Radical Arylation of Anilines and Pyrroles via Aryldiazotates

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Accepted Article

Title: Radical arylation of anilines and pyrroles via aryldiazotates

Authors: Josefa Hofmann, Eva Gans, Timothy Clark, and Markus Rolf

Heinrich

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To be cited as: Chem. Eur. J. 10.1002/chem.201701429

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Radical arylation of anilines and pyrroles via aryldiazotates

Josefa Hofmann,^[a]Eva Gans,^[a]Timothy Clark^[b]and Markus R. Heinrich*^[a]

Dedication ((optional))

Abstract: The radical arylation of anilines and pyrroles can be

achieved under transition metal- and catalyst-free conditions using

aryldiazotates in strongly alkaline aqueous solutions. The aryl

diazotates act as protected diazonium ions, which do not undergo azo

coupling with electron-rich aromatic substrates, but are still able to

serve as sources for aryl radicals at slightly elevated temperatures.

Based on an improved preparation of aryldiazotates in aqueous

solution, homolytic aromatic substitutions of anilines and pyrroles can

now be conducted with good overall yields and with high regio-

selectivity. Moreover, further mechanistic insights were obtained and

could be supported through calculations.

a general overview over radical arylations of arenes and

heteroarenes, mainly with regard to the precursors that have

recently been used for the generation of the aryl radicals.

Introduction

Homo- and heterobiaryls are present as substructures in many

natural products, pharmaceuticals as well as in compounds for

diverse other applications including optics and material

chemistry.^[1]Besides the widely used Suzuki cross-coupling

approach,^[2]a variety of aryl-aryl coupling reactions based on

aromatic C-H activation have recently been developed.^[3]A third

option for the synthesis of biaryls are radical arylations,^[4]which

have raised much interest over the last years, especially through

the manifold advances in the field of photoredox catalysis.^[5]

Although such radical arylations are formally comparable with

C-H functionalizations, and relatively simple starting materials can

thus be employed, the insufficient regioselectivity of the radical

attack on most substituted benzenes represents a major

drawback.^[6]Notable exceptions are arylations of anilines,

phenols and nitrobenzenes, which can be conducted with good to

high regioselectivity.^[7]

Heteroarenes, on the other hand, are in most cases more

effective radical acceptors than substituted benzenes,^[8]and high

selectivities for particular positions on the aromatic core are often

observed.^[4c-e]However, the reaction conditions may need to be

chosen more carefully, as rearomatization following the aryl

radical attack is not as straightforward for heterocyclic aromatic

systems as it is for benzene and its derivatives.^[9]Scheme 1 gives

Scheme 1. Radical arylations of arenes and heteroarenes.

Among the radical precursors, aryldiazonium salts,^[10]which may

also be generated in situ,^[11]as well as aryl chlorides, bromides

and iodides^[12]are the most commonly used. This variety has

recently been complemented by arylhydrazines,^[13]diaryliodonium

salts^[14]and arylboronic acids.^[15]Regarding aryldiazonium salts in

particular, a limitation exists in the way that arylations of strongly

nucleophilic arenes (e.g. anilines, phenolates) cannot directly be

carried out, as side reactions such as azo coupling or triazene

formation would then prevail.^[16],[17]A suitable strategy to circum-

vent this difficulty is the use of protected diazonium ions, which

however need to retain the ability to serve as precursors for aryl

radicals. Known examples are arylazo sulfides,^[18]which even

allow the radical arylation of strongly nucleophilic phenolates. The

arylation of anilines had remained unknown under metal-free,

basic Gomberg-Bachmann type conditions for a long time, but it

could recently be achieved with aryldiazotates.^[19,20]In comparison

to aryldiazo anhydrides, which are the generally accepted

intermediates in classical Gomberg-Bachmann reactions,^[21]

aryldiazotates show a much better stability towards an attack of

nucleophiles.^[22]Also very recently, an ortho-selective arylation of

anilines proceeding via benzyne intermediates has been reported

by Daugulis.^[23]

[a]

[b]

M.Sc. J. Hofmann, Eva Gans, Prof. Dr. M. R. Heinrich

Department of Chemistry and Pharmacy, Pharmaceutical Chemistry

Friedrich-Alexander Universität Erlangen-Nürnberg

Schuhstraße 19, 91052 Erlangen, Germany

E-mail: markus.heinrich@fau.de

In this article, we now give a comprehensive overview over the

applicability of aryldiazotates in transition metal- and catalyst-free

radical arylations of arenes and heteroarenes including results

from computational studies.

Prof. Dr. T. Clark

Computer-Chemie-Centrum and Interdisciplinary Center for

Molecular Materials

Friedrich-Alexander-Universität Erlangen-Nürnberg

Nägelsbachstraße 25, 91052 Erlangen, Germany

Supporting information for this article is given via a link at the end of

the document.

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Results and Discussion

the diazotate 2a is indeed strong enough to prevent the attack of

nucleophiles such as aromatic amines.

In the series of experiments, the diazotate formation was

investigated using the previously optimized conditions for

diazotization (Table 2). In the diazotate forming step, the cooled

aqueous solution of the diazonium salt is typically added dropwise

to an as well cooled aqueous solution of a strong base.

Our investigations started with a preliminary study on optimized

conditions for the preparation of aryldiazotate 2a from 4-chloro-

aniline (1a), which is conducted in two steps via the corresponding

aryldiazonium chloride (Table 1). To monitor the effect of different

conditions in the diazotization step, the diazotate 2a was

subsequently submitted to the known arylation of aniline (3a) to

give 2-aminobiphenyl 4a along with smaller amounts of its

regioisomer 4a’.^[19]Through several variations, a procedure

providing the aryldiazotate 2a as a clear and almost colorless

aqueous solution could be established.

Table 2. Optimization of reaction conditions for diazotate formation.

Table 1. Optimization of reaction conditions for diazotization.

Yield^b

4a/4a’ (%/%)^b

50/16

Yield^b

5a (%)

<5

10

11

12

10

9

Atmos-

phere

Variation of general

reaction conditions^a

Entry

1

2

3

4

5

6

7

8

9

Ar

N₂

Air

N₂

Ar

-

48/13

44/15

48/15

30/13

38/12

45/11

39/12

41/15

-

6 N NaOH (2 mL)^c

Addition in one batch

0.5 min

NaNO₂

(equiv.)

Variation of general

reaction conditions^a

Yield^b

4a/4a’ (%/%)

Yield^b

5a (%)

Entry

6 N NaOH (3 mL)

4 N LiOH (3 mL)

4 N KOH (3 mL)

4 N CsOH (3 mL)

1

2

3

4

5

6

7

8

1.05

1.10

1.30

1.05

2.00^c

-

50/16

43/17

33/11

42/16

n.d.^d

34/11

34/12

19/7

< 5

15

10

6

12

10

13

10

13

10

34/12

Urea added (3 mmol)

3 N HCl (20 mL)

1 M H₂SO₄(15 mL)

Reverse addition

-

[a] An aliquot of the 0.4 M 4-chlorophenyldiazonium chloride solution (2.00 mmol,

5.00 mL) was added to a pre-cooled and vigorously stirred aqueous solution of

sodium hydroxide (4 N, 3 mL) under argon. The homogeneous solution was

stirred for five minutes in total. [b] Yield determined by ¹H NMR spectroscopy

using 1,4-dimethyl terephthalate and 1,3,5-trimethoxybenzene as internal

standards. [c] CH₃CN (1 mL) added.

[a] A degassed solution of sodium nitrite (10.5-13.0 mmol, see Table) in water

(5 mL) was added dropwise to an ice-cooled degassed solution of 4-

chloroaniline (10.0 mmol) in hydrochloric acid (1.5 N, 20 mL) under nitrogen

over a period of 15 min. The clear solution was stirred for 15 more minutes at

0 °C. [b] Yield determined by ¹H NMR spectroscopy using 1,4-dimethyl

terephtalate and 1,3,5-trimethoxybenzene as internal standards. [c]

Diazotization with NO (2 equiv.) under air in a 250 mL round bottom flask

equipped with a balloon for pressure equilibration . [d] Complex product mixture

formed.

The best results considering desired biaryl and undesired triazene

formation were obtained under argon (entries 1-3). Further

attempts to improve the yields of 4a/4a’ under nitrogen or air

through a variation of the reaction conditions remained unsuc-

cessful (entries 4-6). The use of more concentrated sodium

hydroxide (entry 7) or the change to other alkali metal bases

(entries 8-10) did not lead to improvements either.

Although one might assume that a larger excess of sodium nitrite

should lead to a reliable and full diazotization of 1a (entries 1-3),

this variation was accompanied by an increased formation of the

undesired triazene 5a. It thus appears likely that an excess of

nitrite ions can cause a reduction of the aromatic diazonium ions

back to the aniline 1a under the strongly basic conditions required

for the consecutive diazotate formation.^[24]Albeit the addition of

urea,^[25]the use of more concentrated hydrochloric acid and the

change to sulfuric acid led to less triazene 5a, these modifications

were not able to increase the overall result concerning the

biphenyls 4a and 4a’ (entries 5-7). Further attempts using an

inverse addition of the reagents (entry 8)^[26]or a recently

developed diazotization with nitrogen oxides (entry 8) were not

successful either.^[27]

In general, an effective preparation of the diazotate 2a can easily

be monitored as a clear and colorless aqueous solution of 2a is

then typically obtained. In less successful attempts, the formation

of precipitates and an emergence of yellow color indicate the

formation of undesired side-products such as diazo anhydrides.^[28]

With optimized conditions now available, we re-evaluated the

synthesis of a number of 2-aminobiphenyls 4. A comparison of

the yields obtained from the previous protocol^[19]and the newly

developed procedure is summarized in Table 3. In this study, all

2-aminobiphenyls could be prepared in better yields than before.

The most significant improvements were determined for biphenyls

4c and 4e (entries 3 and 5), which were isolated in yields

increased by 21% and 24%, respectively. The smallest gain of 6%

was observed for 4,5’-difluorobiphenyl-2-amine (4d).

Regarding other possible side-products of overall reaction

sequence, it is remarkable that unsymmetrical triazenes, as they

could be formed from diazotized 4-chloroaniline and aniline (3),

were not detected. This indicates that the protective character of

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Table 4. Comparison of arylation with diazotates to phase-transfer Gomberg-

Bachmann conditions.^[a],[b]

Table 3. Arylation of anilines with aryldiazotates under optimized conditions.

Diazotate^[a]

2: R¹=

Aniline

3: R²=

Yield (this work)^[b]

Yield (ref. 19)^[b]

Entry

4 (%)

1

2

3

4

5

2a: Cl

2b: F

3a: H

3b: F

3c: Cl

3b: F

3c: Cl

4a [4a’]: 48 [8]^[c]

4a [4a’]: 35 [7]^[c]

4b: 53

4c: 60

4d: 48

4e: 58

4b: 41

4c: 39

4d: 42

4e: 34

[a] To a vigorously stirred aniline (20.0 mmol) at 75 °C under argon was added

dropwise the previously prepared solution of the aryl diazotate (2.00 mmol, 8.00

mL) over a period of ten minutes. After the addition was complete, the mixture

was left to stir for 20 more minutes. [b] Yield after purification by column

chromatography. [c] 4a’: regioisomer of 4a (see Table 3).

Moreover, and as a result of the optimization, triazenes could no

longer be detected by ¹H NMR spectroscopy as by-products in the

crude reaction mixtures, which indicates that they were formed in

yields lower than 5%. As easily removable, volatile halobenzenes

are now the only by-products from arylations with diazotate 2a

and 2b, the final purification of the 2-aminobiphenyl 4 simplifies

and just requires separation from the excess of aniline (see

Supporting Information).

To further underline the usefulness of the diazotate-based

arylation for preparative purposes, a reaction on a 50 mmol scale

was conducted (Scheme 2). This experiment gave 4a (4.31 g) and

its regioisomer 4a’ (1.52 g) in a total yield of 57%, whereat we do

not yet have an explanation for the slight change in product

distribution (c.f. Table 3, entry 1). After work-up, 92% of the

remaining excess of aniline (3a) could be recovered through

distillation. 4’-Chlorobiphenyl-2-amine (4a), which is currently

prepared on large industrial scale via a Suzuki aryl-aryl coupling

reaction, represents an important building block for the synthesis

of the fungizide Boscalid.^[29]

[a] ptGB_72-138: Yields from phase-transfer Gomberg-Bachmann as reported by

Gokel et al.^[6b]Biaryls 4a, 13 and 14a (not reported in ref. [6b]) synthesized

according to this reference. Subscript number indicates equivalents of radical

acceptor 3a,d-l. ptGB₁₀: Repetition of ptGB reaction under conditions of ref. [6b],

but with 10 equivalents of radical acceptor. Diaz₁₀: Diazotate-based arylation

according to conditions used in Table 3. Ratios given in brackets indicate the

regioisomeric distribution (ortho:meta:para). [b] For ptGB₁₀and Diaz₁₀: Yields

determined after column chromatography. [c] Ratio does not sum up to 100 in

ref. 6b. [d] Yields determined by ¹H NMR using 1,4-dimethyl terephthalate and

1,3,5-trimethoxybenzene as internal standards. [e] Diarylazo compound formed

as main product.

An inspection of the results summarized in Table 4 reveals that

the diazotate method is not beneficial for benzene (3d), toluene

(3e), mesitylene (3f) and anisole (3g), which were converted to

biaryls 6-9. Interestingly, some ptGB reactions showed a strong

dependence on the excess of radical acceptor (biphenyls 6 and

7), but almost no difference was observed for mesitylene and

anisole when lowering the excess of radical from 72 or 92 to 10

equivalents (biphenyls 8 and 9). Starting from aniline (3a), only

the diazotate method is able to give useful yield of biphenyl 4a.

Among the heterocyclic substrates, the arylation of pyridine (3h)

turned out as inefficient when following the diazotate protocol.

Under ptGB conditions, biaryl 10 can be prepared in useful yields

with an only small dependence on the excess of pyridine.

Experiments with furan (3i) and thiophene (3j) gave slightly better

yields of biaryls 11 and 12 under the diazotate conditions, which

are however far from competitive to the ptGB protocol. In the case

of pyrrole (3k), all methods failed to give the desired biaryl 13 in a

detectable yield, which is most probably due to an insufficient

stability of diazotate 2a towards pyrrole as a nucleophile.

Scheme 2. Large scale experiment.

In the next stage, the diazotate-based radical arylation was

evaluated in combination with other substituted benzenes and

heterocycles (Table 4). In addition, the diazotate variant was

compared to the established phase-transfer Gomberg-Bachmann

conditions developed by Gokel (ptGB).^[6b]As this method uses a

large excess of radical acceptor of around 100 equivalents

(excess given as subscript in Table 4), and to allow better

comparison, the ptGB protocol was repeated with same excess of

arene or heteroarene as it is typically used in diazotate method,

namely 10 equivalents (labeled as ptGB₁₀). The diazotate method

was conducted under conditions identical to those applied for the

experiments of Table 3 (labeled as Diaz₁₀).

For 1-methylpyrrol (3l), the diazotate variant appears as superior

to the ptGB conditions. However, the biaryl 14a (25%) was

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isolated along with 44% of the corresponding diarylazo compound

in this initial experiment.

The large amount of azo compound 15 (44%) obtained in the

initial attempt revealed that the excess of base remaining from

generation of the diazotate 2a is not sufficient to maintain the

protection of the diazonium ion in the aryl-aryl coupling step (entry

1). Subsequent experiments with additional sodium hydroxide

gave lower amounts of 15 and led to an optimum temperature of

70 °C (entries 2-6), which is comparable to results from earlier

studies on the arylation of aniline.^[19]Increases in the amount of

pyrrole 3l, base and conduction of the reaction under air, which

could facilitate rearomatization,^[31]did not lead to improvements

(entries 7-9). Whereas the use of tetra-n-butyl ammonium

hydroxide resulted in a complete failure (entry 10), the change to

sodium hydroxide in tert-butanol as main solvent led to increases

in yield (entries 11-14) and a full suppression of 15.^[32]Finally, the

yield of 14a could be improved to 66% through a change of the

base to lithium hydroxide in the diazotate formation and the aryl-

aryl coupling step (entries 15-17). A control experiment, in which

the diazotate formation was performed with sodium hydroxide and

the arylation under addition of lithium hydroxide gave 14a in a

lower yield of 59%.

Based on these results and the assumption that 1-methylpyrrol

(3l) could be suitable for a diazotate-based arylation, attempts to

optimize the reaction conditions were made. The major aim

thereby was to avoid the formation of azo compound 15 (Table 5).

An previous examination of the existing radical transformations

revealed that reactions using aryldiazonium ions as radical

sources or intermediates, such as the methods developed by

Felpin^[11b], Carrillo^[10b]and Maulide^[10c]are limited to pyrroles

bearing an electron-withdrawing group on the nitrogen atom due

to competing azo coupling.^[30]A related silver nitrite assisted

arylation by Gowrisankar and Seayad,^[11c]of which the

mechanism is yet unknown, might not proceed via free diazonium

ions as electron-rich pyrroles are tolerated. Alternatively, as

shown by König,^[12g]aryl bromides can be employed as radical

sources which are insensitive towards azo coupling as side

reaction.

In our study, the optimized conditions for the preparation of 4-

chlorophenyldiazotate (2a) from 4-chloroaniline (1a) (see Tables

1 and 2) were also used as a basis for the arylation of 1-methyl-

pyrrole (3l). An overview is shown in Table 5. Control experiments

had confirmed that a pre-formation of diazotate 2a is required for

the successful synthesis of 14a as the direct addition of the

diazonium salt to a mixture of 3l and base only provided the azo

compound 15.

The optimized conditions (Table 5, entry 15) were next applied to

determine scope and limitations of the arylation procedure (Table

6). Starting from 1-methylpyrrole (3l), synthetically useful yields

(based on anilines 1a-l) were obtained for most substitution

patterns on the aryldiazotate with the exception of the 2-fluoro, 4-

methoxy and 4-trifluoromethyl substituents (c.f. 14e, 14i, 14k).

Table 5. Arylation of 1-methylpyrrole (3l) with 4-chlorophenyldiazotate (2a):

optimization of reaction conditions.

Table 6. Arylation of pyrroles with aryldiazotates: substrate scope.

Temp

(°C)

Variation of general reaction

conditions^[^a]

Yield^[b]

14a (%)

Yield^[b]

15 (%)

Entry

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

rt

--

25%

21%

40%

50%

42%

34%

50%

42%

-

54%

55%

52%

53%

66%

58%

59%

44%

7%

34%

8%

6%

7%

8%

7%

-

4N NaOH (3 mL)

4N NaOH (3 mL)^[c]

8N NaOH (3 mL)

4N NaOH (3 mL), under air

1.5N TBAH (6 mL)

NaOH (12 mmol)^[c,d]

NaOH (12 mmol)^[d,e]

NaOtBu (12 mmol)^[d]

NaOtBu/NaOH (6/6 mmol)^[d]

LiOH (12 mmol)^[d,f]

KOH (12 mmol)^[d,f]

CsOH (12 mmol)^[d,f]

50

70

80

100

70

A variation of the pyrrole unit showed that 2-aryl-1-methylpyrroles

14a,b,g are excellent acceptors and thus making the new

methodology a valuable tool for the preparation of symmetrical

and unsymmetrical 2,5-diarylpyrroles such as 14m-p.^[33]The

slightly lower yields of biaryls 14q-s and 14t obtained from 1-

phenylpyrrol (3m) and 1-Boc-pyrrole (3n) can be explained by the

fact that the aryl group, and even more the tert-butyloxycarbonyl

group, act as electron acceptors. Beneficially, on the other hand,

arylation of 1-phenylpyrrol selectively occurred on the pyrrole

unit.^[34]When using 1-benzylpyrrole (3o) as radical acceptor to

[a] General conditions: To 1-methylpyrrole (3l) (20.0 mmol) under argon was

added dropwise the previously prepared solution of the aryldiazotate 2a (max.

2.00 mmol, 8.00 mL) over a period of seven minutes. After the addition was

complete, the mixture was left to stir for 23 more minutes. [b] Yield determined

by ¹H NMR spectroscopy using 1,4-dimethyl terephthalate and 1,3,5-trimethoxy-

benzene as internal standards. [c] 20 Equiv. of 3l. [d] tBuOH (3 mL) added. [e]

18-Crown-6 (5 mol%) added. [f] Base also used in diazotate formation instead

of NaOH.

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give 14u, the arylation is to some extent complicated by hydrogen

abstraction from the benzylic position.^[4c]Reactions with

unsubstituted pyrrole or indole under comparable conditions

furnished four azo compounds (c.f. compound 15, Table 5) in 85%

to quantitative yield, thus showing that diazotates –when

combined with pyrrole or indole – may also be used for a yet

unknown, highly efficient azo coupling reaction (see Supporting

Information).^[35]

Regarding radical arylation, Figure 1 depicts the dependency of

the product distribution on the excess of 1-methylpyrrole (3l). With

a lower excess of only 2.5 equivalents, biaryl 14a could still be

obtained in 49% yield. A 1:1 ratio of 2a:3l provided almost equal

amounts of 14a (25%) and the diarylated pyrrole 14n (26%).

radical 18 is facilitated through the occurrence of the diazo ether

17 as a more effective radical source than the diazohydroxide

16.^[37]The significant differences observed between the ptGB

conditions and the diazotate method (Table 4) are indirectly also

in agreement with the tert-butanol effect and can be explained as

described below. Control experiments with the previously studied

anilines 3a and 3b (c.f. Table 3) revealed that the arylation of

anilines can not be further improved through the addition of tert-

butanol, as similar yields for 2-aminobiphenyls 4a and 4d were

obtained.

Scheme 4. Plausible reaction mechanism.

Basically, and in the absence of tert-butanol, the formation of aryl

radicals 18 from diazohydroxides is slow. To nevertheless avoid

long reaction times and higher concentrations of the diazotate,

under which the diazotate may undergo undesired side-reactions,

it would be helpful if the conversion of 16 to aryl radical 18 was

not only dependent on the thermally induced homolytic bond

cleavage of 16. Regarding Scheme 4, this step could alternatively

be induced, if it was coupled to the rearomatization of adduct 19

leading to the final biaryl product 20.^[38]Strongly reducing adducts

19 should then provide better product yields as the reductive

cleavage of the diazohydroxide 16 to an aryl radical 18, nitrogen

and an hydroxide anion could smoothly occur as part of a chain

process and thermal initiation would only be of minor importance.

To gain further insight, this assumption was evaluated using

quantum chemical calculations. All calculations used the B3LYP

hybrid density functional^[39]with the aug-cc-pVBDZ basis set^[40]

including the Grimme D3 dispersion correction.^[41]Geometries

were optimized without symmetry constraints and all structures

reported were confirmed to be local minima by calculating their

normal vibrations within the harmonic approximation. All

calculations used the Gaussian 09 program.^[42]

Figure 1. Variation of equivalents of 1-methylpyrrole (3l).

These results show that radical arylation reactions can so far not

compete with modern Pd-catalyzed C-H functionalizations of

heteroarenes, even if good radical acceptors such as anilines and

pyrroles are employed. Related Pd-catalyzed transformations are

able to provide good to high yields when the reactants are used

in a 1:1 ratio.^[36]For the arylation of anilines, which can be

considered as slightly less efficient aryl radical acceptors than 1-

methylpyrrole (3l), the results of Table 3 suggest that an excess

of five to ten equivalents of aniline per diazonium salt is necessary

to obtain aminobiphenyls in useful yields of around 50%.

Reactions on a larger, approximately 10-fold reaction scale were

also conducted with 1-methylpyrrole (3l) to underline the useful-

ness of the methodology for preparative purposes (Scheme 3).

The desired biaryls 14a,b,g were obtained from these reactions

in yields of 60-67%.

s 6*, 9*, 4a* and 14a* derived from benzene, anisole, aniline and

1-methylpyrrole, each for two possible reaction mechanisms

(Scheme 5).^[37]In the first, the general radical adduct 19 is

deprotonated to give the radical anion 19^•-, which is then oxidized

to give the product 20. The second mechanism reverses the order

of the deprotonation and oxidation steps to give first the adduct

cation 19⁺, which deprotonates to give the biaryl 20.

Scheme 3. Reactions on larger scale.

The positive effect of tert-butanol (Table 5, entries 11-17) on the

arylation of 1-methylpyrrole can be rationalized by the mechanism

depicted below (Scheme 4),^[32]in which the generation of aryl

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protected diazonium ions so that common ionic side reactions,

such as azo coupling or triazene formation, are suppressed.

Beneficially, aryldiazotates are nevertheless able to act as

precursors for aryl radicals at slightly elevated temperatures.

Computational studies gave further insight and supported the

experimentally derived assumption that the reduction potential in

the rearomatization step plays a critical role in the overall reaction

course. In this way, the comparably narrow substrate scope of

radical arylations with diazotates, which basically comprises

anilines and 1-substituted pyrroles, can be explained. An

interesting challenge for future research is to reduce the required

excess of aromatic radical acceptor, as this is yet a significant

drawback of intermolecular radical aryl-aryl coupling reactions.

Scheme 5. Pathways for rearomatization of radical adduct 19.

Table 7. Calculated reaction energies for the substeps in the rearomatization of

radical adduct 19.^[a]

Proton

affinity

19^•-19

Ionization

potential^[b]

19^•-20

Ionization

potential

1919⁺

(step 2a)

Radical adduct

(from radical acceptor)

(step 1a)

(step 1b)

Experimental Section

6* (from benzene)

9* (from anisole)

4a* (from aniline)

-334

-342

-347

-0.03

-0.18

-0.24

-0.27

6.66

6.04

5.59

5.43

Experimental Details: Solvents and reagents were used as

1

received. H NMR spectra were recorded on 360 and 600 MHz

14a* (from 1-methylpyrrole)

spectrometers using CDCl₃as solvents referenced to TMS (0

ppm) and CHCl₃(7.26 ppm). Chemical shifts are reported in parts

per million (ppm). Coupling constants are in Hertz (J Hz). The

following abbreviations are used for the description of signals: s

(singlet), d (doublet), dd (double doublet), t (triplet), q (quadruplet),

m (multiplet). ¹³C NMR spectra were recorded at 90.6 and 150.9

MHz in CDCl₃using CHCl₃(77.0 ppm) as standard. Chemical

shifts are given in parts per million (ppm). ¹⁹F NMR spectra were

recorded at 338.8 MHz using CFCl₃(0 ppm) or C₆F₆(-164.9 ppm)

as standard. Mass spectra were recorded using electron impact

(EI). Analytical TLC was carried out on Merck silica gel plates

using short wave (254 nm) UV light and ninhydrin to visualize

components. Silica gel (Kieselgel 60, 40-63 μm, Merck) was used

for flash column chromatography.

[a] B3LYP-D3/aug-cc-pVDZ + zero-point energy, proton affinities in kcal mol^-1,

electron affinities and ionization potentials in eV. [b] Ionization potential of 19^•-

corresponds to negative electron affinity of 20.

Table 7 shows the calculated gas phase proton affinity of 19^•-, and

the ionization potentials of 19^•-and 19. The first two govern the

thermodynamics of the two steps of the deprotonation/oxidation

mechanism 1919^•-20 (Scheme 5, steps 1a and 1b), and the

last the oxidation step 1919⁺of the oxidation/deprotonation

mechanistic sequence shown below (Scheme 5, step 2a).

The calculated proton affinities (19^•-19) hardly distinguish

between the different radical adducts suggesting that the

deprotonation step 1a is not rate-determining. The oxidation step

in the deprotonation/oxidation reaction sequence (step 1b), which

is governed by the ionization potential of the radical anion 19^•-

does distinguish the four reactants in correct order, although the

difference is more distinct for the oxidation step 2a in the

oxidation/deprotonation reaction sequence, suggesting that this

step controls the outcome of the reaction sequence.

On the basis of the experimental and computational results, it is

thus likely that diazotate-based arylations of anilines and pyrroles

benefit from two distinct factors: Firstly, the aryldiazotate acts as

a nucleophile-resistant diazonium salt with the ability to suppress

azo coupling reactions and triazene formation, and secondly, the

radical adducts 19 -derived from anilines and pyrroles- are able to

serve as chain propagators as they are sufficiently strong

reductants to generate new aryl radicals (Scheme 4, Table 7).

General procedure for Table 1: For preparation of the diazonium

salt, see Table 1. An aliquot of this 0.4

M

4-

chlorophenyldiazonium chloride solution (max. 2.00 mmol, 5.00

mL) was added to a pre-cooled and vigorously stirred aqueous

solution of sodium hydroxide (4 N, 3 mL) under argon. The

homogeneous solution was stirred for five minutes in total. To

vigorously stirred aniline (3a) (20.0 mmol, 1.82 mL) at 70 °C was

added dropwise the previously prepared solution of the aryl

diazotate (max. 2.00 mmol, 8.00 mL) under argon over a period

of ten minutes. After the addition was complete, the mixture was

left to stir for 20 more minutes. The resulting reaction mixture was

then extracted with dichloromethane (3 × 75 mL). The combined

organic phases were washed with saturated aqueous sodium

chloride and dried over sodium sulfate. The solvent was removed

under reduced pressure. Further purification was carried out by

Kugelrohr distillation and column chromatography on silica gel.

4’-Chlorobiphenyl-2-amine (4a) and 4’-chlorobiphenyl-4-

amine (4a`): The crude products were purified by Kugelrohr

distillation under reduced pressure at 80 °C and flash

chromatography on silica gel (hexane / EtOAc = 10 : 1) to give the

two isomers as brown oils: 4’-Chlorobiphenyl-2-amine (4a):

R_f: 0.6 (hexane / EtOAc = 4 : 1) [UV]; ¹H-NMR (600 MHz, CDCl₃):

δ (ppm) = 6.76 (dd, J = 1.2 Hz, J = 8.6 Hz, 1 H), 6.86 (dt,

J = 1.2 Hz, J = 7.5 Hz, 1 H), 7.08 (dd, J = 1.6 Hz, J = 7.6 Hz, 1 H),

7.16 (ddd, J = 1.6 Hz, J = 7.4 Hz, J = 8.0 Hz, 1 H), 7.38 - 7.42 (m,

4 H); ¹³C-NMR (91 MHz, CDCl₃): δ (ppm) = 115.6 (CH), 118.4

Conclusions

In conclusion, aryldiazotates have been found to be useful

reactants for the radical arylation of anilines and 1-substituted

pyrroles. Based on a significantly optimized preparation of

aryldiazotates from anilines, a variety of biaryls could be obtained,

even on larger reaction scales. The key feature of diazotate-

based arylations is that these intermediates can serve as

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CDCl₃): δ (ppm) = 6.70 (dd, J_HF= 4.8 Hz, J = 8.7 Hz, 1 H), 6.83

(dd, J = 3.0 Hz, J_HF= 9.2 Hz, 1 H), 6.85 (ddd, J = 3.0 Hz,

J_HF= 8.2 Hz, J = 8.3 Hz, 1 H), 7.38 (d, J = 8.8 Hz, 2 H), 7.43 (d,

J = 8.8 Hz, 2 H). ¹³C-NMR (91 MHz, CDCl₃): δ (ppm) = 115.2 (d,

J_CF= 22.2 Hz, CH), 116.5 (d, J_CF= 22.6 Hz, CH), 116.8 (d,

J_CF= 7.8 Hz, CH), 127.5 (d, J_CF= 7.3 Hz, C_q), 129.1 (2 × CH),

130.3 (2 × CH), 133.6 (C_q) 136.9 (d, J_CF= 1.7 Hz, C_q), 139.2 (d,

J_CF= 2.2 Hz, C_q), 155.1 (d, J_CF= 243.9 Hz, C_q). The analytical

data obtained is in agreement with those reported in literature.^[19]

(CH), 126.3 (C_q), 128.7 (CH), 129.1 (2 × CH), 130.3 (CH), 130.5

(2 × CH), 133.6 (C_q), 136.9 (C_q), 143.2 (C_q). 4’-Chlorobiphenyl-4-

amine (4a`): R_f: 0.3 (hexane / EtOAc = 4 : 1) [UV]. ¹H-NMR

(600 MHz, CDCl₃): δ (ppm) = 6.76 (d, J = 8.6 Hz, 2 H), 7.35 (d,

J = 8.6 Hz, 2 H), 7.38 (d, J = 8.6 Hz, 2 H), 7.46 (d, J = 8.5 Hz,

2 H). ¹³C-NMR (151 MHz, CDCl₃): δ (ppm) = 115.4 (2 × CH),

127.4 (2 × CH), 127.9 (2 × CH), 128.7 (2 × CH), 130.2 (C_q), 132.5

(C_q), 139.8 (C_q), 146.7 (C_q). The analytical data obtained is in

agreement with those reported in literature.^[19]

4’,5-Dichlorobiphenyl-2-amine (4c): The crude product was

purified by Kugelrohr distillation under reduced pressure at 85 °C

and flash chromatography on silica gel (hexane / EtOAc = 10 : 1)

to give the product as a dark brown oil (284 mg, 1.20 mmol, 60%).

General procedure for Table 2: A degassed solution of sodium

nitrite (10.5 mmol, 714 mg) in water (5 mL) was added dropwise

to an ice-cooled degassed solution of 4-chloroaniline (1a) (10.0

mmol, 1.27 g) in hydrochloric acid (1.5 N, 20 mL) over a period of

15 min. The clear solution was stirred for 15 more minutes at 0 °C.

For preparation of the 4-chlorophenyldiazotate (2a), see Table 2.

To vigorously stirred aniline (3a) (20.0 mmol, 1.82 mL) at 70 °C

was added dropwise the previously prepared solution of the aryl

diazotate (max. 2.00 mmol, 8.00 mL) under argon over a period

of ten minutes. After the addition was complete, the mixture was

left to stir for 20 more minutes. The resulting reaction mixture was

then extracted with dichloromethane (3 × 75 mL). The combined

organic phases were washed with saturated aqueous sodium

chloride and dried over sodium sulfate. The solvent was removed

under reduced pressure. Further purification was carried out by

Kugelrohr distillation and column chromatography on silica gel to

give 4’-chlorobiphenyl-2-amine (4a) and 4’-chlorobiphenyl-4-

amine (4a’). For analytical data, see general procedure for Table

1.

1

R_f: 0.5 (hexane / EtOAc = 4:1) [UV]. H-NMR (600 MHz, CDCl₃):

δ (ppm) = 6.69 (d, J = 8.2 Hz, 1 H), 7.07 (d, J = 2.5 Hz, 1 H), 7.11

(dd, J = 2.5 Hz, J = 8.5 Hz, 1 H), 7.36 (d, J = 8.7 Hz, 2 H), 7.41 (d,

J = 8.6 Hz, 2 H). ¹³C-NMR (91 MHz, CDCl₃): δ (ppm) = 116.9

(CH), 124.0 (C_q), 128.3 (CH), 129.1 (2 × CH), 130.0 (2 × CH),

130.6 (CH), 131.6 (C_q), 133.5 (C_q), 136.1 (C_q), 141.8 (C_q). The

analytical data obtained is in agreement with those reported in

literature.^[19]

4’,5-Difluorobiphenyl-2-amine (4d): The crude product was

purified by Kugelrohr distillation under reduced pressure at 80 °C

and flash chromatography on silica gel (hexane / EtOAc = 10 : 1)

to give the product as a dark brown oil (199 mg, 0.96 mmol, 48%).

R_f:0.4 (hexane / EtOAc = 4 : 1) [UV]. ¹H-NMR (600 MHz, CDCl₃):

δ (ppm) = 6.69 (dd, J_HF= 4.8 Hz, J = 8.7 Hz, 1 H), 6.83 (dd,

J = 3.0 Hz, J_HF= 9.2 Hz, 1 H), 6.84 - 6.89 (m, 1 H), 7.13 (t,

J = 8.7 Hz, J_HF= 8.7 Hz, 2 H), 7.40 (dd, J_HF= 5.4 Hz, J = 8.8 Hz,

2 H). ¹³C-NMR (91 MHz, CDCl₃): δ (ppm) = 115.0 (d,

J_CF= 22.3 Hz, CH), 115.8 (d, J_CF= 21.4 Hz, 2 × CH), 116.6 (d,

J_CF= 7.7 Hz, CH), 116.7 (d, J_CF= 22.5 Hz, CH), 127.7 (d,

J_CF= 7.2 Hz, C_q), 130.6 (d, J_CF= 8.0 Hz, 2 × CH), 134.4 (dd,

J_CF= 1.6 Hz, J_CF= 3.3 Hz, C_q), 139.4 (d, J_CF= 2.3 Hz, C_q), 156.3

General procedure for Table 3: A degassed solution of sodium

nitrite (10.5 mmol, 714 mg) in water (5 mL) was added dropwise

to an ice-cooled degassed solution of aniline 1a or 1b (10.0 mmol,

1.27 g) in hydrochloric acid (1.5 N, 20 mL) over a period of 15 min.

The clear solution was stirred for 15 more minutes at 0 °C. An

aliquot of this 0.4 M aryldiazonium chloride solution (max. 2.00

mmol, 5.00 mL) was added to a pre-cooled and vigorously stirred

aqueous solution of sodium hydroxide (4 N, 3 mL) under argon.

The homogeneous solution of the diazotate 2a or 2b was stirred

for five minutes in total. To the vigorously stirred aniline 3a,b or c

(20.0 mmol) at 70 °C was added dropwise the previously prepared

solution of the aryl diazotate 2a or 2b (max. 2.00 mmol, 8.00 mL)

under argon over a period of ten minutes. After the addition was

complete, the mixture was left to stir for 20 more minutes. The

resulting reaction mixture was then extracted with

dichloromethane (3 × 75 mL). The combined organic phases were

washed with saturated aqueous sodium chloride and dried over

sodium sulfate. The solvent was removed under reduced

pressure. Further purification was carried out by Kugelrohr

distillation and column chromatography on silica gel.

(d, J_CF

= 237.5 Hz, C_q), 162.3 (d, J_CF= 247.2 Hz, C_q). The

analytical data obtained is in agreement with those reported in

literature.^[19]

5-Chloro-4’-fluorobiphenyl-2-amine (4e): The crude product

was purified by Kugelrohr distillation under reduced pressure at

85 °C and flash chromatography on silica gel (hexane / EtOAc =

10 : 1) to give the product as a dark brown oil (255 mg, 1.16 mmol,

58%). R_f: 0.4 (hexane / EtOAc = 4:1) [UV]. ¹H-NMR (360 MHz,

CDCl₃): δ (ppm) = 6.69 (d, J = 8.4 Hz, 1 H), 7.07 (d, J = 2.2 Hz,

1 H), 7.08-7.16 (m, 3 H), 7.39 (dd, J_HF= 5.3 Hz, J = 8.8 Hz, 2 H).

¹³C-NMR (91 MHz, CDCl₃): δ (ppm) = 115.9 (d, J_CF= 21.4 Hz,

2 × CH), 116.7 (CH), 123.2 (CH), 127.9 (C_q), 128.3 (CH), 130.0

(d, J_CF= 0.7 Hz, C_q), 130.7 (d, J_CF= 8.1 Hz, 2 × CH), 134.2 (d,

J_CF= 3.5 Hz, C_q), 142.2 (C_q), 162.3 (d, J_CF= 247.2 Hz, C_q). The

analytical data obtained is in agreement with those reported in

literature.^[19]

4’-Chlorobiphenyl-2-amine (4a) and 4’-chlorobiphenyl-4-

amine (4a`): The crude products were purified by Kugelrohr

distillation under reduced pressure at 80 °C and flash

chromatography on silica gel (hexane / EtOAc = 10 : 1) to give

the two isomers as brown oils (4a = 195 mg, 0.96 mmol, 48%; 4a`

= 30 mg, 0.16 mmol, 8%). For analytical data, see general

procedure for Table 1.

General procedure for Scheme 2: A degassed solution of

sodium nitrite (52.5 mmol, 3.57 g) in water (25 mL) was added

dropwise to an ice-cooled degassed solution of 4-chloroaniline

(1a) (50.0 mmol, 6.38 g) in hydrochloric acid (1.5 N, 100 mL) over

a period of 15 min. The clear solution was stirred for 15 more

minutes at 0 °C. This 0.4 M aryldiazonium chloride solution (max.

50.0 mmol, 125 mL) was added to a pre-cooled and vigorously

stirred aqueous solution of sodium hydroxide (4 N, 75 mL) under

argon. The homogeneous solution of diazotate 2a was stirred for

five minutes in total. To vigorously stirred aniline (3a) (100 mmol,

9.11 mL) at 70 °C was added dropwise the previously prepared

4’-Chloro-5-fluorobiphenyl-2-amine (4b): The crude product

was purified by Kugelrohr distillation under reduced pressure at

80 °C and flash chromatography on silica gel (hexane / EtOAc =

10 : 1) to give the product as a dark brown oil (233 mg, 1.06 mmol,

1

53%). R_f: 0.4 (hexane / EtOAc = 4 : 1) [UV]. H-NMR (360 MHz,

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7.40-7.43 (m, 2 H), 7.48 (d, J = 8.8 Hz, 2 H), 7.50-7.54 (m, 2 H).

¹³C-NMR (91 MHz, CDCl₃):  (ppm) = 127.0 (2  CH), 127.6

(2  CH), 128.4 (2  CH), 128.8 (CH), 128.9 (2  CH), 133.3 (C_q),

139.7 (C_q), 140.0 (C_q). The analytical data obtained is in

agreement with those reported in literature.^[19]

solution of the aryl diazotate 2a (max. 50.0 mmol, 200 mL) under

argon over a period of ten minutes. After the addition was

complete, the mixture was left to stir for 20 more minutes. The

resulting reaction mixture was then extracted with

dichloromethane (3 × 100 mL). The combined organic phases

were washed with saturated aqueous sodium chloride and dried

over sodium sulfate. The solvent was removed under reduced

pressure. Further purification was carried out by distillation and

column chromatography on silica gel to give 4’-chlorobiphenyl-2-

amine (4a) (4.26 g, 21.0 mmol, 42%) and 4’-chlorobiphenyl-4-

amine (4a`) (1.50 g, 7.50 mmol, 15%). For analytical data, see

general procedure for Table 1.

4'-Chloro-2-methylbiphenyl (7a), 4'-chloro-3-methylbiphenyl

(7a`) and 4'-chloro-4-methylbiphenyl (7a``): The crude products

were purified by flash chromatography on silica gel (hexane

100%) to give a mixture of the three isomers: 4'-Chloro-2-

methylbiphenyl (7a): R_f: 0.6 (hexane 100%) [UV]. ¹H-NMR

(600 MHz, CDCl₃):  (ppm) = 2.28 (s, 3 H), 7.23-7.29 (m, 6 H),

7.41 (m, 2 H). 4'-Chloro-3-methylbiphenyl (7a`): R_f: 0.6

(hexane 100%) [UV]. ¹H-NMR (600 MHz, CDCl₃):  (ppm) = 2.45

(s, 3 H), 7.20 (d, J = 8.8 Hz, 2 H), 7.35-7.43 (m, 5 H), 7.53 (m,

1 H). 4'-Chloro-4-methylbiphenyl (7a``): R_f: 0.6 (hexane 100%)

[UV]. ¹H-NMR (600 MHz, CDCl₃):  (ppm) = 2.39 (s, 3 H), 7.24 (d,

J = 7.4 Hz, 2 H), 7.38 (d, J = 7.8 Hz, 2 H), 7.45 (d, J = 7.6 Hz,

2 H), 7.49 (d, J = 8.0 Hz, 2 H). The analytical data obtained is in

agreement with those reported in literature.^[43]

General procedures for Table 4:

”

a) Procedure “ptGB_106-145for biaryls 4a, 13 and 14a: To a

mixture of 4-chlorphenyldiazonium tetrafluoroborate (2.00 mmol,

452 mg) and 18-crown-6 (5 mol %, 26 mg) in 10 mL of radical

acceptor (3a, 3k or 3l) at ambient temperature was added KOAc

(4.00 mmol, 393 mg). Stirring was continued for 90 minutes. The

red coloured mixture was filtered and the filtrate washed with

saturated aqueous sodium chloride and water. The organic layer

was dried over sodium sulfate. The solvent was removed under

reduced pressure and evaporated to dryness. Depending on the

product, further purification was carried out by eventual distillation

and column chromatography on silica gel.

4'-Chloro-2,4,6-trimethylbiphenyl (8): The crude product was

purified by flash chromatography on silica gel (hexane 100%) to

give 8 as a yellow oil. R_f: 0.7 (hexane 100%) [UV]. ¹H-NMR

(360 MHz, CDCl₃):  (ppm) = 1.99 (s, 6 H), 2.32 (s, 3 H), 6.93 (s,

2 H), 7.07 (d, J = 8.6 Hz, 2 H), 7.38 (d, J = 8.6 Hz, 2 H). ¹³C-NMR

(91 MHz, CDCl₃):  (ppm) = 20.7 (2 × CH₃), 21.0 (CH₃), 128.1

(2 × CH), 128.6 (2 × CH), 130.7 (2 × CH), 132.5 (C_q), 135.9 (C_q),

136.9 (C_q), 137.7 (C_q), 139.5 (C_q). The analytical data obtained is

in agreement with those reported in literature.^[44]

b) Procedure “ptGB₁₀^”for biaryls 4a, 6-13, 14a: To a mixture of

the 4-chlorophenyldiazonium tetrafluoroborate (2.00 mmol,

452 mg), 18-crown-6 (5 mol %, 26 mg) and the radical acceptor

(3a, 3d-l) (20.0 mmol) at ambient temperature was added KOAc

(4.00 mmol, 393 mg). Stirring was continued for 90 minutes. The

red coloured mixture was filtered and the filtrate washed with

saturated aqueous sodium chloride and water. The organic layer

was dried over sodium sulfate. The solvent was removed under

reduced pressure. Depending on the product, further purification

was carried out by eventual distillation and column

chromatography on silica gel.

4'-Chloro-2-methoxybiphenyl

(9),

4'-chloro-3-methoxy-

biphenyl (9`) and 4'-chloro-4-methoxybiphenyl (9``): The crude

products were purified by flash chromatography on silica gel

(hexane 100%) to give a mixture of the three isomers: 4'-chloro-

2-methoxybiphenyl (9): R_f: 0.2 (hexane 100%) [UV]. ¹H-NMR

(360 MHz, CDCl₃):  (ppm) = 3.81 (s, 3 H), 6.98 (dd, J = 0.9 Hz,

J = 8.3 Hz, 1 H), 7.02 (dt, J = 1.1 Hz, J = 7.5 Hz, 1 H), 7.28 (dd,

J = 1.8 Hz, J = 7.6 Hz, 1 H), 7.30-7.34 (m, 1 H), 7.36 (d, J = 8.8

Hz, 2 H), 7.46 (d, J = 8.8 Hz, 2 H). 4'-Chloro-3-methoxybiphenyl

(9`): R_f: 0.2 (hexane 100%) [UV]. ¹H-NMR (360 MHz, CDCl₃):

 (ppm) = 3.86 (s, 3 H), 6.91 (ddd, J = 0.9 Hz, J = 2.4 Hz,

J = 8.2 Hz, 1 H), 7.08 (dd, J = 1.9 Hz, J = 2.4 Hz, 1 H), 7.14 (ddd,

J = 0.9 Hz, J = 1.9 Hz, J = 7.6 Hz, 1 H), 7.35 (d, J = 7.9 Hz, 1 H),

7.40 (d, J = 8.7 Hz, 2 H), 7.51 (d, J = 8.7 Hz, 2 H). 4'-Chloro-4-

methoxybiphenyl (9``): R_f: 0.2 (hexane 100%) [UV]. ¹H-NMR

(360 MHz, CDCl₃):  (ppm) = 3.85 (s, 3 H), 6.97 (d, J = 8.9 Hz,

2 H), 7.37 (d, J = 8.7 Hz, 2 H), 7.45-7.50 (m, 4 H). The analytical

data obtained is in agreement with those reported in literature.^[45]

”

c) Procedure “Diaz₁₀for biaryls 4a, 6-13, 14a: A degassed

solution of sodium nitrite (10.5 mmol, 714 mg) in water (5 mL) was

added dropwise to an ice-cooled degassed solution of 4-

chloroaniline (1a) (10.0 mmol, 1.27 g) in hydrochloric acid (1.5 N,

20 mL) over a period of 15 min. The clear solution was stirred for

15 more minutes at 0 °C. An aliquot of this 0.4 M 4-

chlorophenyldiazonium chloride solution (max. 2.00 mmol, 5.00

mL) was added to a pre-cooled and vigorously stirred aqueous

solution of sodium hydroxide (4 N, 3 mL) under argon. The

homogeneous solution of the diazotate 2a was stirred for five

minutes in total. To vigorously stirred radical acceptor (3a,d-l)

(20.0 mmol) at 70 °C was added dropwise the previously prepared

solution of the aryl diazotate 2a (max. 2.00 mmol, 8.00 mL) under

argon over a period of ten minutes. After the addition was

complete, the mixture was left to stir for 20 more minutes. The

resulting reaction mixture was then extracted with

dichloromethane (3 × 75 mL). The combined organic phases were

washed with saturated aqueous sodium chloride and dried over

sodium sulfate. The solvent was removed under reduced

pressure. Further purification was carried out by Kugelrohr

distillation and column chromatography on silica gel.

4’-Chlorobiphenyl-2-amine (4a) and 4’-chlorobiphenyl-4-

amine (4a`): The crude products were purified by Kugelrohr

distillation under reduced pressure at 80 °C and flash

chromatography on silica gel (hexane / EtOAc = 10 : 1) to give the

two isomers as brown oils. For analytical data, see general

procedure for Table 1.

2-(4'-Chlorophenyl)pyridine (10), 3-(4'-chlorophenyl)pyridine

(10`) and 4-(4'-chlorophenyl)pyridine (10``): The crude

products were purified by flash chromatography on silica gel

(hexane 100%) to give a mixture of the three isomers: 2-(4'-

chlorophenyl)pyridine (10): R_f: 0.2 (hexane 100%) [UV]. ¹H-NMR

(360 MHz, CDCl₃):  (ppm) = 7.03 (m, 1 H), 7.28 (d, J = 8.3 Hz,

2 H), 7.48-7.50 (m, 5 H), 7.81 (d, J = 8.3 Hz, 2 H). 3-(4'-

4'-Chlorobiphenyl (6): The crude product was purified by flash

chromatography on silica gel (hexane 100%) to give 6 as a dark

red oil. R_f: 0.7 (hexane / EtOAc = 19 : 1) [UV]. ¹H-NMR (360 MHz,

CDCl₃):  (ppm) = 7.32-7.35 (m, 1 H), 7.37 (d, J = 8.8 Hz, 2 H),

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chlorophenyl)pyridine (10`): R_f: 0.2 (hexane 100%) [UV]. ¹H-NMR

(360 MHz, CDCl₃):  (ppm) = 7.37-7.41 (m, 1 H), 7.45 (d,

J = 8.5 Hz, 2 H), 7.50 (d, J = 8.5 Hz, 2 H), 7.86 (dt, J = 1.7 Hz,

J = 7.8 Hz, 1 H), 8.61 (d, J = 2.7 Hz, 1 H) 8.83 (s, 1 H). 4-(4'-

chlorphenyl)pyridine (10``): R_f: 0.2 (hexane 100%) [UV]. ¹H-NMR

(360 MHz, CDCl₃):  (ppm) = 7.45-7.52 (m, 4 H), 7.58 (d,

J = 8.9 Hz, 2 H), 8.68 (bs, 2 H). The analytical data obtained is in

agreement with those reported in literature.^[46]

aqueous sodium chloride and dried over sodium sulfate. The

solvent was removed under reduced pressure. The yields of biaryl

14a and azo compound 15 were determined by H-NMR using

1,4-dimethyl terephthalate and 1,3,5-trimethoxybenzene as

internal standards. 1-Methyl-2-(4-chlorophenyl)pyrrole (14a): For

analytical data, see general procedure for Table 4.

1

General procedure for Table 6: A degassed solution of sodium

nitrite (10.5 mmol, 714 mg) in water (5 mL) was added dropwise

to an ice-cooled degassed solution of the aniline 1a-l (10.0 mmol)

in hydrochloric acid (1.5 N, 20 mL) over a period of 15 min. The

clear solution was stirred for 15 more minutes at 0 °C. An aliquot

of this 0.4 M aryldiazonium chloride solution (max. 2.00 mmol,

5.00 mL) was added to a pre-cooled and vigorously stirred

aqueous solution of lithium hydroxide (4 N, 3 mL) under argon.

The homogeneous solution of the diazotate 2a-l was stirred for

five minutes in total. To a mixture of the pyrrole derivative (20.0

mmol) and lithium hydroxide (12.0 mmol, 288 mg) in tert-butanol

(3.0 mL) at 70 °C under argon was added dropwise the previously

prepared solution of the aryl diazotate 2a-l (max. 2.00 mmol, 8.00

mL) over a period of seven minutes. After the addition was

complete, the mixture was left to stir for 23 more minutes. The

resulting reaction mixture was then extracted with

dichloromethane (3 × 75 mL). The combined organic phases were

washed with saturated aqueous sodium chloride and dried over

sodium sulfate. The solvent was removed under reduced

pressure. Depending on the product, further purification was

carried out by eventual distillation and column chromatography on

silica gel.

2-(4'-Chlorophenyl)furan (11): The crude product was purified

by flash chromatography on silica gel (hexane 100%) to give 11

as a light brown oil. R_f: 0.7 (hexane 100%) [UV]. ¹H-NMR

(360 MHz, CDCl₃):  (ppm) = 6.47 (dd, J = 1.8 Hz, J = 3.4 Hz,

1 H), 6.64 (dd, J = 0.8 Hz, J = 3.4 Hz, 1 H), 7.35 (d, J = 8.8 Hz,

2 H), 7.46 (dd, J = 0.8 Hz, J = 1.8 Hz, 1 H), 7.59 (d, J = 8.8 Hz,

2 H). ¹³C-NMR (151 MHz, CDCl₃):  (ppm) = 105.4 (CH), 111.7

(CH), 125.0 (2 × CH), 128.8 (2 × CH), 129.4 (CH), 132.9 (C_q),

142.3 (C_q), 152.9 (C_q). The analytical data obtained is in

agreement with those reported in literature.^[47]

2-(4'-Chlorophenyl)thiophene (12): The crude product was

purified by flash chromatography on silica gel (hexane 100%) to

give 12 as a yellow oil. R_f: 0.7 (hexane 100%) [UV]. ¹H-NMR

(360 MHz, CDCl₃):  (ppm) = 7.07 (dd, J = 3.8 Hz, J = 4.9 Hz,

1 H), 7.28 (m, 1 H), 7.29 (dd, J = 1.2 Hz, J = 2.9 Hz, 1 H), 7.34 (d,

J = 8.8 Hz, 2 H), 7.53 (d, J = 8.8 Hz, 2 H). The analytical data

obtained is in agreement with those reported in literature.^[43a]

2-(4'-Chlorophenyl)pyrrole (13): The crude product was purified

by flash chromatography on silica gel (hexane / EtOAc = 10 : 1)

to give 13 as a brown oil. R_f: 0.6 (hexane / EtOAc = 4 : 1) [UV].

¹H-NMR (360 MHz, CDCl₃):  (ppm= 6.30 (m, 1 H), 6.50 (ddd,

J = 1.5 Hz, J = 2.7 Hz, J = 3.6 Hz, 1 H), 6.86 (dt, J = 1.5 Hz,

J = 2.7 Hz, J = 2.7 Hz, 1 H), 7.32 (d, J = 8.9 Hz, 2 H) 7.39 (d,

J = 8.9 Hz, 2 H) 8.32 (bs, 1 H). ¹³C-NMR (91 MHz, CDCl₃):

 (ppm) = 106.4 (CH), 110.4 (CH), 119.2 (CH), 125.0 (2 × CH),

129.0 (2 × CH), 131.0 (C_q), 131.3 (C_q), 131.8 (C_q). HRMS (EI)

calcd. for C₁₀H₇ClN^-[-H⁺]: 176.0273, found: 176.0281.

1-Methyl-2-(4-chlorophenyl)pyrrole (14a): The crude product

was purified by flash chromatography on silica gel

(hexane / dichloromethane = 30 / 1) to give 14a as a dark red oil

(251 mg, 1.32 mmol, 66%). For analytical data, see general

procedure for Table 4.

1-Methyl-2-(4-fluorophenyl)pyrrole (14b): The crude product

was purified by flash chromatography on silica gel

(hexane / dichloromethane = 30 : 1) to give 14b as light brown

solid (233 mg, 1.34 mmol, 67%). R_f: 0.5 (hexane / EtOAc = 10 : 1)

[UV]. ¹H-NMR (600 MHz, CDCl₃):  (ppm) = 3.62 (s, 3 H), 6.17-

6.20 (m, 2 H), 6.73 (t, J = 4.5 Hz, 1 H), 7.11 (dd, J_HF= 8.7 Hz,

J = 8.7 Hz, 2 H), 7.38 (dd, J_HF= 5.4 Hz, J = 8.8 Hz, 2 H). ¹³C-

NMR (101 MHz, CDCl₃):  (ppm) = 34.9 (CH₃), 107.7 (CH), 108.6

(CH), 115.3 (d, J_CF= 21.3 Hz, 2 × CH), 123.5 (CH), 129.4 (d,

J_CF= 3.4 Hz, C_q), 130.3 (d, J_CF= 7.8 Hz, 2 × CH), 133.5 (C_q),

161.9 (d, J_CF= 246.4 Hz, C_q). HRMS (EI) calcd. for C₁₁H₁₁FN [H⁺]:

176.0970, found: 176.0973. The analytical data obtained is in

agreement with those reported in literature.^[48]

1-Methyl-2-(4-chlorophenyl)pyrrole (14a): The crude product

was purified by flash chromatography on silica gel

(hexane / dichloromethane = 30 / 1) to give 14a as light brown

crystals. R_f: 0.6 (hexane / EtOAc = 10 : 1) [UV]. ¹H-NMR

(600 MHz, CDCl₃):  (ppm) = 3.65 (s, 3 H), 6.18-6.23 (m, 2 H),

6.72 (m, 1 H), 7.32 (d, J = 8.6 Hz, 2 H), 7.36 (d, J = 8.6 Hz, 2 H).

¹³C-NMR (151 MHz, CDCl₃):  (ppm) = 35.0 (CH₃), 107.9 (CH),

109.0 (CH), 124.0 (CH), 128.7 (2 × CH), 129.8 (2 × CH), 131.8

(C_q), 132.7 (C_q), 133.3 (C_q). HRMS (EI) calcd. for C₁₁H₁₁ClN [H⁺]:

192.0578, found: 192.0576. The analytical data obtained is in

agreement with those reported in literature. ^[48]

1-Methyl-2-phenylpyrrole (14c): The crude product was purified

by flash chromatography on silica gel (hexane / dichloromethane

= 30 : 1) to give 14c as light brown crystals (151 mg, 0.96 mmol,

48%). R_f: 0.6 (hexane / EtOAc = 10 : 1) [UV]. ¹H-NMR (600 MHz,

CDCl₃):  (ppm) = 3.03 (s, 3 H), 6.18 (dd, J = 2.7 Hz, J = 3.6 Hz,

1 H), 6.24 (dd, J = 1.8 Hz, J = 3.6 Hz, 1 H), 6.73 (t, J = 4.5 Hz,

1 H), 7.26-7.32 (m, 1 H), 7.36-7.42 (m, 4 H). ¹³C-NMR (151 MHz,

CDCl₃):  (ppm) = 35.0 (CH₃), 107.7 (CH), 108.6 (CH), 123.6 (CH),

126.7 (CH), 128.3 (2 × CH), 128.6 (2 × CH), 133.3 (C_q), 134.6

(C_q). HRMS (EI) calcd. for C₁₁H₁₂N [H⁺]: 158.0964, found:

158.0965. The analytical data obtained is in agreement with those

reported in literature.^[48]

General procedure for Table 5: A degassed solution of sodium

nitrite (10.5 mmol, 714 mg) in water (5 mL) was added dropwise

to an ice-cooled degassed solution of 4-chloroaniline (1a) (10.0

mmol, 1.27 mg) in hydrochloric acid (1.5 N, 20 mL) over a period

of 15 min. The clear solution was stirred for 15 more minutes at

0 °C. An aliquot of this 0.4 M aryldiazonium chloride solution (max.

2.00 mmol, 5.00 mL) was added to a pre-cooled and vigorously

stirred aqueous solution of sodium hydroxide (4 N, 3 mL) under

argon. The homogeneous solution of the diazotate 2a was stirred

for five minutes in total. For the conditions used in the radical

arylation of 1-methylpyrrole (3l), see Table 5. The resulting

reaction mixture was extracted with dichloromethane (3 × 75 mL).

The combined organic phases were washed with saturated

1-Methyl-2-(3-fluorophenyl)pyrrole (14d): The crude product

was purified by flash chromatography on silica gel

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(hexane / dichloromethane = 30 : 1) to give 14d as a dark red oil

(200 mg, 1.16 mmol, 58%). R_f: 0.5 (hexane / EtOAc = 10:1) [UV].

¹H-NMR (600 MHz, CDCl₃):  (ppm) = 3.67 (s, 3 H), 6.19 (dd,

J = 3.6 Hz, 1 H), 6.75 (dd, J = 1.9 Hz, J = 2.5 Hz, 1 H), 7.16 (d,

J = 8.5 Hz, 2 H), 7.73 (d, J = 8.5 Hz, 2 H). ¹³C-NMR (101 MHz,

CDCl₃):  (ppm) = 35.1 (CH₃), 92.1 (C_q), 108.0 (CH), 109.0 (CH),

J = 2.7 Hz, J = 3.6 Hz, 1 H), 6.25 (dd, J = 1.8 Hz, J = 3.6 Hz, 1 H), 124.2 (CH), 130.2 (2 × CH), 132.8 (C_q), 133.4 (C_q), 137.4

6.72 (dd, J = 1.8 Hz, J = 2.7 Hz, 1 H), 6.98 (dt, J_HF= 3.1 Hz,

J = 8.7 Hz, 1 H), 7.09 (ddd, J_HF= 0.8 Hz, J = 3.1 Hz, J = 10.1 Hz,

1 H), 7.16 (ddd, J_HF= 1.0 Hz, J = 1.6 Hz, J = 7.7 Hz, 1 H), 7.33

(dt, J_HF= 6.3 Hz, J = 8.0 Hz, J = 8.2 Hz, 1 H). ¹³C-NMR (101 MHz,

CDCl₃):  (ppm) = 35.1 (CH₃), 107.9 (CH), 109.3 (CH), 113.4 (d,

J_CF= 21.2 Hz, CH), 115.2 (d, J_CF= 21.7 Hz, CH), 124.1 (d,

J_CF= 3.0 Hz, CH), 124.2 (CH), 129.8 (d, J_CF= 8.8 Hz, CH), 133.3

(C_q), 135.4 (d, J_CF= 8.7 Hz, C_q), 162,7 (d, J_CF= 245.6 Hz, C_q).

¹⁹F-NMR (235 MHz, CDCl₃): (ppm) = −113.6. HRMS (EI) calcd.

for C₁₁H₁₁FN: 176.0870, found: 176.0877. The analytical data

obtained is in agreement with those reported in literature.^[48]

(2 × CH). The analytical data obtained is in agreement with those

reported in literature.^[49]

1-Methyl-2-(4-methoxyphenyl)pyrrole (14i): The crude product

was purified by flash chromatography on silica gel

(hexane / dichloromethane = 30 : 1) to give 14i as dark brown

crystals (142 mg, 0.68 mmol, 34%). R_f: 0.7 (hexane / EtOAc =

10 : 1) [UV]. ¹H-NMR (600 MHz, CDCl₃):  (ppm) = 3.62 (s, 3 H),

3.83 (s, 3 H), 6.12-6.20 (m, 2 H), 6.68 (m, 1 H), 6.93 (d, J = 8.8 Hz,

2 H) 7.31 (d, J = 8.8 Hz, 2 H). ¹³C-NMR (101 MHz, CDCl₃):

 (ppm) = 34.8 (CH₃), 55.3 (CH₃), 107.5 (CH), 108.0 (CH), 113.8

(2 × CH), 122.9 (CH), 125.9 (C_q), 130.0 (2 × CH), 134.3 (C_q),

158.6 (C_q). HRMS (EI) calcd. for C₁₂H₁₄NO [H⁺]: 188.1070, found:

188.1070. The analytical data obtained is in agreement with those

reported in literature.^[48]

1-Methyl-2-(2-fluorophenyl)pyrrole (14e): The crude product

was purified by flash chromatography on silica gel

(hexane / dichloromethane = 30 : 1) to give 14e as a dark red oil

(81 mg, 0.56 mmol, 23%). R_f: 0.5 (hexane / EtOAc = 10 : 1) [UV].

¹H-NMR (600 MHz, CDCl₃):  (ppm) = 3.56 (s, 3 H), 6.20-6.24 (m,

2 H), 6.25 (dd, J = 1.8 Hz, J = 3.6 Hz, 2 H), 6.75 (t, J = 2.2 Hz,

2 H), 7.08-7.7.15 (m, 1 H), 7.17 (dd, J_HF= 0.6 Hz, J = 2.8 Hz, 1 H),

7.28-7.37 (m, 2 H). ¹³C-NMR (101 MHz, CDCl₃):  (ppm) = 34.6

(CH₃), 107.9 (CH), 110.0 (CH), 115.7 (d, J_CF= 22.2 Hz, CH),

115.7 (d, J_CF= 22.2 Hz, C_q), 124.0 (d, J_CF= 3.6 Hz, CH), 124.1 (d,

J_CF= 3.3 Hz, CH), 128.2 (C_q), 129.2 (d, J_CF= 7.8 Hz, CH), 132.5

(d, J_CF= 7.8 Hz, CH), 159.9 (d, J_CF= 246.7 Hz, C_q). HRMS (EI)

calcd. for C₁₁H₁₁FN [H⁺]: 176.0870, found: 176.0870. The

analytical data obtained is in agreement with those reported in

literature.^[48]

1-Methyl-2-(3-methoxyphenyl)pyrrole (14j): The crude product

was purified by flash chromatography on silica gel

(hexane / dichloromethane = 30 : 1) to give 14j as a brown oil

(158 mg, 0.84 mmol, 42%). R_f: 0.7 (hexane / EtOAc = 10 : 1) [UV].

¹H-NMR (600 MHz, CDCl₃):  (ppm) = 3.66 (s, 3 H), 3.83 (s, 3 H),

6.19 (d, J = 3.4 Hz, 1 H), 6.22 (d, J = 3.6 Hz, 1 H), 6.70 (t,

J = 4.5 Hz, 1 H), 6.84 (ddd, J = 1.0 Hz, J = 2.6 Hz, J = 8.3 Hz,

1 H), 6.94 (dd, J = 1.5 Hz, J = 2.5 Hz, 1 H), 6.98 (ddd, J = 1.0 Hz,

J = 1.6 Hz, J = 7.6 Hz, 1 H) 7.30 (m, 1 H). ¹³C-NMR (101 MHz,

CDCl₃):  (ppm) = 35.0 (CH₃), 55.2 (CH₃), 107.7 (CH), 108.7 (CH),

112.2 (CH), 114.3 (CH), 121.1 (CH), 123.7 (CH), 128.4 (CH),

134.4 (C_q), 134.7 (C_q), 159.5 (C_q). HRMS (EI) calcd. for C₁₂H₁₄NO

[H⁺]: 188.1067, found: 188.1070.

1-Methyl-2-(3-chlorophenyl)pyrrole (14f): The crude product

was purified by flash chromatography on silica gel

(hexane / dichloromethane = 30 : 1) to give 14f as a dark red oil

(202 mg, 1.08 mmol, 54%). R_f: 0.5 (hexane / EtOAc = 10 : 1) [UV].

¹H-NMR (600 MHz, CDCl₃):  (ppm) = 3.69 (s, 3 H), 6.23 (dd,

J = 2.7 Hz, J = 3.6 Hz, 1 H), 6.27 (dd, J = 1.8 Hz, J = 3.6 Hz, 1 H),

6.75 (t, J = 4.5 Hz, 1 H), 7.26 (m, 3 H), 7.421 (t, J = 1.8 Hz, 1 H).

¹³C-NMR (101 MHz, CDCl₃):  (ppm) = 35.1 (CH₃), 108.0 (CH),

109.3 (CH), 124.3 (CH), 126.6 (CH), 126.7 (CH), 128.4 (CH),

129.6 (CH), 133.1 (C_q), 134.2 (C_q), 135.1 (C_q). HRMS (EI) calcd.

for C₁₁H₁₁ClN [H⁺]: 192.0574, found: 192.0579.

1-Methyl-2-(4-trifluoromethylphenyl)pyrrole (14k): The crude

product was purified by flash chromatography on silica gel

(hexane / dichloromethane = 30 : 1) to give 14k as a brown solid

(130 mg, 0.58 mmol, 29%). R_f: 0.4 (hexane / EtOAc = 10:1) [UV].

¹H-NMR (600 MHz, CDCl₃):  (ppm) = 3.72 (s, 3 H), 6.24 (dd,

J = 2.7 Hz, J = 3.6 Hz, 1 H), 6.33 (dd, J = 1.7 Hz, J = 3.6 Hz, 1 H),

6.78 (t, J = 4.4 Hz, 1 H), 7.53 (d, J = 8.0 Hz, 2 H), 7.66 (d,

J = 8.2 Hz, 2 H). ¹³C-NMR (151 MHz, CDCl₃):  (ppm) = 35.2

(CH₃), 108.2 (CH), 109.9 (CH), 124.3 (q, J_CF= 273.3 Hz, C_q),

124.9 (2 × CH), 125.4 (q, J_CF= 273.3 Hz, 2 × CH), 128.3 (2 × CH),

128.3 (q, J_CF= 65.2 Hz, C_q), 133.1 (C_q), 136.8 (C_q). ¹⁹F-NMR

(235 MHz, CFCl₃): (ppm) = −62.9. HRMS (EI) calcd. for

C₁₂H₁₁F₃N [H⁺]: 226.0838, found: 226.0840. The analytical data

obtained is in agreement with those reported in literature.^[48]

1-Methyl-2-(4-bromophenyl)pyrrole (14g): The crude product

was purified by flash chromatography on silica gel

(hexane / dichloromethane = 30 : 1) to give 14g as orange

crystals (288 mg, 1.22 mmol, 61%). R_f: 0.5 (hexane / EtOAc =

10 : 1) [UV]. ¹H-NMR (600 MHz, CDCl₃):  (ppm) = 3.64 (s, 3 H),

6.19 (dd, J = 2.7 Hz, J = 3.6 Hz, 1 H), 6.22 (dd, J = 1.8 Hz,

J = 3.6 Hz, 1 H), 6.72 (dd, J = 1.9 Hz, J = 2.5 Hz, 1 H), 7.26 (d,

J = 8.6 Hz, 2 H), 7.51 (d, J = 8.6 Hz, 2 H). ¹³C-NMR (101 MHz,

CDCl₃):  (ppm) = 35.0 (CH₃), 107.9 (CH), 109.0 (CH), 120.7 (C_q),

124.1 (CH), 130.0 (2 × CH), 131.5 (2 × CH), 132.2 (C_q), 133.3

(C_q). HRMS (EI) calcd. for C₁₁H₁₁BrN [H⁺]: 236.0069, found:

236.0063. The analytical data obtained is in agreement with those

reported in literature.^[48]

1-Methyl-2-(4-methylphenyl)pyrrole (14l): The crude product

was purified by flash chromatography on silica gel

(hexane / dichloromethane = 30 : 1) to give 14l as dark red

crystals (172 mg, 1.00 mmol, 50%). R_f: 0.7 (hexane / EtOAc =

10 : 1) [UV]. ¹H-NMR (600 MHz, CDCl₃):  (ppm) = 2.38 (s, 3 H),

3.64 (s, 3 H), 6.18 (d, J = 2.2 Hz, 2 H), 6.69 (t, J = 2.25 Hz, 1 H),

7.20 (d, J = 8.6 Hz, 2 H), 7.29 (d, J = 8.6 Hz, 2 H). ¹³C-NMR

(151 MHz, CDCl₃):  (ppm) = 21.1 (CH₃), 35.0 (CH₃), 107.6 (CH),

108.3 (CH), 123.3 (CH), 128.3 (2 × CH), 129.0 (2 × CH), 130.5

(C_q), 134.6 (C_q), 136.5 (C_q). HRMS (EI) calcd. for C₁₂H₁₄N [H⁺]:

172.1121, found: 172.1121. The analytical data obtained is in

agreement with those reported in literature.^[48]

1-Methyl-2-(4-iodophenyl)pyrrole (14h): The crude product was

puriThe crude product was purified by flash chromatography on

silica gel (hexane / dichloromethane = 30 : 1) to give 14h as a

brownish solid (318 mg, 1.12 mmol, 56%). R_f: 0.5

(hexane / EtOAc = 10 : 1) [UV]. ¹H-NMR (600 MHz, CDCl₃):

 (ppm) = 3.67 (s, 3 H), 6.21 (m, 1 H), 6.25 (dd, J = 1.5 Hz,

1-Methyl-2,5-bis(4-fluorophenyl)pyrrole (14m): Due to the

required amount of the heteroaryl substrate the reaction scale

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was reduced to 0.5 mmol of 4c. The crude product was purified

by flash chromatography on silica gel (hexane / dichloromethane

= 30 : 1) to give 14m as red crystals (113 mg,0.42 mmol, 84%).

R_f: 0.8 (hexane / EtOAc = 10 : 1) [UV]. ¹H-NMR (600 MHz,

CDCl₃):  (ppm) = 3.54 (s, 3 H), 6.26 (s, 2 H), 7.11 (t, J_HF= 8.7 Hz,

J = 8.7 Hz, 4 H), 7.41 (dd, J_HF= 5.4 Hz, J = 8.8 Hz, 4 H). ¹³C-

NMR (151 MHz, CDCl₃):  (ppm) = 33.9 (CH₃), 108.6 (2 × CH),

125.7 (d, J_CF= 21.4 Hz, 4 × CH), 129.5 (d, J_CF= 3.2 Hz, 2 × C_q),

130.4 (d, J_CF= 7.9 Hz, 4 × CH), 135.6 (2 × C_q), 140.2 (d,

J_CF= 246.7 Hz, 2 × C_q). HRMS (EI) calcd. for C₁₇H₁₄F₂N [H⁺]:

270.1088, found: 270.1082.

129.1 (2 × CH), 129.1 (d, J_CF= 3.4 Hz, C_q), 129.9 (d, J_CF= 7.9 Hz,

2 × CH), 132.8 (C_q), 140.3 (C_q), 161.5 (d, J_CF= 245.9 Hz, C_q).

HRMS (EI) calcd. for C₁₇H₁₅FN [H⁺]: 238.1027, found: 238.1024.

The analytical data obtained is in agreement with those reported

in literature.^[50]

1-Phenyl-2-(4-chlorophenyl)pyrrole (14r): The excess of 1-

phenylpyrrole (3m) was removed by Kugelrohr distillation in

vacuo at 85 °C. The crude product was purified by flash

chromatography on silica gel (hexane / dichloromethane = 30 : 1)

to give 14r as light brown crytals (240 mg, 0.94 mmol, 47%). R_f:

0.5 (hexane / EtOAc = 10 : 1) [UV]. ¹H-NMR (600 MHz, CDCl₃):

 (ppm) = 6.35 (dd, J = 2.9 Hz, J = 3.5 Hz,1 H), 6.43 (dd,

J = 1.8 Hz, J = 3.6 Hz, 1 H), 6.94 (dd, J = 1.8 Hz, J = 2.9 Hz, 1 H),

7.04 (d, J = 8.7 Hz, 2 H), 7.12-7.18 (m, 4 H), 7.28 (t, J = 7.4 Hz,

1 H), 7.33 (dt, J = 3.2 Hz, J = 7.4 Hz, 2 H). ¹³C-NMR (151 MHz,

CDCl₃):  (ppm) = 109.3 (CH), 109.9 (CH), 124.7 (CH), 125.7

(2 × CH), 126.8 (CH), 128.2 (2 × CH), 129.1 (2 × CH), 129.3

(2 × CH), 131.4 (C_q), 132.1 (C_q), 132.5 (C_q), 140.2 (C_q). HRMS

(EI) calcd. for C₁₆H₁₃ClN [H⁺]: 254.0731, found: 254.0734. The

analytical data obtained is in agreement with those reported in

literature.^[50]

1-Methyl-2,5-bis(4-chlorophenyl)pyrrole (14n): Due to the

required amount of the heteroaryl substrate the reaction scale

was reduced to 0.5 mmol of 4a. The crude product was purified

by flash chromatography on silica gel (hexane / dichloromethane

= 30 : 1) to give 14n as red crystals (127 mg, 0.42 mmol, 84%).

R_f: 0.8 (hexane / EtOAc = 10 : 1) [UV]. ¹H-NMR (600 MHz,

CDCl₃):  (ppm) = 3.57 (s, 3 H), 6.30 (s, 2 H), 7.39 (s, 8 H). ¹³C-

NMR (151 MHz, CDCl₃):  (ppm) = 34.2 (CH₃), 109.1 (2 × CH),

128.7 (4 × CH), 129.8 (4 × CH), 131.7 (2 × C_q), 132.9 (2 × C_q),

136.0 (2 × C_q). HRMS (EI) calcd. for C₁₇H₁₄Cl₂N: 303.0397, found:

303.0392.

1-Phenyl-2-(4-bromophenyl)pyrrole (14s): The excess of 1-

phenylpyrrole (3m) was removed by Kugelrohr distillation in

vacuo at 85 °C. The crude product was purified by flash

chromatography on silica gel (hexane / dichloromethane = 30 : 1)

to give 14s as light brown crytals (193 mg, 0.82 mmol, 41%). R_f:

0.5 (hexane / EtOAc = 10 : 1) [UV]. ¹H-NMR (600 MHz, CDCl₃):

 (ppm) = 6.35 (dd, J = 2.8 Hz, J = 3.5 Hz, 1 H), 6.43 (dd,

J = 1.7 Hz, J = 3.6 Hz, 1 H), 6.94 (dd, J = 1.7 Hz, J = 2.8 Hz, 1 H),

6.98 (d, J = 8.7 Hz, 2 H), 7.13-7.18 (m, 2 H), 7.28 (t, J = 7.4 Hz,

1 H), 7.30-7.36 (m, 4 H). ¹³C-NMR (151 MHz, CDCl₃):

 (ppm) = 109.4 (CH), 111.0 (CH), 120.2 (C_q), 124.8 (CH), 125.7

(2 × CH), 126.8 (CH), 129.1 (2 × CH), 129.6 (2 × CH), 131.2

(2 × CH), 131.9 (C_q), 132.5 (C_q), 140.2 (C_q). HRMS (EI) calcd. for

C₁₆H₁₃BrN [H⁺]: 298.0226, found: 298.0229.

1-Methyl-2,5-bis(4-bromophenyl)pyrrole (14o): Due to the

required amount of the heteroaryl substrate the reaction scale

was reduced to 0.5 mmol of 4g. The crude product was purified

by flash chromatography on silica gel (hexane / dichloromethane

= 30 : 1) to give 14o as red crystals (156 mg, 0.40 mmol, 80%).

R_f: 0.7 (hexane / EtOAc = 10 : 1) [UV]. ¹H-NMR (600 MHz,

CDCl₃):  (ppm) = 3.57 (s, 3 H), 6.30 (s, 2 H), 7.32 (d, J = 8.6 Hz,

4 H), 7.55 (d, J = 8.6 Hz, 4 H). ¹³C-NMR (151 MHz, CDCl₃):

 (ppm) = 34.2 (CH₃), 109.2 (2 × CH), 121.0 (2 × C_q), 130.1

(4 × CH), 131.6 (4 × CH), 132.1 (2 × C_q), 136.1 (2 × C_q). HRMS

(EI) calcd. for C₁₇H₁₄Br₂N [H⁺]: 389.9445, found: 389.9442. The

analytical data obtained is in agreement with those reported in

literature.^[49]

1-Methyl-2-(4-bromophenyl)-5-(4-chlorophenyl)pyrrole (14p):

Due to the required amount of the heteroaryl substrate the

reaction scale was reduced to 0.5 mmol of 4g. The crude product

was purified by flash chromatography on silica gel

(hexane / dichloromethane = 30 : 1) to give 14p as red crystals

1-tert-Butoxycarbonyl-2-(4-chlorophenyl)pyrrole (14t): The

excess of 1-tert-butoxycarbonylpyrrole (3n) was removed by

Kugelrohr distillation under reduced pressure at 80 °C. The crude

product was purified by flash chromatography on silica gel

(hexane / dichloromethane = 30 : 1) to give 14t as a dark red oil

(142 mg, 0.41 mmol, 82%). R_f: 0.7 (hexane / EtOAc = 10 : 1) [UV]. (171 mg,0.61 mmol, 31%). R_f:0.7 (hexane / EtOAc = 10 : 1) [UV].

¹H-NMR (600 MHz, CDCl₃):  (ppm) = 3.57 (s, 3 H), 6.29-6.31 (m,

2 H), 7.32 (d, J = 8.0 Hz, 2 H), 7.36-4.41 (m, 4 H), 7.54 (d,

J = 8.4 Hz, 2 H). ¹³C-NMR (151 MHz, CDCl₃):  (ppm) = 34.2

(CH₃), 109.1 (CH), 109.2 (CH), 120.9 (C_q), 121.0 (C_q), 128.7

(2 × CH), 129.8 (2 × CH), 130.1 (2 × CH), 131.6 (2 × CH), 131.7

(C_q), 132.2 (C_q), 132.9 (C_q), 136.1 (C_q). HRMS (EI) calcd. for

C₁₇H₁₄BrClN [H⁺]: 345.9993, found: 345.9984.

¹H-NMR (600 MHz, CDCl₃):  (ppm) = 1.41 (s, 9 H), 6.20 (dd,

J = 1.8 Hz, J = 3.2 Hz, 1 H), 6.23 (t J = 3.3 Hz, 1 H), 7.29 (d,

J = 8.7 Hz, 2 H), 7.33 (d, J = 8.7 Hz, 2 H), 7.33 (dd, J = 1.8 Hz,

J = 2.8 Hz, 1 H). ¹³C-NMR (101 MHz, CDCl₃):  (ppm) = 27.6

(3 × CH₃), 83.8 (C_q), 110.6 (CH), 114.7 (CH), 122.8 (CH), 127.7

(2 × CH), 130.4 (2 × CH), 132.8 (C_q), 133.1 (C_q), 133.7 (C_q), 149.1

(C_q). HRMS (EI) calcd. for C₁₅H₁₆ClNNaO₂[M+H⁺]: 300.0762,

found: 300.0760. The analytical data obtained is in agreement

with those reported in literature. ^[11b]

1-Phenyl-2-(4-fluorophenyl)pyrrole (14q): The excess of 1-

phenylpyrrole (3m) was removed by Kugelrohr distillation in

vacuo at 85 °C. The crude product was purified by flash

chromatography on silica gel (hexane / dichloromethane = 30 : 1)

to give 14q as light brown crytals (240 mg, 1.02 mmol, 51%). R_f:

1-Benzyl-2-(4-chlorophenyl)pyrrole (14u): The excess of 1-

benzylpyrrole (3o) was removed by Kugelrohr distillation in vacuo

at 80 °C. The crude product was purified by flash chromatography

on silica gel (hexane / dichloromethane = 30 : 1) to give 14u as

an orange oil (201 mg, 0.76 mmol, 38%). R_f: 0.5 (hexane / EtOAc

= 10 : 1) [UV].¹H-NMR (600 MHz, CDCl₃):  (ppm) = 5.14 (s, 2 H),

6.27-6.31 (m, 2 H), 6.79 (t, J = 4.5 Hz, 1 H), 7.01 (d, J = 7.4 Hz,

2 H), 7.22-7.36 (m, 7 H). ¹³C-NMR (151 MHz, CDCl₃):

 (ppm) = 50.7 (CH₂), 108.6 (CH), 109.3 (CH), 123.4 (CH), 126.3

(2 × CH), 127.8 (CH), 128.5 (2 × CH), 128.7 (2 × CH), 130.0

1

0.5 (Hexan / EtOAc = 10 : 1) [UV]. H-NMR (600 MHz, CDCl₃):

 (ppm) = 6.35 (dd, J = 2.8 Hz, J = 3.6 Hz,1 H), 6.39 (dd,

J = 1.8 Hz, J = 3.6 Hz, 1 H), 6.89 (t, J = 8.8 Hz, J_HF= 8.8 Hz, 2 H)

6.93 (dd, J = 1.8 Hz, J = 2.8 Hz, 1 H), 7.08 (dd, J_HF= 5.4 Hz,

J = 9.0 Hz, 2 H), 7.12-7.17 (m, 2 H), 7.25-7.35 (m, 3 H). ¹³C-NMR

(151 MHz, CDCl₃):  (ppm) = 109.2 (CH), 110.5 (CH), 114.9 (CH),

124.2 (CH), 125.7 (2 × CH), 126.7 (d, J_CF= 5.7 Hz, 2 × CH),

10.1002/chem.201701429

Chemistry - A European Journal

FULL PAPER

(2 × CH), 131.7 (C_q), 132.9 (C_q), 133.6 (C_q), 138.5 (C_q). HRMS

(EI) calcd. for C₁₇H₁₅ClN [H⁺]: 268.0889, found: 268.0888.

Keywords: Radical reaction • Arylation • Aniline • Pyrrole •

Homolytic aromatic substitution

General procedure for Figure 1: A degassed solution of sodium

nitrite (21.0 mmol, 1.43 g) in water (10 mL) was added dropwise

to an ice-cooled degassed solution of the 4-chloroaniline (1a)

(20.0 mmol, 2.54 mg) in hydrochloric acid (1.5 N, 40 mL) over a

period of 15 min. The clear solution was stirred for 15 more

minutes at 0 °C. An aliquot of this 0.4 M aryldiazonium chloride

solution (max. 2.00 mmol, 5.00 mL) was added to a pre-cooled

and vigorously stirred aqueous solution of lithium hydroxide (4 N,

3 mL) under argon. To a mixture of 1-methylpyrrole (3l) (20.0

mmol) and lithium hydroxide (1-10 × 12.0 mmol, 288 mg) in tert-

butanol (1-10 × 3.0 mL) at 70 °C under argon was added

dropwise the previously prepared solution of the aryl diazotate

(stepwise 1-10 × 2.00 mmol, 8.00 mL) over a period of seven

minutes. After the addition was complete, the mixture was left to

stir for 23 more minutes. The resulting reaction mixture was then

extracted with dichloromethane (3 × 75 mL). The combined

organic phases were washed with saturated aqueous sodium

chloride and dried over sodium sulfate. The solvent was removed

under reduced pressure. The yields of biaryls 14a and azo

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1

compound 14n were determined by H NMR using 1,4-dimethyl

terephthalate and 1,3,5-trimethoxybenzene as internal standards.

1-Methyl-2-(4-chlorophenyl)pyrrole (14a): For analytical data, see

general

procedure

for

Table

4.

1-Methyl-2,5-bis(4-

chlorophenyl)pyrrole (14n): For analytical data, see general

procedure for Table 6.

[5]

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General procedure for Scheme 3: A degassed solution of

sodium nitrite (21.0 mmol, 1.43 g) in water (10 mL) was added

dropwise to an ice-cooled degassed solution of the aniline 1a,b or

g (20.0 mmol) in hydrochloric acid (1.5 N, 40 mL) over a period of

15 min. The clear solution was stirred for 15 more minutes at 0 °C.

An aliquot of this 0.4 M aryldiazonium chloride solution (17-

20 mmol) was added to a pre-cooled and vigorously stirred

aqueous solution of lithium hydroxide (4 N) under argon to give

the aryldiazotate 2a,b or g. To a mixture of 1-methylpyrrole (10.0

equiv. per diazotate) and lithium hydroxide (6.0 equiv.) in tert-

butanol at 70 °C under argon was added dropwise the previously

prepared solution of the aryl diazotate over a period of seven

minutes. After the addition was complete, the mixture was left to

stir for 23 more minutes. The resulting reaction mixture was then

extracted with dichloromethane (3 × 75 mL). The combined

organic phases were washed with saturated aqueous sodium

chloride and dried over sodium sulfate. The solvent was removed

under reduced pressure and the crude product was purified by

column chromatography on silica gel. 1-Methyl-2-(4-

chlorophenyl)pyrrole (14a): For analytical data, see general

procedure for Table 4. 1-Methyl-2-(4-fluorophenyl)pyrrole (14b)

and 1-methyl-2-(4-bromophenyl)pyrrole (14g): For analytical data,

see general procedure for Table 6.

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Acknowledgements

The authors are grateful for financial support by the Deutsche

Forschungsgemeinschaft (DFG, GRK1910/A6 and B3) and the

Graduate School Molecular Science (GSMS) (J.H.). We would

also like to thank Oliver Fischer for experimental assistance within

this research project.

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10.1002/chem.201701429

Chemistry - A European Journal

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10.1002/chem.201701429

Chemistry - A European Journal

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J. Hofmann, E. Gans, T. Clark, M. R.

Heinrich*

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Radical arylation of anilines and

pyrroles via aryldiazotates

Based on an improved preparation of aryldiazotates, the arylation of anilines and 1-

substituted pyrroles could be achieved under transition metal- and catalyst-free

conditions. Combining manifold experimental and computational results, this study

gives insights into the particular features of the underlying reaction mechanism.

Article Doi

Radical Arylation of Anilines and Pyrroles via Aryldiazotates

DOI: 10.1002/chem.201701429

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Article abstract of DOI:10.1002/chem.201701429

Full text of DOI:10.1002/chem.201701429

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