b

R²= i-Pr

(7f)

8k (59%)

^aIn CH₃CN.

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R. U. Braun, T. J. J. Müller

FEATURE ARTICLE

Methodologically, these novel sequential multi-compo- vestigate the absorption and emission properties of the

nent furan and pyrrole syntheses are relatively broad in furans 6 and pyrroles 8 (Table 4).

their scope. Interestingly, there is no interference of the

palladium/copper catalyst system, necessary for the initial

CIR, with the Paal–Knorr cyclocondensation. Therefore,

Upon UV excitation of the longest wavelength absorption

band, furans 6 and pyrroles 8 exhibit considerable Stokes

shifts and spontaneously fluoresce with emission of blue

the substitution pattern of furans is essentially the same as

light (Table 4). Their fluorescence behaviors are fairly

that of the preceding 1,4-diketones 5. Even notoriously

similar as illustrated by furan 6a and pyrrole 8a, having

acid-sensitive monofuryl substituents (6b, Table 2, entry

2) and p-fluorophenyl groups (6c, Table 2, entry 3), capa-

the same substitution pattern and a difference of Stokes

shifts of only 200 cm^–1. The phenomenon of large Stokes

ble of nucleophilic aromatic substitution, are compatible

shifts arises from significant structural changes upon ex-

with the reaction conditions of the sequence. For the syn-

citation from singlet ground state S₀and subsequent relax-

thesis of 2,3,5-trisubstituted pyrroles (Table 3, entries 1

ation to the lowest vibrational level of the first excited

and 3–6), ammonium chloride is a suitable source for the

singlet state S₁.²³In particular, since all furans 6 and pyr-

roles 8 are acceptor-substituted, a considerable charge

pyrryl nitrogen. Primary aliphatic amines are transformed

into 1,2,3,5-tetrasubstituted pyrroles (Table 3, entries 7–

transfer can be expected. However, the interpretation is

12); however, in the case of glycine derivatives (Table 3,

complicated since these systems are highly substituted.

entries 9 and 10) the reaction temperature in the cyclocon-

Therefore, additional sub-chromophores, as in the pair 8a/

8b, have to be taken into account where the electron-rich

anisyl group (8b) causes a bathochromic shift only of the

emission maximum. The same situation is found in the

pair 8f/8g where the furyl substituent (8g) acts as a donor

and enhances the push-pull character and its influence in

densation step has to be lowered considerably to avoid C-

N bond scission that leads to 1-unsubstituted pyrroles

(Table 3, entry 2). Unfortunately, due to their reduced nu-

cleophilicity, anilines cannot successfully be used for the

synthesis of 1-arylpyrrole derivatives, instead N-acetyl-

anilides are isolated as the major product. As a conse-

the stabilization of the S₁state.

quence of esterification of the primary alcohol that results

In conclusion, we have shown that the mild reaction con-

ditions of the CIR can be extended to a one-pot three-com-

ponent synthesis of 1,4-diketones in the sense of a

sequential CI-Stetter reaction. Combination of CIR, Stet-

ter reaction and Paal–Knorr cyclocondensation culmi-

from cyclocondensation with aminoethanol, with acetic

acid the acylated product 8j (Table 3, entry 11) can be

considered to be the product of a five-component reaction.

nates in the development of novel one-pot three-

component furan and four-component pyrrole syntheses.

Fluorescence of Furans 6 and Pyrroles 8

Interestingly, this novel modular strategy opens a rapid

access to highly substituted furan and pyrrole fluoro-

Most conspicuously, all furans 6 and pyrroles 8 display an

intense blue fluorescence upon irradiation with UV light.

phores. Further studies directed to extend these one-pot

Since fluorescent compounds are of significant interest as

heterocycle syntheses to pharmaceutically and electroni-

cally interesting systems like oligopyrroles, oligofurans,

and alternating oligo(pyrrylthiophenes) are currently un-

derway.

optical brighteners in detergents,¹⁸in optical data storage

media,¹⁹as probes in fluorescence microscopy for study-

ing biological processes on a cellular or sub-cellular lev-

el,²⁰as antibody markers in immunofluorescence

methods,²¹and as polarity or pH probes,²²we set out to in-

Table 4 Selected UV Absorptions (Longest Wavelength Maxima),

Fluorescence Emissions and Stokes Shifts of Furans 6 and Pyrroles 8

(Recorded in CHCl₃, Excitation at l_max(UV) + 20 nm)

Compound Absorption

Emission

_{max, em}[nm]

Stokes Shift

l

_{max, abs}[nm] (e)

l

D [cm^–1]

6a

6d

8a

8b

8f

313 (27600)

312 (20700)

317 (30700)

319 (26400)

318 (17000)

320 (30200)

314 (19500)

312 (9900)

315 (21100)

327 (13900)

432

407

436

451

428

446

427

401

418

425

8800

7500

8600

9100

8000

8900

8400

7200

7800

7100

8g

8h

8i

8j

Scheme 5 CI-Stetter–Paal–Knorr synthesis of pyrroles 8.

8k

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FEATURE ARTICLE

A Multicomponent Approach to Furans and Pyrroles

2399

phy on silica gel and/or recrystallized to give the pure 1,4-diketones

5 (for experimental details, see Table 5).

All reactions involving water-sensitive compounds were carried out

in oven-dried Schlenk glassware under a nitrogen atmosphere. The

solvents were dried according to standard procedures²⁴and were

distilled prior to use. Column chromatography: silica gel 60 M,

230–400 mesh (Macherey–Nagel) or aluminium oxide 5016 A ba-

sic (Fluka). Thin layer chromatography (TLC): silica gel layered

aluminium foil (60 F₂₅₄Merck, Darmstadt) or aluminum oxide lay-

ered aluminum foil (60 F₂₅₄Merck, Darmstadt). Melting points (un-

corrected): Büchi Melting Point B-540. The (hetero)aryl propynols

2,²⁵and the aldehydes 3e²⁶and 3l²⁷were synthesized according to

literature procedures. Electron-poor (hetero)aryl halides 1, the alde-

hydes 3, 3,4-dimethyl-5-(2-hydroxyethyl) thiazolium iodide (4a),

3-benzyl-4-methyl-5-(2-hydroxyethyl)-thiazolium chloride (4b),

and the amines 7 were purchased from ACROS or Merck and used

without further purification. Petroleum ether (PE) used had a boil-

ing range of 30–40 °C. ¹H and ¹³C NMR spectra: Bruker ARX250,

Bruker DRX 300, Bruker ARX 300, Varian VXR 400S, Bruker

DRX500 or Bruker AC300 with CDCl₃as a solvent. The assign-

ments of quaternary C, CH, CH₂and CH₃was made on the basis of

DEPT spectra. IR: Bruker Vector 22 FT-IR or Perkin Elmer Models

Lambda 16. UV/VIS: Hewlett Packard HP8452 A. MS: Finnigan

MAT 90, MAT 95 Q, Jeol JMS-700 and Finnigan TSQ 700. Ele-

mental analyses were carried out in the microanalytical laboratories

of Department Chemie der Universität München and the Organisch-

Chemisches Institut der Universität Heidelberg.

1,2-Bis(4-cyanophenyl)-4-phenylbutane-1,4-dione (5a)

Purification by chromatography on silica gel (PE–Et₂O, 3:1), beige

crystals, mp 130 °C (EtOH).

IR (KBr): 2230 (m), 1682 (s), 1606 (m), 1581 (w), 1504 (m), 1448

(m), 1405 (m), 1363 (w), 1339 (w), 1292 (w), 1230 (m), 1208 (w),

1177 (w), 1001 (m), 952 (w), 836 (m), 762 (m), 690 (m), 571 (m),

544 (w) cm^–1.

¹H NMR (CDCl₃, 300 MHz): d = 3.39 (dd, J = 3.7, 18.0 Hz, 1 H),

4.21 (dd, J = 10.1, 18.1 Hz, 1 H), 5.32 (dd, J = 3.7, 10.1 Hz, 1 H),

7.44–7.49 (m, 4 H), 7.57–7.65 (m, 3 H), 7.74 (d, J = 8.5 Hz, 2 H),

7.96 (d, J = 7.2 Hz, 2 H), 8.08 (d, J = 8.4 Hz, 2 H).

¹³C NMR (CDCl₃, 75 MHz): d = 43.8 (CH₂), 48.9 (CH), 112.0

(C_quat), 116.6 (C_quat), 117.8 (C_quat), 118.2 (C_quat), 128.2 (CH), 128.8

(CH), 129.1 (CH), 129.1 (CH), 132.6 (CH), 133.2 (CH), 133.8

(CH), 135.8 (C_quat), 139.3 (C_quat), 142.7 (C_quat), 197.1 (C_quat), 197.1

(C_quat).

MS (70 eV, EI): m/z (%) = 364 ([M]⁺, 4), 234 ([M – NCC₆H₄CO]⁺,

6), 130 ([NCC₆H₄CO]⁺, 100), 105 ([C₆H₅CO]⁺, 26), 102

([NCC₆H₅]⁺, 14), 77 ([Ph]⁺, 16).

UV/Vis (CHCl₃): l_max(e) = 250 nm (45700).

Anal. Calcd for C₂₄H₁₆N₂O₂(364.4): C, 79.11; H, 4.43; N, 7.69.

Found: C, 79.19; H, 4.25; N, 7.72.

Synthesis of 1,4-Diketones 5; General Procedure

A stirred mixture of halide 1 (1.00 mmol) and propargyl alcohol 2

(1.05 mmol) in solvent (either Et₃N, EtOH, or THF), was degassed

for 5 min. Then, Pd(PPh₃)₂Cl₂(14 mg, 0.02 mmol) and CuI (7 mg,

0.04 mmol) were added and the reaction mixture was heated to re-

flux for 14 h. After cooling to r.t., aldehyde 3 (1.20 mmol), 4a (for

aromatic aldehydes, 57 mg, 0.20 mmol) or 4b (for aliphatic alde-

hydes, 54 mg, 0.20 mmol), and 0.5 mL of Et₃N were added. The

mixture was then heated to reflux for the times indicated. After

cooling to r.t., Et₂O (15 mL) was added and the precipitated ammo-

nium salts were removed by filtration. The remaining solution was

concentrated in vacuo and the residue was purified by chromatogra-

2-(4-Cyanophenyl)-1,4-diphenylbutane-1,4-dione (5b)

Purification by chromatography on silica gel (PE–Et₂O, 4:1), color-

less solid, mp 159–160 °C (EtOH–acetone) (Lit.²⁸mp 161–162 °C).

¹H NMR (CDCl₃, 300 MHz): d = 3.34 (dd, J = 18.0, 4.2 Hz, 1 H),

4.18 (dd, J = 18.0, 9.5 Hz, 1 H), 5.40 (dd, J = 4.2, 9.5 Hz, 1 H),

7.40–7.62 (m, 10 H), 7.95–8.01 (m, 4 H).

¹³C NMR (CDCl₃, 75 MHz): d = 43.4 (CH₂), 48.5 (CH), 111.5

(C_quat), 118.4 (C_quat), 128.2 (CH), 128.7 (CH), 128.7 (CH), 128.9

(CH), 129.1 (CH), 132.9 (CH), 133.4 (CH), 133.6 (CH), 136.0

(C_quat), 136.1 (C_quat), 144.1 (C_quat), 197.2 (C_quat), 198.0 (C_quat).

Table 5 Experimental Details for the Synthesis of 1,4-Diketones 5

(Hetero)aryl Halide 1

mg (mmol)

Propargyl Alcohol 2

mg (mmol)

NEt₃

(mL)

EtOH

(mL)

Aldehyde 3

mg (mmol)

Reaction Time

(h)

Yield

mg (%)

182 (1.00) of 1a

158 (1.00) of 1b

182 (1.00) of 1a

^aTHF.

139 (1.05) of 2a

128 (1.05) of 2b

139 (1.05) of 2a

6.0

3.5

6.0

4.0

3.5

6.0

3.0

4.0

2.0

1.5

–

157 (1.20) of 3a

127 (1.20) of 3b

115 (1.20) of 3c

163 (1.20) of 3d

290 (1.20) of 3e

114 (1.20) of 3f

80 (0.60) of 3g

163 (1.20) of 3d

87 (1.20) of 3h

87 (1.20) of 3i

185 (1.20) of 3j

139 (1.20) of 3l

8

24

8

322 (88) of 5a

285 (84) of 5b

261 (81) of 5c

277 (75) of 5d

387 (82) of 5e

113 (34) of 5f

207 (69) of 5g

234 (70) of 5h

165 (54) of 5i

254 (76) of 5j

255 (66) of 5k

205 (59) of 5l

6.0^a

–

8

–

23

24

22

24

8

–

1.5

–

1.0

1.5

2.0

3.5

Synthesis 2004, No. 14, 2391–2406 © Thieme Stuttgart · New York

2400

R. U. Braun, T. J. J. Müller

FEATURE ARTICLE

2-(4-Cyanophenyl)-1-(2-furyl)-4-phenylbutane-1,4-dione (5c)

Light beige crystals, mp 179 °C (EtOH).

UV/Vis (CHCl₃): l_max(e) = 245 (45100), 282 (22700), 384 nm

(7200).

IR (KBr): 2228 (s), 1674 (s), 1604 (m), 1568 (s), 1504 (m), 1568 (s),

1396 (m), 1338 (m), 1328 (m), 1271 (m), 1238 (m), 1210 (w), 1092

(w), 1016 (s), 1002 (m), 882 (m), 781 (m), 738 (s), 760 (w), 691 (m),

592 (w), 568 (m) cm^–1.

HRMS: m/z calcd for C₃₀H₂₂N₂O₂S: 474.1402; found: 474.1421.

2-(4-Cyanophenyl)-4-phenyl-1-(2-pyrrolyl)-butane-1,4-dione

(5f)

Purification by chromatography on silica gel (PE–Et₂O, 2:1), pale

yellow crystals, mp 170 °C (EtOH).

¹H NMR (CDCl₃, 300 MHz): d = 3.36 (dd, J = 18.0, 4.3 Hz, 1 H)

4.13 (dd, J = 18.1, 9.6 Hz, 1 H), 5.21 (dd, J = 9.6, 4.4 Hz, 1 H), 6.53

(dd, J = 1.7, 3.6 Hz, 1 H), 7.27 (m, 1 H), 7.42–7.63 (m, 8 H), 7.96

(d, J = 7.2 Hz, 2 H).

¹³C NMR (CDCl₃, 75 MHz): d = 40.5 (CH₂), 46.9 (CH), 109.8

(C_quat), 110.9 (CH), 116.8 (CH), 116.8 (C_quat), 126.4 (CH), 127.0

(CH), 127.5 (CH), 131.0 (CH), 131.8 (CH), 134.4 (C_quat), 141.9

(C_quat), 145.2 (CH), 150.2 (C_quat), 184.9 (C_quat), 195.3 (C_quat).

IR (KBr): 2229 (m), 1683 (m), 1641 (s), 1605 (w), 1545 (w), 1448

(w), 1403 (s), 1360 (w), 1323 (w), 1296 (w), 1244 (w), 1207 (w),

1110 (m), 1045 (m), 904 (w), 795 (m), 690 (w), 603 (w), 570 (m)

cm^–1.

¹H NMR (CDCl₃, 300 MHz): d = 3.36 (dd, J = 18.0, 4.8 Hz, 1 H),

4.07 (dd, J = 18.0, 9.1 Hz, 1 H), 5.09 (dd, J = 9.1, 4.8 Hz, 1 H),

6.25–6.28 (m, 1 H), 6.99–7.01 (m, 2 H), 7.44 (t, J = 7.8, 2 H), 7.51–

7.59 (m, 5 H), 7.95 (d, J = 7.1, 2 H), 9.29 (br s, 1 H).

¹³C NMR (CDCl₃, 75 MHz): d = 42.3 (CH₂), 48.5 (CH), 111.2 (CH),

111.3 (C_quat), 117.4 (CH), 118.5 (C_quat), 125.2 (CH), 128.1 (CH),

128.7 (CH), 128.9 (CH), 130.9 (C_quat), 132.7 (CH), 133.5 (CH),

136.3 (C_quat), 145.0 (C_quat), 187.4 (C_quat), 197.1 (C_quat).

MS (70 eV, EI): m/z (%) = 329 ([M]⁺, 17), 224 ([M – C₆H₅CO]⁺,

11), 105 ([C₆H₅CO]⁺, 40), 95 ([C₄H₃OCO]⁺, 100), 77 ([Ph]⁺, 26).

UV/Vis (CHCl₃): l_max(e) = 246 (29300), 278 nm (17800).

Anal. Calcd for C₂₁H₁₅NO₃(329.4): C, 76.58; H, 4.59; N, 4.25.

Found: C,7 6.54; H, 4.69; N, 4.19.

MS (70eV, EI): m/z (%) = 328 ([M]⁺, 56), 311 (14), 105

2-(4-Cyanophenyl)-1-(4-methoxyphenyl)-4-phenylbutane-1,4-

dione (5d)

([C₆H₅CO]⁺, 19), 94 ([C₄H₄NCO]⁺, 100), 77 ([C₆H₅]⁺, 19), 66 (14).

Light beige crystals, mp 144 °C (EtOH).

UV/Vis (CHCl₃): l_max(e) = 296 (16800), 244 nm (27800).

IR (KBr): 2229 (m), 1674 (s), 1599 (s), 1511 (m), 1449 (w), 1420

(m), 1339 (m), 1320 (m), 1254 (s), 1169 (s), 1115 (w), 1029 (m),

1001 (m), 953 (w), 835 (m), 778 (w), 764 (w), 691 (w), 572 (m)

cm^–1.

¹H NMR (CDCl₃, 300 MHz): d = 3.31 (dd, J = 4.4, 18.0 Hz, 1 H),

3.84 (s, 3 H), 4.16 (dd, J = 9.3, 18.0 Hz, 1 H), 5.37 (dd, J = 4.4, 9.3

Hz, 1 H), 6.90 (d, J = 8.8 Hz, 2 H), 7.43–7.61 (m, 7 H), 7.97 (d,

J = 7.2 Hz, 2 H), 7.99 (d, J = 8.8 Hz, 2 H).

¹³C NMR (CDCl₃, 75 MHz): d = 43.7 (CH₂), 48.5 (CH), 55.9 (CH₃),

111.7 (C_quat), 114.3 (CH), 118.9 (C_quat), 128.5 (CH), 129.0 (CH),

129.3 (C_quat), 129.4 (CH), 131.6 (CH), 133.3 (CH), 133.9 (CH),

136.6 (C_quat), 145.0 (C_quat), 164.2 (C_quat), 196.7 (C_quat), 197.7 (C_quat).

Anal. Calcd for C₂₁H₁₆N₂O₂(328.4): C, 76.81; H, 4.91; N, 8.53.

Found: C, 76.58; H, 4.90; N, 8.53.

1,4-Bis[2-(4-cyanophenyl)-4-phenylbutane-1,4-dioxo-1-yl]ben-

zene (5g)

Colorless solid, mp 197 °C (EtOH).

IR (KBr): 2229 (m), 1681 (s), 1608 (m), 1581 (w), 1504 (m), 1449

(m), 1404 (m), 1363 (w), 1322 (w), 1290 (w), 1231 (m), 1208 (w),

1001 (m), 951 (w), 837 (w), 752 (m), 690 (m), 572 (m) cm^–1.

¹H NMR (CDCl₃, 300 MHz): d = 3.36 (m, 2 H), 4.18 (dd, J = 9.8,

18.0 Hz, 2 H), 5.33 (m, 2 H), 7.43–7.48 (m, 8 H), 7.56–7.63 (m, 6

H), 7.94 (d, J = 8.4 Hz, 4 H), 8.04 (s, 4 H).

MS (FAB): m/z (%) = 392 ([M + Na]⁺, 14), 135 ([MeOC₆H₄CO]⁺,

¹³C NMR (CDCl₃, 75 MHz): d = 44.0 (CH₂), 44.1 (CH₂), 49.2 (CH),

49.2 (CH), 112.2 (C_quat), 118.7 (C_quat), 128.5 (CH), 129.1 (CH),

129.5 (CH), 129.6 (CH), 133.4 (CH), 134.1 (CH), 136.3 (C_quat),

139.8 (C_quat), 139.9 (C_quat), 139.9 (C_quat), 143.5 (C_quat), 143.5 (C_quat),

197.4 (C_quat), 197.5 (C_quat), 197.9 (C_quat), 198.0 (C_quat).

MS (FAB, NBA): m/z (%) = 601 ([M + H]⁺, 12), 366 ([M –

NCC₆H₅CHCH₂COPh]⁺, 100), 348 (12), 132 ([COC₆H₄CO]⁺, 6),

105 (PhCO⁺, 27).

100), 77 ([Ph]⁺, 7).

UV/Vis (CHCl₃): l_max(e) = 246 (31600), 286 nm (19500).

Anal. Calcd for C₂₄H₁₉NO₃(369.4): C, 78.03; H, 5.18; N, 3.79.

Found: C, 77.73; H, 5.16; N, 3.77.

2-(4-Cyanophenyl)-1-(10-methyl-10H-phenothiazin-3-yl)-4-

phenylbutane-1,4-dione (5e)

Purification by chromatography on silica gel (PE–Et₂O, 3:1), yel-

low crystals, mp 116–117 °C (EtOH–acetone).

HRMS: m/z calcd for C₄₀H₂₈N₂O₄+ Na⁺: 623.1947; found:

623.1873. HRMS: m/z calcd for C₄₀H₂₈N₂O₄+ H⁺: 601.2127;

found: 601.2098.

IR (KBr): 2228 (m), 1673 (s), 1598 (s), 1573 (m), 1503 (w), 1466

(s), 1396 (w), 1340 (s), 1258 (s), 1228 (m), 1142 (m), 1002 (w), 845

(w), 819 (w), 752 (m), 690 (w), 573 (w) cm^–1.

¹H NMR (CDCl₃, 300 MHz): d = 3.30 (dd, J = 4.3, 18.1 Hz, 1 H),

3.37 (s, 3 H), 4.14 (dd, J = 17.9, 9.3 Hz, 1 H), 5.30 (dd, J = 4.3, 9.4

Hz, 1 H), 6.74–6.81 (m, 2 H), 6.95 (dt, J = 0.9, 7.4 Hz, 1 H), 7.08–

7.19 (m, 2 H), 7.42–7.49 (m, 7 H), 7.75 (d, J = 2.0 Hz, 1 H), 7.82

(dd, J = 8.5, 1.9 Hz, 1 H), 7.95 (d, J = 7.2 Hz, 2 H).

¹³C NMR (CDCl₃, 75 MHz): d = 35.6 (CH₃), 43.3 (CH₂), 48.0 (CH),

111.4 (C_quat), 113.4 (CH), 114.6 (CH), 118.5 (C_quat), 122.6 (C_quat),

123.5 (CH), 123.5 (C_quat), 127.3 (CH), 127.7 (CH), 127.8 (CH),

128.2 (CH), 128.7 (CH), 129.0 (CH), 129.3 (CH), 130.2 (C_quat),

132.9 (CH), 133.5 (CH), 136.2 (C_quat), 144.2 (C_quat), 144.4 (C_quat),

150.2 (C_quat), 195.7 (C_quat), 197.3 (C_quat).

UV/Vis (CHCl₃): l_max(e) = 246 nm (52600).

Anal. Calcd for C₄₀H₂₈N₂O₄(600.7): C, 79.98; H, 4.70; N, 4.66.

Found: C, 79.18; H, 4.75; N, 4.63.

4-(2-Furyl)-1-(4-methoxyphenyl)-2-pyridin-2-ylbutane-1,4-di-

one (5h)

Purification by chromatography on silica gel (PE–Et₂O, 1:1), light

beige crystals, mp 99–100 °C (EtOH, under N₂).

IR (KBr): 1674 (s), 1600 (s), 1570 (s), 1511 (m), 1469 (s), 1434 (m),

1420 (w), 1396 (m), 1316 (m), 1250 (s), 1169 (s), 1027 (s), 947 (m),

883 (w), 843 (m), 763 (m), 596 (w), 581 (w), 553 (m) cm^–1.

¹H NMR (CDCl₃, 300 MHz): d = 3.40 (dd, J = 17.7, 4.9 Hz, 1 H),

3.83 (s, 3 H), 4.01 (dd, J = 17.7, 9.2 Hz, 1 H), 5.60 (dd, J = 9.2, 4.9

Hz, 1 H), 6.52 (dd, J = 3.7, 1.8 Hz, 1 H), 6.89 (d, J = 8.8 Hz, 2 H),

MS (70 eV, EI): m/z (%) = 474 ([M]⁺, 90), 240 ([methylphenothiaz-

inylCO]⁺, 100), 212 ([methylphenothiazinyl]⁺, 34).

Synthesis 2004, No. 14, 2391–2406 © Thieme Stuttgart · New York

FEATURE ARTICLE

A Multicomponent Approach to Furans and Pyrroles

2401

7.18–7.21 (m, 2 H), 7.39–7.71 (m, 3 H), 8.08 (d, J = 8.9 Hz, 2 H),

8.56 (d, J = 4.3 Hz, 1 H).

3-(4-Cyanophenyl)-6,10-dimethyl-1-phenylundecan-9-en-1,4-

dione (5k)

Purification by chromatography on silica gel (PE–Et₂O, 6:1), color-

less oil.

¹³C NMR (CDCl₃, 75 MHz): d = 41.6 (CH₂), 49.8 (CH), 55.5 (CH₃),

112.3 (CH), 113.8 (CH), 117.4 (CH), 122.5 (CH), 123.4 (C_quat),

129.1 (C_quat), 131.5 (CH), 138.2 (CH), 146.4 (CH), 148.6 (CH),

152.4 (C_quat), 158.1 (C_quat), 163.7 (CH), 186.5 (C_quat), 195.8 (C_quat).

IR (film): 2962 (m), 2915 (m), 2229 (m), 1716 (s), 1685 (s), 1606

(m), 1598 (m), 1504 (m), 1449 (m), 1400 (w), 1364 (w), 1323 (w),

1248 (w), 1209 (w), 1180 (w), 989 (w), 758 (m), 735 (w), 690 (m),

581 (w) cm^–1.

MS (FAB, NBA): m/z (%) = 336 ([M + H]⁺, 100), 135

([MeOC₆H₄CO]⁺, 31).

¹H NMR (CDCl₃, 300 MHz), inseparable 1:1 mixture of diastereo-

mers: d = 0.68 (d, J = 6.6 Hz, 3 H), 0.87 (d, J = 6.7 Hz, 3 H), 0.94–

1.34 (m, 4 H), 1.50 (s, 3 H), 1.55 (s, 3 H), 1.63 (s, 3 H), 1.65 (s, 3

H), 1.79–2.02 (m, 6 H), 2.19–2.68 (m, 4 H), 3.14 (dd, J = 5.1, 18.0

Hz, 2 H), 3.98 (dd, J = 9.6, 18.0 Hz, 2 H), 4.41–4.48 (m, 2 H), 4.94–

5.05 (m, 2 H), 7.38–7.45 (m, 8 H), 7.55 (t, J = 7.4 Hz, 2 H), 7.63 (d,

J = 7.5 Hz, 4 H), 7.93 (d, J = 7.2 Hz, 4 H).

¹³C NMR (CDCl₃, 75 MHz): d = 17.4 (CH₃), 17.4 (CH₃), 19.2

(CH₃), 19.4 (CH₃), 25.0 (CH₂), 25.2 (CH₂), 25.4 (CH₃), 25.5 (CH₃),

28.1 (CH), 28.1 (CH), 36.3 (CH₂), 36.6 (CH₂), 41.8 (CH₂), 42.0

(CH₂), 49.4 (CH₂), 49.5 (CH₂), 53.3 (CH), 53.5 (CH), 111.4 (C_quat),

111.4 (C_quat), 118.2 (C_quat), 124.0 (CH), 127.8 (CH), 128.4 (CH),

129.0 (CH), 129.0 (CH), 131.2 (C_quat), 131.2 (C_quat), 132.6 (CH),

133.2 (CH), 136.0 (C_quat), 136.0 (C_quat), 143.2 (C_quat), 143.3 (C_quat),

197.1 (C_quat), 197.1 (C_quat), 207.4 (C_quat), 207.6 (C_quat).

MS (70 eV, EI): m/z (%) = 387 ([M]⁺, 9), 267 ([M – PhCOMe]⁺,

48), 235 (14), 153 ([CH₃(CH₃)C=CHCH₂CH₂CH(CH₃)CH₂CO]⁺,

100), 135 ([CH₂CHC(O)CH₂CHCH₂CH₂CHC]⁺, 14), 130 (16), 109

(78), 105 (PhCO⁺, 62), 81 ([CH₃(CH₃)C=CHCH₂CH₂-

CH(CH₃)CH₂CO, –CO, –CH₂, –2 × CH₃]⁺, 23), 77 ([Ph]⁺, 26), 69

([CH₃(CH₃)C=CHCH₂]⁺, 74), 55 ([CH₃(CH₃)C=CH]⁺, 15), 41

([CH₂CCH₃]⁺, 25).

UV/Vis (CHCl₃): l_max(e) = 276 nm (57200).

Anal. Calcd for C₂₀H₁₇NO₄(335.4): C, 71.63; H, 5.11; N, 4.18.

Found: C, 71.47; H, 4.85; N, 4.15.

3-(4-Cyanophenyl)-5-methyl-1-phenylhexane-1,4-dione (5i)

Purification by chromatography on silica gel (PE–Et₂O, 4:1), pale

yellow solid, mp 127 °C (EtOH).

IR (KBr): 2225 (m), 1705 (s), 1676 (s), 1607 (m), 1596 (m), 1580

(w), 1505 (w), 1448 (m), 1370 (w), 1328 (w), 1240 (w), 1208 (w),

1179 (w), 1099 (w), 1019 (m), 988 (w), 852 (w), 746 (w), 694 (m),

571 (m) cm^–1.

¹H NMR (CDCl₃, 300 MHz): d = 0.93 (d, J = 6.9 Hz, 3 H), 1.23 (d,

J = 7.0 Hz, 3 H), 2.79 (sept, J = 6.9 Hz, 1 H), 3.13 (dd, J = 4.1, 18.0

Hz, 1 H), 3.99 (dd, J = 9.8, 18.0 Hz, 1 H), 4.66 (dd, J = 9.7, 4.0 Hz,

1 H), 7.41–7.47 (m, 4 H), 7.54–7.59 (m, 1 H), 7.64 (d, J = 8.4 Hz, 2

H), 7.94 (d, J = 7.1 Hz, 2 H).

¹³C NMR (CDCl₃, 75 MHz): d = 18.7 (CH₃), 19.3 (CH₃), 41.0 (CH),

43.1 (CH₂), 52.0 (CH), 112.0 (C_quat), 118.8 (C_quat), 128.4 (CH),

129.0 (CH), 129.6 (CH), 133.2 (CH), 133.8 (CH), 136.6 (C_quat),

144.2 (C_quat), 197.7 (C_quat), 212.4 (C_quat).

MS (70 eV, EI): m/z (%) = 305 ([M]⁺, 2), 130 (16), 105 (PhCO⁺,

37), 77 ([Ph]⁺, 23), 71 ([COCH(CH₃)₂]⁺, 100), 43 ([CH(CH₃)₂]⁺,

66).

UV/Vis (CHCl₃): l_max(e) = 244 nm (28400).

Anal. Calcd for C₂₆H₂₉NO₂(387.5): C, 80.59; H, 7.54; N, 3.61.

Found: C, 80.23; H, 7.53; N, 3.69.

UV/Vis (CHCl₃): l_max(e) = 244 nm (30500).

Anal. Calcd for C₂₀H₁₉NO₂(305.4): C, 78.66; H, 6.27; N, 4.59.

Found: C, 78.57; H, 6.21; N, 4.62.

3-(4-Cyanophenyl)-9-hydroxy-1-phenylnonane-1,4-dione (5l)

Purification by chromatography on silica gel (PE–Et₂O, 1:1), color-

less oil.

3-(4-Cyanophenyl)-1-phenylnonane-1,4-dione (5j)

Purification by chromatography on silica gel (PE–Et₂O, 4:1), pale

yellow solid, mp 82–83 °C (EtOH).

IR (film): 3063 (w), 2937 (s), 2864 (m), 2229 (m), 1715 (s), 1683

(s), 1606 (m), 1597 (m), 1581 (w), 1491 (m), 1449 (m), 1363 (m),

1248 (m), 1208 (m), 1052 (w), 1002 (w), 757 (w), 733 (m), 690 (m)

cm^–1.

¹H NMR (CDCl₃, 300 MHz): d = 1.44–1.69 (m, 6 H), 2.36–2.47 (m,

1 H), 2.64–2.74 (m, 1 H), 3.14 (dd, J = 3.6, 18.0 Hz, 1 H), 3.55–3.59

(m, 2 H), 4.45 (dd, J = 3.3, 18.1 Hz, 1 H), 4.45 (dd, J = 10.0, 3.7 Hz,

1 H), 7.38–7.45 (m, 4 H), 7.53–7.57 (m, 1 H), 7.61–7.64 (m, 2 H),

7.90–7.92 (m, 2 H).

¹³C NMR (CDCl₃, 75 MHz): d = 23.1 (CH₂), 24.9 (CH₂), 32.2

(CH₂), 42.1 (CH₂), 42.3 (CH₂), 53.1 (CH), 62.4 (CH₂), 111.6 (C_quat),

118.4 (C_quat), 128.0 (CH), 128.6 (CH), 129.1 (CH), 132.8 (CH),

133.5 (CH), 136.0 (C_quat), 143.4 (C_quat), 197.4 (C_quat), 208.2 (C_quat).

IR (KBr): 2955 (m), 2930 (m), 2228 (m), 1713 (s), 1682 (s), 1606

(m), 1504 (w), 1449 (m), 1402 (w), 1363 (w), 1244 (w), 1209 (w),

1127 (w), 1002 (w), 848 (w), 756 (m), 690 (m) cm^–1.

¹H NMR (CDCl₃, 300 MHz): d = 0.83 (t, J = 7.3 Hz, 3 H), 1.10–1.30

(m, 4 H), 1.43–1.66 (m, 2 H), 2.38–2.48 (m, 1 H), 2.60–2.71 (m, 1

H), 3.16 (dd, J = 4.0, 18.0 Hz, 1 H), 4.00 (dd, J = 9.7, 18.0 Hz, 1 H),

4.48 (dd, J = 9.7, 4.0 Hz, 1 H), 7.42 (d, J = 8.0 Hz, 2 H), 7.43–7.47

(m, 2 H), 7.55–7.59 (m, 1 H), 7.65 (d, J = 8.0 Hz, 2 H), 7.94 (d,

J = 7.5 Hz, 2 H).

¹³C NMR (CDCl₃, 75 MHz): d = 14.2 (CH₃), 22.7 (CH₂), 23.6

(CH₂), 31.5 (CH₂), 42.6 (CH₂), 42.7 (CH₂), 53.6 (CH), 112.0 (C_quat),

118.8 (C_quat), 128.5 (CH), 129.1 (CH), 129.5 (CH), 133.2 (CH),

133.9 (CH), 136.6 (C_quat), 144.0 (C_quat), 197.8 (C_quat), 208.7 (C_quat).

MS (FAB, NBA) m/z (%): 350 ([M + H]⁺, 12), 349 ([M]⁺, 3) 332

([M – OH]⁺, 100).

HRMS: m/z calcd for C₂₂H₂₃NO₃+ H⁺: 350.1756; found: 350.1748.

MS (70 eV, EI) m/z (%): 333 ([M]⁺, 2), 258 (37), 129

([NCC₆H₄CHCH₂]⁺, 13), 105 (Ph-CO⁺, 38), 99 ([COC₅H₁₁]⁺, 100),

77 ([Ph]⁺, 22), 71 ([C₅H₁₁]⁺, 29), 43 ([CH₃CH₂CH₂]⁺, 29).

UV/Vis (CHCl₃): l_max(e) = 244 nm (24700).

Synthesis of Furans 6; General Procedure

UV/Vis (CHCl₃): l_max(e) = 243 nm (32300).

A stirred mixture of the halide 1 (1.00 mmol), the propargyl alcohol

2a (1.05 mmol), and solvent (Et₃N, EtOH or MeCN) was degassed

for 5 min. Then, Pd(PPh₃)₂Cl₂(14 mg, 0.02 mmol), and CuI (7 mg,

0.04 mmol) were added and the reaction mixture was heated to re-

flux for 14 h. After cooling to r.t., the aldehyde 3 (1.20 mmol), 4a

(for aromatic aldehydes, 57 mg, 0.20 mmol) or 4b (for aliphatic al-

dehydes, 54 mg, 0.20 mmol), and Et₃N (0.5 mL) were added, and

Anal. Calcd for C₂₂H₂₃NO₂(333.4): C, 79.25; H, 6.95; N, 4.20.

Found: C, 78.86; H, 6.82; N, 4.17.

Synthesis 2004, No. 14, 2391–2406 © Thieme Stuttgart · New York

2402

R. U. Braun, T. J. J. Müller

Table 6 Experimental Details for the Synthesis of Furans 6

(Hetero)aryl Halide 1 Propargyl Alcohol 2 NEt₃EtOH Aldehyde 3

FEATURE ARTICLE

Reaction

Yield

mg (mmol)

(mL)

mg (mmol)

Time t₁(h)

Time t₂(h)

mg (%)

364 (2.00) of 1a

182 (1.00) of 1a

194 (1.00) of 1c

164 (1.00) of 1d

182 (1.00) of 1a

^aCH₃CN.

278 (2.10) of 2a

139 (1.05) of 2a

4.0

–

254 (2.40) of 3b

115 (1.20) of 3c

149 (1.20) of 3m

127 (1.20) of 3b

120 (1.20) of 3j

8.5

23

12

507 (79) of 6a

231 (74) of 6b

146 (46) of 6c

128 (42) of 6d

197 (64) of 6e

4.0

–

9

2.5

1.5^a

1.0

1.5

24

28

3.0

23

5.75

3.5

24

then the mixture was heated to reflux for 8.5–24 h (t₁). After cooling

to r.t., glacial HOAc (0.5 mL) and concentrated HCl (2.5 mL) were

added and the mixture was heated to reflux for 5.75–12 h (t₂). Then,

after cooling to r.t., a sat. aq solution of K₂CO₃was added. The

aqueous phase was extracted several times with Et₂O or EtOAc, and

the combined organic layers were dried with anhydrous Na₂SO₄and

filtered. The remaining solution was concentrated in vacuo and the

residue was purified by chromatography on silica gel and/or recrys-

tallized to give the pure furans 6 (for experimental details see

Table 6).

UV/Vis (CHCl₃): l_max(e) = 257 (23900), 319 nm (22700).

Anal. Calcd for C₂₁H₁₃NO₂(311.3): C, 81.01; H, 4.21; N, 4.50.

Found: C, 80.89; H, 4.70; N, 4.55.

4-[2-(4-Fluorophenyl)-5-phenyl-3-furyl]pyridine (6c)

After an aqueous workup and extraction with EtOAc and purifica-

tion by chromatography on silica gel (hexane–EtOAc 1:1), beige

solid, mp 120–122 °C (isopropanol).

IR (KBr): 3072 (w), 1604 (s), 1578 (w), 1543 (m), 1511 (s), 1490

(s), 1418 (w), 1409 (w), 1225 (s), 1159 (m), 1097 (w), 1054 (w), 836

(s), 815 (s), 760 (s), 716 (m), 691 (m), 665 (m), 588 (m) cm^–1.

¹H NMR (CDCl₃, 300 MHz): d = 6.84 (s, 1 H), 7.03–7.08 (m, 2 H),

7.25–7.45 (m, 5 H), 7.53–7.58 (m, 2 H), 7.74 (d, J = 7.0 Hz, 2 H),

8.60 (d, J = 6.2 Hz, 2 H).

4-(2,5-Diphenyl-3-furyl)benzonitrile (6a)

After an aqueous workup and extraction with EtOAc, beige solid,

mp 130–131 °C (EtOH).

IR (KBr): 2227 (s), 1607 (s), 1550 (w), 1508 (w), 1490 (s), 1446

(m), 1178 (w), 1148 (m), 1075 (w), 1053 (w), 1027 (w), 953 (m),

932 (w), 916 (w), 847 (m), 825 (w), 768 (s), 697 (s), 673 (w), 599

(m), 565 (m), 552 (w), 484 (w) cm^–1.

¹³C NMR (CDCl₃, 75 MHz): d = 107.7 (CH), 115.6 (d, 21,8 Hz,

CH), 121.3 (C_quat), 122.8 (CH), 123.7 (CH), 126.4 (d, J = 3.5 Hz,

C_quat), 127.8 (CH), 128.4 (d, J = 8.2 Hz, CH), 128.6 (CH), 129.7

¹H NMR (CDCl₃, 300 MHz): d = 6.80 (s, 1 H), 7.24–7.44 (m, 6 H),

7.54 (d, J = 8.5 Hz, 4 H), 7.63 (d, J = 6.7 Hz, 2 H), 7.74 (d, J = 7.2

Hz, 2 H).

(C_quat), 141.9 (C_quat), 148.3 (C_quat), 150.0 (CH), 153.3 (C_quat), 162.5

(d, J = 249 Hz, C_quat).

MS (70 eV, EI) m/z (%): 315 ([M]⁺, 100).

¹³C NMR (CDCl₃, 75 MHz): d = 108.3 (CH), 110.8 (C_quat), 118.9

(C_quat), 122.6 (C_quat), 123.9 (CH), 126.6 (CH), 127.9 (CH), 128.3

(CH), 128.7 (CH), 128.8 (CH), 129.1 (CH), 130.0 (C_quat),130.4

(C_quat), 132.5 (CH), 139.2 (C_quat), 149.0 (C_quat), 153.4 (C_quat).

MS (70 eV, EI) m/z (%): 321 ([M]⁺, 100), 216 ([M – OCPh]⁺, 14).

UV/Vis (CHCl₃): l_max(e) = 253 (23300), 313 nm (27600).

Fluorescence (CHCl₃): l_max= 432 nm.

HRMS: m/z calcd for C₂₁H₁₄FNO: 315.1059; found: 315.1062.

UV/Vis (CHCl₃): l_max(e) = 232 (10200), 306 nm (10900).

Anal. Calcd for C₂₁H₁₄FNO (315.3): C, 79.99; H, 4.47; N, 4.44.

Found: C, 79.48, H, 4.61; N, 4.51.

2-(2,5-Diphenyl-3-furyl)-1,3-thiazole (6d)

After an aqueous workup and extraction with EtOAc and purifica-

tion by chromatography on silica gel (hexane–EtOAc 6:1), beige

solid, mp 88 °C (hexane).

Anal. Calcd for C₂₃H₁₅NO (321.4): C, 85.59; H, 4.65; N, 4.33.

Found: C, 85.35; H, 4.70; N, 4.32.

IR (KBr): 3054 (m), 1593 (m), 1552 (m), 1509 (m), 1490 (s), 1476

(s), 1447 (m), 1155 (m), 1131 (s), 1076 (w), 1052 (s), 931 (w), 919

(s), 872 (s), 812 (m), 763 (s), 695 (s), 673 (w), 535 (w) cm^–1.

¹H NMR (CDCl₃, 300 MHz): d = 7.12 (s, 1 H), 7.29 (d, J = 3.3 Hz,

1 H), 7.32–7.34 (m, 1 H), 7.41–7.46 (m, 5 H), 7.77–7.80 (m, 2 H),

7.88 (d, J = 3.3 Hz, 1 H), 7.99–8.02 (m, 2 H).

¹³C NMR (CDCl₃, 75 MHz): d = 108.2 (CH), 118.3 (C_quat), 118.8

(CH), 124.0 (CH), 127.7 (CH), 128.0 (CH), 128.5 (CH), 128.8

(CH), 129.0 (CH), 130.0 (C_quat), 130.2 (C_quat), 143.1 (CH), 150.6

(C_quat), 153.0 (C_quat), 161.1 (C_quat).

MS (70 eV, EI) m/z (%): 303 ([M]⁺, 86), 302 ([M – H]⁺, 100).

UV/Vis (CHCl₃): l_max(e) = 290 (20900), 312 nm (20700).

Fluorescence (CHCl₃): l_max= 407 nm.

4-(5-Phenyl-2,2¢-bifuran-3-yl)benzonitrile (6b)

After an aqueous workup and extraction with Et₂O and trituration

with EtOH, beige solid, mp 118–120 °C (EtOH).

IR (KBr): 2225 (s), 1607 (s), 1535 (w), 1487 (m), 1462 (w), 1448

(w), 1256 (w), 1174 (m), 1160 (w), 1077 (w), 1012 (w), 965 (m),

930 (w), 895 (m), 852 (m), 824 (m), 809 (w), 760 (s), 739 (w), 702

(w), 691 (s), 594 (m), 567 (w), 551 (w) cm^–1.

¹H NMR (CDCl₃, 300 MHz): d = 6.49 (dd, J = 1.8, 3.4 Hz, 1 H),

6.68 (dd, J = 0.7, 3.4 Hz, 1 H), 6.82 (s, 1 H), 7.28–7.34 (m, 1 H),

7.40–7.45 (m, 3 H), 7.64–7.74 (m, 6 H).

¹³C NMR (CDCl₃, 75 MHz): d = 107.8 (CH), 108.4 (CH), 110.8

(C_quat), 111.6 (CH), 119.0 (C_quat), 122.8 (C_quat), 124.0 (CH), 128.1

(CH), 128.8 (CH), 129.2 (CH), 129.8 (C_quat), 132.1 (CH), 138.0

(C_quat), 141.2 (C_quat), 142.5 (CH), 145.7 (C_quat), 153.5 (C_quat).

Anal. Calcd for C₁₉H₁₃NOS (303.4): C, 75.22; H, 4.32; N, 4.62; S,

10.57. Found: C, 75.03; H, 4.35; N, 4.67; S, 10.48.

MS (70 eV, EI) m/z (%): 311 ([M]⁺, 100), 282 ([M – CHO]⁺, 38).

Synthesis 2004, No. 14, 2391–2406 © Thieme Stuttgart · New York

FEATURE ARTICLE

A Multicomponent Approach to Furans and Pyrroles

2403

4-(2-Pentyl-5-phenyl-3-furyl)benzonitrile (6e)

by chromatography on silica gel and/or recrystallized to give the

After an aqueous workup and extraction with Et₂O and purification

by chromatography on silica gel (hexane–EtOAc 6:1), yellow resin.

pure pyrroles 8 (for experimental details see Table 7).

4-(2,5-Diphenyl-1H-pyrrol-3-yl)benzonitrile (8a)

After an aqueous workup and extraction with Et₂O and trituration

with EtOH, light beige crystals, mp 233–234 °C (EtOH).

IR (KBr): 2956 (s), 2930 (s), 2871 (m), 2228 (s), 1702 (s), 1658 (s),

1599 (s), 1554 (w), 1504 (m), 1449 (s), 1405 (w), 1377 (w), 1275

(s), 1216 (s), 1179 (m), 1019 (w), 844 (m), 762 (m), 693 (s) cm^–1.

IR (KBr): 3316 (s), 2226 (s), 1604 (s), 1510 (m), 1488 (m), 1468

(w), 1458 (w), 1180 (m), 956 (w), 844 (m), 806 (m), 762 (s), 695

(s), 552 (w) cm^–1.

¹H NMR (CDCl₃, 300 MHz): d = 6.71 (d, J = 2.9 Hz, 1 H), 7.25–

7.56 (m, 14 H), 8.51 (br s, 1 H, NH).

¹³C NMR (CDCl₃, 75 MHz): d = 107.8 (CH), 109.0 (C_quat), 119.4

(C_quat), 121.8 (C_quat), 123.9 (CH), 127.0 (CH), 127.8 (CH), 127.9

(CH), 128.5 (CH), 129.0 (CH), 129.1 (CH), 130.7 (C_quat), 131.8

(C_quat), 132.2 (CH), 132.4 (C_quat), 132.9 (C_quat), 141.3 (C_quat).

¹H NMR (CDCl₃, 300 MHz): d = 0.87–0.92 (m, 3 H), 1.30–1.41 (m,

4 H), 1.72–1.82 (m, 2 H), 2.83 (t, J = 7.4 Hz, 2 H), 6.75 (s, 1 H),

7.25–7.29 (m, 1 H), 7.37–7.42 (m, 2 H), 7.51 (d, J = 8.5 Hz, 2 H),

7.66–7.76 (m, 4 H).

¹³C NMR (CDCl₃, 75 MHz): d = 13.7 (CH₃), 22.1 (CH₂), 27.0

(CH₂), 27.9 (CH₂), 31.3 (CH₂), 105.4 (CH), 109.7 (C_quat), 118.8

(C_quat), 121.4 (C_quat), 123.4 (CH), 127.2 (CH), 127.8 (CH), 128.5

(CH), 130.2 (C_quat), 132.2 (CH), 138.8 (C_quat), 152.1 (C_quat), 152.9

(C_quat).

MS (70 eV, EI) m/z (%): 315 ([M]⁺, 51), 258 ([M – C₄H₉]⁺, 100).

MS (70 eV, EI) m/z (%): 320 ([M]⁺, 100).

UV/Vis (CHCl₃): l_max(e) = 248 (14200), 294 nm (15500).

UV/Vis (CHCl₃): l_max(e) = 272 (27100), 317 nm (30700).

Fluorescence (CHCl₃): l_max= 436 nm.

Anal. Calcd for C₂₂H₂₁NO (315.4): C, 83.78; H, 6.71; N, 4.44.

Found: C, 83.63; H, 6.81; N, 4.31.

Anal. Calcd for C₂₃H₁₆N₂(320.4): C, 86.22; H, 5.03; N, 8.74.

Found: C, 86.07; H, 4.95; N, 8.80.

Synthesis of Pyrroles 8; General Procedure

A stirred mixture of the halide 1 (1.0 equiv), propargyl alcohol 2a

(1.05 equiv), and solvent (Et₃N, EtOH or MeCN) was degassed for

5 min. Then, Pd(PPh₃)₂Cl₂(0.02 equiv) and CuI (0.01 equiv) were

added and the reaction mixture was heated to reflux for 14 h. After

cooling to r.t., the aldehyde 3 (1.20 equiv), 4a (for aromatic alde-

hydes, 0.20 equiv) or 4b (for aliphatic aldehydes, 0.20 equiv), and

Et₃N (0.5 mL) were added, and the mixture was heated to reflux for

9–24 h (t₁). After cooling to r.t., glacial acetic acid (2.5 mL) and the

primary amine or ammonium chloride 7 were added, and the mix-

ture was heated to reflux for 22–120 h (t₂). Then, after cooling to r.t.,

a sat. aq solution of NH₄Cl was added. The aqueous phase was ex-

tracted several times with Et₂O or EtOAc and the combined organic

layers were dried with anhydrous Na₂SO₄and filtered. The remain-

ing solution was concentrated in vacuo and the residue was purified

4-[2-(4-Methoxyphenyl)-5-phenyl-1H-pyrrol-3-yl]benzonitrile

(8b)

After an aqueous workup and extraction with Et₂O and trituration

with EtOH, light yellow crystals, mp 225–226 °C (EtOH).

IR (KBr): 2225 (m), 1603 (s), 1518 (m), 1493 (s), 1454 (m), 1293

(w), 1249 (s), 1177 (m), 1029 (m), 834 (m), 807 (w), 760 (m), 562

(w) cm^–1.

¹H NMR (CDCl₃, 300 MHz): d = 3.84 (s, 3 H), 6.70 (d, J = 2.8 Hz,

1 H), 6.91 (d, J = 8.9 Hz, 2 H), 7.23–7.33 (m, 3 H), 7.38–7.46 (m, 4

H), 7.51–7.55 (m, 4 H).

¹³C NMR (CDCl₃, 75 MHz): d = 55.7 (CH₃), 107.9 (CH), 109.1

(C_quat), 114.9 (CH), 119.8 (C_quat), 121.5 (C_quat), 124.2 (CH), 125.3

Table 7 Experimental Details for the Synthesis of Pyrroles 8

(Hetero)aryl Halide 1 Propargyl Alcohol 2 NEt₃

EtOH Aldehyde 3

Reaction Amine 7

Reaction Yield

mg (mmol)

(mL)

6.0

4.0

2.5

4.0

3.5

6.0

4.0

3.0

4.0

2.5

(mL) mg (mmol)

Time t₁(h) mg (mmol)

Time t₂(h) mg (%)

182 (1.00) of 1a

364 (2.00) of 1a

388 (2.00) of 1c

364 (2.00) of 1a

182 (1.00) of 1a

364 (2.00) of 1a

139 (1.05) of 2a

278 (2.10) of 2a

139 (1.05) of 2a

278 (2.10) of 2a

-

127 (1.20) of 3b

24

9

111 (1.50) of 7b

33

189 (59) of 8a

-

254 (2.40) of 3b

326 (2.40) of 3d

298 (2.40) of 3m

240 (2.40) of 3j

279 (2.40) of 3l

127 (1.20) of 3b

230 (2.40) of 3c

254 (2.40) of 3b

370 (2.40) of 3j

254 (2.40) of 3b

240 (2.40) of 3j

428 (8.00) of 7a

535 (10.0) of 7a

214 (4.00) of 7a

428 (8.00) of 7a

129 (1.20) of 7c

857 (8.00) of 7c

255 (2.50) of 7d

553 (5.00) of 7b

488 (8.00) of 7e

296 (7.00) of 7f

30

224 (70) of 8a

422 (60) of 8b

339 (54) of 8c

507 (81) of 8d

348 (53) of 8e

248 (60) of 8f

444 (55) of 8g

440 (54) of 8h

480 (56) of 8i

462 (57) of 8j

418 (59) of 8k

-

9

24

2.0^a

-

24

9

30

24

1.5

-

24

10

9

24^b

56

-

120

111^c

24^d

22

-

1.0

-

24

10

24

1.5

120

^aIn CH₃CN.

^bAt 65 °C (oil bath).

^cAt 80 °C (oil bath).

^dAt 85 °C (oil bath).

2404

R. U. Braun, T. J. J. Müller

FEATURE ARTICLE

(C_quat), 127.2 (CH), 128.6 (CH), 129.4 (CH), 129.7 (CH), 131.2

(C_quat), 132.2 (C_quat), 132.5 (CH), 132.8 (C_quat), 141.8 (C_quat), 159.8

(C_quat).

MS (70 eV, EI) m/z (%): 350 ([M]⁺, 100), 335 ([M – CH₃]⁺, 43).

UV/Vis (CHCl₃): l_max(e) = 270 (24000), 319 nm (26400).

Fluorescence (CHCl₃): l_max= 451 nm.

¹H NMR (CDCl₃, 300 MHz): d = 1.48–1.68 (m, 4 H), 1.71–1.78 (m,

2 H), 2.81–2.86 (m, 2 H), 3.64–3.68 (m, 2 H), 6.60 (d, J = 2.8 Hz, 1

H), 7.19–7.24 (m, 1 H), 7.35–7.37 (m, 2 H), 7.48–7.52 (m, 4 H),

7.64 (d, J = 8.4 Hz, 2 H), 8.57 (br s, 1 H).

¹³C NMR (CDCl₃, 75 MHz): d = 25.2 (CH₂), 26.4 (CH₂), 29.2

(CH₂), 31.8 (CH₂), 62.4 (CH₂), 105.8 (CH), 108.2 (C_quat), 119.3

(C_quat), 121.0 (C_quat), 123.4 (CH), 126.2 (CH), 127.5 (CH), 128.7

(CH), 130.9 (C_quat), 131.1 (C_quat), 131.9 (C_quat), 132.1 (CH), 141.6

(C_quat).

Anal. Calcd for C₂₄H₁₈N₂O (350.4): C, 82.26; H, 5.18; N, 7.99.

Found: C, 82.02; H, 5.17; N, 7.95.

MS (FAB, NBA) m/z (%): 330 ([M]⁺, 100), 257 ([M – (CH₂)₄-OH]⁺,

69).

4-[2-(4-Fluorophenyl)-5-phenyl-1H-pyrrol-3-yl]pyridine (8c)

After an aqueous workup and extraction with EtOAc and purifica-

tion by chromatography on silica gel (hexane–EtOAc 1:2), beige

powder, mp >300 °C (isopropanol).

UV/Vis (CHCl₃): l_max(e) = 268 (16800), 306 (16000), 328 nm

(14500).

Anal. Calcd for C₂₂H₂₂N₂O (349.4): C, 79.97; H, 6.71; N, 8.48.

Found: C, 79.48; H, 6.75; N, 8.50.

IR (KBr): 1600 (s), 1513 (m), 1493 (m), 1421 (w), 1222 (m), 1158

(w), 1095 (w), 1000 (w), 964 (w), 838 (m), 814 (m), 761 (m), 723

(w), 695 (m), 668 (w), 612 (w), 585 (w), 520 (w) cm^–1.

¹H NMR (CDCl₃, 300 MHz): d = 6.95 (d, J = 2.6 Hz, 1 H), 7.19–

7.31 (m, 5 H), 7.37–7.49 (m, 4 H), 7.79 (d, J = 7.2 Hz, 2 H), 8.40

(d, J = 4.9 Hz, 2 H), 11.67 (br s, 1 H).

4-(1-Benzyl-2,5-diphenyl-1H-pyrrol-3-yl)benzonitrile (8f)

After an aqueous workup and extraction with EtOAc and purifica-

tion by chromatography on silica gel (hexane–EtOAc 6:1), colorless

crystals, mp 137 °C (EtOH).

¹³C NMR (CDCl₃, 75 MHz): d = 107.4 (CH), 115.7 (d, J = 21.4 Hz,

CH), 119.7 (C_quat), 122.1 (CH), 124.2 (CH), 126.4 (CH), 128.8

(CH), 129.0 (d, J = 3.1 Hz, C_quat), 130.4 (C_quat), 131.0 (d, J = 8.1 Hz,

CH), 132.1 (C_quat), 132.7 (C_quat), 143.9 (C_quat), 149.7 (CH), 161.8 (d,

J = 243.3 Hz, C_quat).

IR (KBr): 2223 (s), 1604 (s), 1508 (w), 1496 (w), 1486 (w), 1467

(w), 1452 (m), 1342 (m), 844 (m), 806 (w), 756 (s), 731 (m), 700

(s), 558 (m), 516 (w) cm^–1.

¹H NMR (CDCl₃, 300 MHz): d = 5.08 (s, 2 H), 6.58 (s, 1 H), 6.62–

6.67 (m, 2 H), 7.09–7.43 (m, 17 H).

¹³C NMR (CDCl₃, 75 MHz): d = 48.5 (CH₂), 108.0 (C_quat), 109.1

(CH), 119.5 (C_quat), 121.5 (C_quat), 126.0 (CH), 127.0 (CH), 127.6

(CH), 127.6 (CH), 128.3 (CH), 128.3 (CH), 128.5 (CH), 128.7

(CH), 129.1 (CH), 131.1 (CH), 131.9 (CH), 132.4 (C_quat), 132.9

(C_quat), 133.6 (C_quat), 136.2 (C_quat), 138.6 (C_quat), 141.1 (C_quat).

MS (70 eV, EI) m/z (%): 314 ([M]⁺, 100).

UV/Vis (CHCl₃): l_max(e) = 256 (19300), 308 nm (25800).

Anal. Calcd for C₂₁H₁₅N₂F (350.4): C, 80.24; H, 4.81; N, 8.91.

Found: C, 79.93; H, 4.96; N, 8.76.

MS (70 eV, EI) m/z (%): 410 ([M]⁺, 100), 319 ([M – benzyl]⁺, 99),

4-(2-Pentyl-5-phenyl-1H-pyrrol-3-yl)benzonitrile (8d)

After an aqueous workup and extraction with Et₂O and trituration

with EtOH, colorless solid, mp 156 °C (EtOH).

91 ([benzyl]⁺, 20).

UV/Vis (CHCl₃): l_max(e) = 277 (22600), 318 nm (17000).

Fluorescence (CHCl₃): l_max= 428 nm.

IR (KBr): 3336 (s), 2956 (w), 2929 (m), 2854 (w), 2224 (s), 1600

(s), 1524 (m), 1498 (m), 1459 (m), 1266 (w), 1178 (m), 1000 (w),

840 (m), 806 (m), 768 (m), 758 (m), 694 (m), 642 (w), 552 (w) cm^–1.

¹H NMR (CDCl₃, 300 MHz): d = 0.89 (t, J = 7.1 Hz, 3 H), 1.31–1.42

(m, 4 H), 1.64–1.74 (m, 2 H), 2.81 (t, J = 7.7 Hz, 2 H), 6.60 (d,

J = 2.9 Hz, 1 H), 7.19–7.25 (m, 1 H), 7.35–7.41 (m, 2 H), 7.48–7.53

(m, 4 H), 7.64 (d, J = 8.5 Hz, 2 H), 8.35 (br s, 1 H, NH).

¹³C NMR (CDCl₃, 75 MHz): d = 14.4 (CH₃), 22.8 (CH₂), 27.3

(CH₂), 29.9 (CH₂), 32.0 (CH₂), 106.4 (CH), 108.7 (C_quat), 119.9

(C_quat), 121.5 (C_quat), 124.0 (CH), 126.8 (CH), 128.2 (CH), 129.4

(CH), 131.3 (C_quat), 132.1 (C_quat), 132.5 (C_quat), 132.7 (CH), 142.2

(C_quat).

Anal. Calcd for C₃₀H₂₂N₂(410.5): C, 87.77; H, 5.40; N, 6.82.

Found: C, 87.36; H, 4.45; N, 6.82.

4-[1-Benzyl-2-(2-furyl)-5-phenyl-1H-pyrrol-3-yl]benzonitrile

(8g)

After an aqueous workup and extraction with Et₂O and purification

by chromatography on silica gel (hexane–EtOAc 6:1), colorless

crystals, mp 104–105 °C (EtOH, low decomp. in air).

IR (KBr): 3062 (w), 3030 (w), 2224 (s), 1605 (s), 1508 (w), 1496

(w), 1454 (m), 1350 (m), 1179 (m), 1007 (w), 946 (w), 894 (w), 841

(m), 761 (s), 732 (m), 700 (s), 552 (w) cm^–1.

¹H NMR (CDCl₃, 300 MHz): d = 5.14 (s, 2 H), 6.15 (d, J = 3.1 Hz,

1 H), 6.36 (dd, J = 1.8 Hz, J = 3.2 Hz, 1 H), 6.55 (s, 1 H), 6.81–6.84

(m, 2 H), 7.18–7.25 (m, 3 H), 7.31–7.36 (m, 7 H), 7.43 (d, J = 1.4

Hz, 1 H), 7.50 (d, J = 8.4 Hz, 2 H).

¹³C NMR (CDCl₃, 75 MHz): d = 48.9 (CH₂), 108.8 (C_quat), 109.2

(CH), 111.2 (CH), 112.1 (CH), 119.4 (C_quat), 122.3 (C_quat), 124.6

(C_quat), 125.9 (CH), 127.1 (CH), 127.6 (CH), 127.9 (CH), 128.5

(CH), 128.5 (CH), 129.1 (CH), 132.1 (CH), 132.5 (C_quat), 137.4

(C_quat), 138.6 (C_quat), 140.6 (C_quat), 143.0 (CH), 145.1 (C_quat).

MS (70 eV, EI) m/z (%): 314 ([M]⁺, 32), 257 ([M – CH₃(CH₂)₃]⁺,

100).

UV/Vis (CHCl₃): l_max(e) = 266 (19500), 307 nm (18300).

Anal. Calcd for C₂₂H₂₂N₂(314.4): C, 84.04; H, 7.05; N, 8.91.

Found: C, 83.60; H, 6.98; N, 8.82.

4-[2-(5-Hydroxypentyl)-5-phenyl-1H-pyrrol-3-yl]benzonitrile

(8e)

After an aqueous workup and extraction with EtOAc and purifica-

tion by chromatography on silica gel (hexane–EtOAc 2:1), colorless

solid, mp 142–144 °C (isopropanol).

MS (70 eV, EI) m/z (%): 400 ([M]⁺, 86), 309 ([M – C₆H₅CH₂]⁺,

100), 281 (21), 91 ([C₆H₅CH₂]⁺, 32).

IR (KBr): 3340 (s), 2935 (w), 2859 (w), 2224 (s), 1640 (w), 1600

(s), 1524 (w), 1498 (w), 1459 (w), 1414 (w), 1179 (w), 1160 (w),

1053 (w), 842 (w), 804 (w), 761 (m), 694 (w), 640 (w), 552 (w)

cm^–1.

UV/Vis (CHCl₃): l_max(e) = 275 nm (30200).

Fluorescence (CHCl₃): l_max= 446 nm.

Anal. Calcd for C₂₈H₂₀N₂O (400.5): C, 83.98; H, 5.03; N, 7.00.

Found: C, 83.88; H, 4.96; N, 6.97.

FEATURE ARTICLE

A Multicomponent Approach to Furans and Pyrroles

2405

Ethyl [3-(4-Cyanophenyl)-2,5-diphenyl-1H-pyrrol-1-yl]acetate

(8h)

After an aqueous workup and extraction with EtOAc and purifica-

tion by chromatography on silica gel (hexane–EtOAc 6:1), colorless

solid, mp 108–109 °C (isopropanol).

¹H NMR (CDCl₃, 300 MHz): d = 1.76 (s, 3 H), 3.76 (t, J = 5.7 Hz,

2 H), 4.22 (t, J = 5.7 Hz, 2 H), 6.48 (s, 1 H), 7.22 (d, J = 8.5 Hz, 2

H), 7.33–7.51 (m, 12 H).

¹³C NMR (CDCl₃, 75 MHz): d = 21.0 (CH₃), 43.8 (CH), 63.5 (CH),

108.6 (C_quat), 110.0 (CH), 119.9 (C_quat), 122.1 (C_quat), 128.1 (CH),

128.1 (CH), 129.0 (CH), 129.1 (CH), 129.5 (CH), 129.6 (CH),

131.5 (CH), 132.3 (CH), 132.6 (C_quat), 133.3 (C_quat), 133.7 (C_quat),

136.5 (C_quat), 141.4 (C_quat), 170.7 (C_quat).

IR (KBr): 2223 (s), 1750 (s), 1605 (s), 1508 (w), 1486 (w), 1469

(w), 1448 (w), 1375 (w), 1350 (w), 1206 (s), 1180 (m), 1028 (w),

846 (w), 806 (w), 761 (m), 702 (s), 555 (m), 517 (w) cm^–1.

¹H NMR (CDCl₃, 300 MHz): d = 1.13 (t, J = 7.1 Hz, 3 H), 4.08 (q,

J = 7.2 Hz, 2 H), 4.44 (s, 2 H), 6.55 (s, 1 H), 7.26–7.33 (m, 5 H),

7.35–7.46 (m, 9 H).

MS (70 eV, EI) m/z (%): 406 ([M]⁺, 100), 333 ([M

–

CH₃COOCH₂]⁺, 18), 320 ([3-cyanophenyl-2,5-diphenyl pyrrole]⁺,

15), 87 ([CH₃COOCH₂CH₂]⁺, 22).

¹³C NMR (CDCl₃, 75 MHz): d = 14.1 (CH₃), 47.2 (CH₂), 61.5

(CH₂), 108.3 (C_quat), 108.9 (CH), 119.5 (C_quat), 121.4 (C_quat), 127.7

(CH), 127.9 (CH) 128.7 (CH), 128.7 (CH), 129.1 (CH), 129.2 (CH),

131.1 (CH), 132.0 (CH), 132.1 (C_quat), 132.5 (C_quat), 133.5 (C_quat),

136.3 (C_quat), 141.0 (C_quat), 169.3 (C_quat).

UV/Vis (CHCl₃): l_max(e) = 272 nm (21100).

Fluorescence (CHCl₃): l_max= 418 nm.

Anal. Calcd for C₂₇H₂₂N₂O₂(406.5): C, 79.78; H, 5.46; N, 6.89.

Found: C, 79.64; H, 5.22; N, 6.83.

MS (70 eV, EI) m/z (%): 406 ([M]⁺, 100), 333 ([M – COOEt]⁺, 40).

UV/Vis (CHCl₃): l_max(e) = 273 (25000), 314 nm (19500).

Fluorescence (CHCl₃): l_max= 427 nm.

4-(1-Isopropyl-2-pentyl-5-phenyl-1H-pyrrol-3-yl)benzonitrile

(8k)

After an aqueous workup and extraction with EtOAc and trituration

with EtOH, colorless solid, mp 129 °C (EtOH).

Anal. Calcd for C₂₇H₂₂N₂O₂(406.5): C, 79.78; H, 5.46; N, 6.89.

Found: C, 79.48; H, 5.37; N, 6.82.

IR (KBr): 2959 (s), 2931 (s), 2869 (w), 2222 (s), 1603 (s), 1528 (w),

1468 (w), 1370 (w), 1356 (m), 1270 (w), 1174 (w), 1074 (w), 742

(m), 787 (w), 773 (m), 704 (m), 558 (m) cm^–1.

¹H NMR (CDCl₃, 300 MHz): d = 0.88 (t, J = 6.9 Hz, 3 H), 1.29–1.37

(m, 4 H), 1.42 (d, J = 7.1 Hz, 6 H), 1.53–1.63 (m, 2 H), 2.82–2.87

(m, 2 H), 4.53 (sept, J = 7.1 Hz, 1 H), 7.37–7.40 (m, 6 H), 7.50 (d,

J = 8.6 Hz, 2 H), 7.62 (d, J = 8.6 Hz, 2 H).

rac-2-[3-(4-Cyanophenyl)-2-(2,6-dimethylhept-5-en-1-yl)-5-

phenyl-1H-pyrrol-1-yl]acetamide (8i)

After an aqueous workup and extraction with EtOAc and purifica-

tion by chromatography on silica gel (hexane–EtOAc 3:1), colorless

solid, mp 111–113 °C (isopropanol).

IR (KBr): 2959 (w), 2924 (w), 2225 (m), 1681 (s), 1604 (s), 1449

(w), 1178 (w), 846 (w), 762 (w), 702 (w), 573 (w) cm^–1.

¹³C NMR (CDCl₃, 75 MHz): d = 14.4 (CH₃), 22.6 (CH₂), 23.8

(CH₃), 26.6 (CH₂), 30.8 (CH₂), 32.4 (CH₂), 48.8 (CH), 108.4 (C_quat),

110.1 (CH), 120.0 (C_quat), 120.8 (C_quat), 127.9 (CH), 128.3 (CH),

128.4 (CH), 130.8 (CH), 132.1 (C_quat), 132.5 (CH), 134.5 (C_quat),

135.1 (C_quat), 143.1 (C_quat).

¹H NMR (CDCl₃, 300 MHz): d = 0.77 (d, J = 6.6 Hz, 3 H), 1.06–

1.35 (m, 2 H), 1.54 (s, 3 H), 1.65 (s, 3 H), 1.57–1.68 (m, 1 H), 1.85–

1.96 (m, 2 H), 2.60 (dd, J = 8.6, 15.2 Hz, 1 H), 2.77 (dd, J = 6.4,

15.2 Hz, 1 H), 4.61 (s, 2 H), 4.94 (t, J = 7.0 Hz, 1 H), 5.33 (br s, 1

H), 5.78 (br s, 1 H), 6.38 (s, 1 H), 7.33–7.45 (m, 5 H), 7.52 (d,

J = 8.5 Hz, 2 H), 7.64 (d, J = 8.5 Hz, 2 H).

¹³C NMR (CDCl₃, 75 MHz): d = 17.5 (CH₃), 19.2 (CH₃), 25.2

(CH₂), 25.5 (CH₃), 32.1 (CH₂), 33.4 (CH), 36.6 (CH₂), 48.0 (CH₂),

108.9 (C_quat), 110.1 (CH), 119.0 (C_quat), 122.8 (C_quat), 123.8 (CH),

127.8 (CH), 128.3 (CH), 128.7 (CH), 128.7 (CH), 130.9 (C_quat),

131.6 (C_quat), 131.7 (C_quat), 132.1 (CH), 134.8 (C_quat), 141.7 (C_quat),

171.0 (C_quat).

MS (70 eV, EI) m/z (%): 356 ([M]⁺, 45), 299 ([M – C₄H₉]⁺, 100),

257 ([M – C₄H₉, – C₃H₆]⁺, 76).

UV/Vis (CHCl₃): l_max(e) = 273 (16600), 327 nm (13900).

Fluorescence (CHCl₃): l_max= 425 nm.

Anal. Calcd for C₂₅H₂₈N₂(356.5): C, 84.23; H, 7.92; N, 7.86.

Found: C, 84.55; H, 7.89; N, 7.93.

Acknowledgment

MS (70 eV, EI) m/z (%): 425 (M⁺, 65), 314 ([M

–

CH₃(CH₃)C=CHCH₂CH₂CHCH₃]⁺, 100), 269 ([M – CH₂CONH₂,

–CH₃, –CH₃(CH₃)C=CHCH₂CH₂]⁺, 23), 257 ([2-methyl-3-(4-cy-

anophenyl)-5-phenylpyrrole]⁺, 24).

The financial support of Deutsche Forschungsgemeinschaft, MOR-

PHOCHEM AG, München, Fonds der Chemischen Industrie and

Dr.-Otto-Röhm Gedächtnisstiftung is gratefully acknowledged. We

also cordially thank Christoph Busche for experimental assistance.

UV/Vis (CHCl₃): l_max(e) = 246 (24000), 266 (15500), 312 nm

(9900).

References

Fluorescence (CHCl₃): l_max= 401 nm.

Anal. Calcd for C₂₈H₃₁N₃O (330.4): C, 79.02; H, 7.34; N, 9.87.

Found: C, 78.89; H, 7.35; N, 9.78.

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Coupling-isomerization-Stetter and coupling-isomerization-Stetter-Paal- Knorr sequences - A multicomponent approach to furans and pyrroles

DOI: 10.1055/s-2004-831192

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