Synthesis of highly functionalized triarylbismuthines by functional group manipulation and use in palladium- and copper-catalyzed arylation reactions

Article

pubs.acs.org/joc

Synthesis of Highly Functionalized Triarylbismuthines by Functional

Group Manipulation and Use in Palladium- and Copper-Catalyzed

Arylation Reactions

Martin Hebert,^†Pauline Petiot,^†Emeline Benoit,^†Julien Dansereau,^†Tabinda Ahmad,^†Adrien Le Roch,^†

́

Xavier Ottenwaelder,^‡and Alexandre Gagnon*^,†

^†Universite

3P8

́

du Queb

́

ec a

̀

Montrea

́

l, Dep

́

artement de Chimie, C.P. 8888, Succursale Centre-Ville, Montrea

́

l, Queb

́

ec, Canada, H3C

ec, Canada, H4B

^‡Concordia University, Department of Chemistry and Biochemistry, 7141 Sherbrooke Street West, Montrea

́

l, Queb

́

1R6

S

* Supporting Information

ABSTRACT: Organobismuthines are an attractive class of organometallic reagents that can be accessed from inexpensive and

nontoxic bismuth salts. Triarylbismuthines are particularly interesting due to their air and moisture stability and high functional

group tolerance. We report herein a detailed study on the preparation of highly functionalized triarylbismuth reagents by triple

functional group manipulation and their use in palladium- and copper-catalyzed C-, N-, and O-arylation reactions.

Rao greatly contributed to expanding the use of this class of

reagents in organic synthesis and more speciﬁcally in palladium-

catalyzed reactions.⁹

INTRODUCTION

■

Triarylbismuthines (also known as triarylbismuthanes) are a

class of organometallic reagents that can be prepared from

inexpensive and nontoxic bismuth salts.^1,2These reagents are

particularly attractive since they are air and moisture stable and

can be puriﬁed by simple ﬂash chromatography or crystal-

lization. Moreover, organobismuth reagents are remarkably

tolerant to numerous functional groups, making them highly

suitable for methodology development.³They have also found

applications in total synthesis,⁴in the preparation of transition

metal complexes,⁵as catalysts for polymerization reactions,⁶

and in medicinal chemistry.⁷Organobismuth reagents are

divided into two main classes: trivalent and pentavalent

organobismuthines, with bismuth in the +3 and +5 oxidation

levels, respectively. Both classes have found applications in

synthesis. For example, Barton and Finet reported in the 1980s

a series of arylation reactions using triphenylbismuth and

triphenylbismuth diacetate as arylating agents.⁸More recently,

Our group has reported in recent years a portfolio of

methods for the formation of C−C,¹⁰C−N,¹¹and C−O¹²

bonds using functionalized trivalent organobismuth reagents.

These methods allow the transfer of functionalized aryl groups

on scaﬀolds as diverse as pyridines 2, pyrimidines 4, pyrazines

6, pyridazines 8, indazoles and pyrazoles 10, indoles and

pyrroles 12, phenols 14, pyridones 16, and 1,2-aminoalcohols

18, providing access to a range of medicinally relevant

compounds (Scheme 1). These methodologies operate under

mild conditions and tolerate a wide variety of functional groups

on both coupling partners.

Received: April 7, 2016

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Scheme 1. Triarylbismuthines 1 in Arylation Reactions: Access to Highly Functionalized and Medicinally Relevant Compounds

Scheme 2. Synthesis of Highly Functionalized Organobismuthines 21 by Functional Group Manipulation Directly on

Organometallic Species 1 (FG = Functional Group)

Triarylbismuth reagents 1 can be easily accessed via addition

of Grignard reagents 20 onto bismuth chloride (Scheme 2).

However, due to the high reactivity of organomagnesium

reagents, organobismuthines bearing electrophilic or acidic

functional groups cannot be synthesized directly using this

approach. Condon reported an elegant and powerful method to

prepare functionalized organobismuth reagents by the addition

of organozinc reagents obtained from a cobalt−zinc metal−

halogen exchange reaction on aryl halides.¹³While this method

is quite general, groups bearing acidic protons such as alcohols

cannot be introduced using this methodology. Therefore,

alternative methods are still desirable to access highly

functionalized organobismuthines. The strategy that we ex-

plored consists of introducing the incompatible functional

group by performing a functional group transformation directly

on the organobismuth species. In the course of our studies, we

found that the C−Bi bond in organobismuthines is remarkably

resistant to acidic, reductive, and even oxidative conditions,

thus enabling the transformation of the functional group FG in

1 into a more elaborated functional group FG′ in 21 (Scheme

2). This reaction actually corresponds to a triple group

manipulation on a single substrate. To be eﬃcient, it therefore

requires a high level of control of the reaction conditions since,

to a ﬁrst approximation, the overall yield is given by the cube of

the yield-per-function. We report herein an extensive study on

the successful preparation of highly functionalized triarylbis-

muth reagents using this approach and their use in palladium-

and copper-catalyzed arylation reactions.

RESULTS AND DISCUSSION

■

a. Preparation of Triarylbismuthines. We began by

synthesizing a set of substituted and unsubstituted organo-

bismuthines 1a−r bearing simple functional groups by adding

organomagnesium reagents 20 to bismuth chloride (Scheme 3).

The Grignard reagents 20 were prepared by reacting the

corresponding aryl halides 22 with metallic magnesium at reﬂux

of ether or THF. Using this approach, 18 diﬀerent

B

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Scheme 3. Direct Preparation of Organobismuthines 1a−r by Addition of Organomagnesium Reagents 20 to Bismuth Chloride

unsubstituted and ortho, meta, and para substituted triaryl- and

triheteroarylbismuthines were synthesized in 53% to 99%

yields.

For the introduction of nitriles and esters, the required

organomagnesium reagents were generated using Knochel’s

procedure.¹⁴Thus, addition of the isopropylmagnesium

chloride lithium chloride complex onto 3-cyanobromobenzene

23 or methyl 4-bromobenzoate 24 at −50 °C aﬀorded the

corresponding Grignard reagents, which were then reacted with

bismuth chloride to provide 1s and 1t in moderate yields (eqs 1

and 2).

To begin our exploration of functional group manipulation

on organobismuthines, we added 6.0 equiv of methylmagne-

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sium bromide on the ester derivative 1t, aﬀording 21a in 84%

yield (i.e., 94% yield per ester function) (eq 3). This simple

Wittig conditions was then performed on 21b, leading to the

corresponding cinnamyl ester and vinyl derivatives 21f and 21g

in 80% and 82% yield, respectively. These examples show that

organobismuthines are resistant to organometallic and

reductive reagents in addition to phosphorus ylides.

Next, we sought to introduce a ketone on the organobismuth

reagent by oxidizing the secondary alcohol in 21d (Scheme 5).

Since trivalent organobismuthines can be oxidized into their

pentavalent counterparts by oxidizing agents¹⁹and by hyper-

valent iodonium reagents,^8c,20it was unclear if the bismuth(III)

center would tolerate the oxidizing conditions required to

oxidize the alcohol into the corresponding ketone. To our

satisfaction, tris(methyl ketone) 21h was obtained in acceptable

yield using Dess-Martin periodinane 25. Alternatively, com-

pound 21h could also be prepared in 63% yield via Swern

oxidation of all three alcohol functions (86% per function).

b. Structural Characterization of Selected Triarylbis-

muthines. To further gain insight into the structure of

triarylbismuthines,²¹we crystallized and analyzed by X-ray

diﬀraction several derivatives bearing a cyclopropyl group at the

meta position (1f), ﬂuorine atoms at the 3 and 5 position (1i), a

methoxy group at the para position (1k), an acetal at the ortho

position (1n), a cyano group at the meta position (1s), a

carbomethoxy function at the para position (1t), an aldehyde at

the meta (21b) and ortho positions (21c), and an

hydroxymethyl group at the meta position (21e).²²The results

show that the organobismuthines have a distorted trigonal

pyramidal structure with Bi−C bond lengths ranging from 2.24

to 2.27 Å and C−Bi−C angles between 91° and 98° (Figure 1).

These Bi−C bond lengths are consistent with known

triarylbismuthines crystal structures²³and with the 2.256 Å

value estimated in the gas phase by gas electron diﬀraction,²⁴

denoting innocuous crystal packing eﬀects. The small C−Bi−C

angles are due to known relativistic eﬀects and fall within the

trend observed when going down the pnictogen family (N > P

> As > Sb > Bi).

transformation demonstrates that the concept of functional

group modiﬁcation in the presence of a C−Bi bond is viable,

giving us an impetus to explore other reactions directly on

organobismuthines.

Due to their high electrophilicity, aldehydes cannot be

present on organomagnesium reagents. Therefore, the

preparation of organometallic reagents bearing aldehydes is

only possible with less electropositive metals such as tin,¹⁵

boron,¹⁶zinc,¹⁷or indium.¹⁸However, the toxic nature of tin

greatly limits its use in synthesis. Although many organo-

boronic acids bearing aldehydes are commercially available,

their use in metal-catalyzed reactions often requires extensive

optimization of the reaction conditions. Conversely, arylzinc

reagents possessing aldehydes have proved to be very useful in

palladium-catalyzed cross-coupling reactions, but strictly

anhydrous conditions are mandatory due to their high

sensitivity to moisture. Finally, while organoindiums have

generated great interest in the synthetic community over the

past decade, the cost of indium greatly limits their application

in synthesis. In this context, organobismuthines bearing

aldehydes can ﬁll an important need in organic synthesis.

Starting from tris((3-diethoxymethyl)phenyl)bismuthine 1o,

we prepared the tris-formyl derivative 21b in excellent yield by

hydrolysis of the acetal function under acidic conditions (eq 4).

Interestingly, the nature and position of the substituent have

little impact on the molecular structure of the organo-

bismuthine, except in the case of the ortho-(diethylacetal) and

ortho-formyl derivatives 1n and 21c. In these compounds with

donor atoms in the ortho functional group, secondary

intramolecular interactions are observed between the oxygen

of the acetals or the carbonyls and the bismuth center (Bi···O

from 3.085 to 3.255 Å in 1n and from 2.911 to 2.991 Å in 21c;

r

_VdW(Bi) = 2.07 Å, r_VdW(O) = 1.52 Å). This is not

unprecedented, as bismuth is capable of acting as a weak

acceptor toward other ligands or even metals²⁵by accepting

electrons in its C−Bi σ* orbitals.^5a,26

c. Palladium-Catalyzed Cross-Coupling Reaction be-

tween Organobismuthines and Aryl or Heteroaryl

Halides. Multiple reports of palladium-catalyzed cross-

coupling reactions involving organobismuth compounds have

been disclosed in recent years.^27,28One important aspect of

triarylbismuth reagents is their ability to deliver three aryl

groups per equivalent of organometallic reagent in cross-

coupling reactions, making them more atom-economical than

other conventional Ar−M reagents. However, in most cases, a

limited array of functional groups were present on the

organobismuth partner. We recently reported a palladium-

catalyzed reaction to cross-couple triarylbismuthines with

halogenated pyridines, pyrimidines, pyrazines, and pyridazi-

nes.^10bTherefore, with our functionalized organobismuthines

in hand, we next explored their reactivity in palladium-catalyzed

Surprisingly, using the same conditions on tris((2-

diethoxymethyl)phenyl)bismuthine 1n led to a much lower

yield of the ortho analogue 21c (eq 5). While this overall yield is

low, it still corresponds to a 67% yield per acetal function. This

example illustrates the need for very eﬃcient conditions to get a

satisfactory triple functional group modiﬁcation.

We then took advantage of the versatility of the aldehyde

function in 21b to introduce other functional groups on the

organobismuth species (Scheme 4). For example, addition of

methylmagnesium bromide on 21b provided tris(3-(1-hydroxy-

ethyl)phenyl)bismuthine 21d in quantitative yield. Reduction

of the aldehyde function in 21b was also accomplished using

sodium borohydride, aﬀording tris(3-(hydroxymethyl)phenyl)-

bismuthine 21e in 97% yield. An oleﬁnation reaction using

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Scheme 4. Synthesis of Highly Functionalized Organobismuthines 21d−g by Derivatization of Tris(3-formylphenyl)bismuthine

21b

Scheme 5. Preparation of Ketone-Bearing

Organobismuthine Derivative 21h by Dess-Martin and

Swern Oxidation Starting from Tris-alcohol 21d

Figure 1. ORTEP view at 50% ellipsoid probability of 1f, 1i, 1k, 1n

(one of three independent molecules), 1s, 1t, 21b,^10b21c and 21e.

Hydrogen atoms are omitted for clarity, except for aldehyde functional

groups. Dashed lines indicate weak intramolecular interactions

between the bismuth atom and donor oxygen atoms at ortho positions.

cross-coupling reactions with other electrophiles in order to

further probe the scope and functional group tolerance of this

transformation.

First, we optimized the reaction conditions using 1.0 equiv of

4-bromobenzaldehyde 26 and 0.4 equiv of organobismuthine

21d. Using our previously reported conditions, we obtained the

desired cross-coupling product 27 in only 37% yield (Table 1,

entry 1). The observed low yield shows that the coupling of

highly functionalized organobismuthines represents a substan-

tial challenge and that the reaction conditions had to be

reoptimized. Suspecting that the high temperature was possibly

responsible for the observed low yield, we performed the

reaction at 80 °C but observed no improvement in yield (entry

2). Changing the catalyst for PdCl₂(PPh₃)₂(entry 3),

Pd(OAc)₂/S-Phos (entry 4), Pd(OAc)₂/PPh₃(entry 5), or

PEPPSI-iPr²⁹(entry 6) did not improve the yield either.

Knowing the beneﬁcial eﬀect of lithium salts on cross-coupling

reactions, as documented by Organ and others,³⁰we found a

substantial amelioration in yield when 2.0 equiv of lithium

chloride were used as an additive (entry 7). Changing the

solvent for THF (entry 8), toluene (entry 9), or a mixture of

DMF and HMPA (entry 10) was detrimental to the reaction or

at best inconsequential. The use of a stronger base such as

potassium tert-butoxide led to a drastic drop in the yield of the

reaction (entry 11). In addition, while potassium carbonate

(entry 12) provided a similar yield as cesium carbonate (entry

7), we found that potassium phosphate (entry 13) and

E

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Table 1. Optimization of Reaction Conditions for the Palladium-Catalyzed Cross-Coupling Reaction of 21d with 4-

Bromobenzaldehyde 26

a

Entry

Catalyst

Ligand

Additive (x equiv)

Base

Solvent

DMF

T (°C)

t (h)

Yield (%)

1

Pd(PPh₃)₄

PdCl₂(PPh₃)₂

Pd(OAc)₂

PEPPSI-iPr

Pd(PPh₃)₄

N.A.

S-Phos

PPh₃

N.A.

Cs₂CO₃

t-BuOK

K₂CO₃

130

80

18

6

37

36

31

7

2

N.A.

DMF

3

N.A.

DMF

4

N.A.

DMF

5

N.A.

DMF

31

23

64

13

25

59

14

69

82

75

57

48

73

83

6

N.A.

DMF

7

LiCl (2.0 equiv)

LiCl (1.0 equiv)

LiCl (2.0 equiv)

DMF

8

THF

9

Toluene

DMF/HMPA

DMF

b

10

11

12

13

14

15

16

17

18

DMF

K₃PO₄

DMF

Rb₂CO₃

K₃PO₄

DMF

c

K₃PO₄

DMF

d

K₃PO₄

DMF/H₂O

CuI (0.4 equiv)

Cs₂CO₃

DMF

a

b

c

d

Isolated yield of pure product. DMF/HMPA (4:1). 1.0 equiv of K₃PO₄was used. DMF/H₂O (5:1).

rubidium carbonate (entry 14) were much more eﬃcient bases

in this transformation, providing the desired cross-coupling

product 27 in 82% and 75% isolated yield, respectively.

Lowering the number of equivalents of lithium chloride (entry

15) or potassium phosphate (entry 16) proved disadvanta-

geous. Interestingly, the yield remained satisfactory when the

reaction was run in a 5:1 ratio of DMF/H₂O, showing that

strictly anhydrous conditions are not mandatory (entry 17).

Rao recently reported the eﬀect of copper salts in cross-

coupling reactions involving organobismuthines.^9aSimultane-

ously to Rao, we independently explored the eﬀect of cuprous

iodide as an additive and obtained a considerable improvement

in the yield of the reaction (entry 18). Conditions from entries

13, 14, and 18 represent a substantial improvement over our

previous protocol, as they allow the coupling reaction to be

performed at a lower temperature, in a shorter time, and with a

higher yield.

Having optimized the conditions for the cross-coupling of

organobismuthine 21d, we next investigated the scope of the

method using organobismuthines 1a−t and 21a−h with

selected arylhalides 28, heteroarylhalides 29, 2-halopyridines

2, 2-halopyrimidines 4, 2-halopyrazines 6, and 3-halopyrida-

zines 8 (Table 2). The choice of the electrophiles was

motivated by the presence of functional groups that could

demonstrate the applicability of our protocols in the

preparation of highly functionalized compounds. In each case,

our best conditions from entries 13, 14, and 18 in Table 1

(named Method A, B, and C, respectively, in Table 2) were

tested in order to obtain the highest possible yield of each

desired product. Thus, 4-(N-BOC-aminoethyl)bromobenzene

28a, methyl 4-iodobenzoate 28b, methyl 4-bromobenzoate 28c,

4-bromobenzaldehyde 28d, 2-iodo-4-furaldehyde 29a, 6-chlor-

opyridine-3-carboxaldehyde 2a, 2-acetyl-6-bromopyridine 2b,

2-chloro-4-methylpyrimidine 4a, 2-chloro-6-dimethylamino-

pyrazine 6a, and 3-chloro-6-phenylpyridazine 8a were engaged

in cross-coupling reactions with organobismuthines 1a−t and

21a−h to aﬀord the corresponding products in acceptable to

excellent yields. The results demonstrate that the reaction

works with aryl bromides (entries 1, 3, 5), aryl or heteroaryl

iodides (entries 2, 4, 6), and 2-chloro and 2-bromo nitro-

genated heterocycles (entries 7−12). However, entries 2 and 3

show that iodides are slightly more reactive than bromides. The

identity of the optimal set of conditions (whether A, B, or C)

depended greatly on the speciﬁc combination of Ar(Het)−X

and Ar₃Bi. Notwithstanding, these examples demonstrate that

our protocols tolerate a wide diversity of functional groups on

the electrophile and on the organobismuthine such as BOC-

protected amines (30a), α,β-unsaturated esters (30a), esters

(30b,c), ethers (30b), nitriles (30c), aldehydes (30d, 31a, 3a),

dialkylamines (7a), and acetals (3b, 9b). More striking is the

ability of this method to transfer in acceptable to good yields

aryl groups that possess functions that are susceptible to

competitive arylation, elimination, or oxidation such as alcohols

(31a, 7a), ketones (9a), and vinyl groups (30d, 5a).

d. Copper-Catalyzed N-Arylation of Indoles, Pyrroles,

Pyrazoles, and Pyridones. We recently reported a protocol

for the copper-catalyzed N-arylation of indoles, pyrroles,

pyrazoles,^11aand pyridones^12busing organobismuthines with

tolerance to a wide variety of functional groups. Other research

groups have also reported various copper-catalyzed reactions

based on trivalent or pentavalent reagents to N-arylate

nitrogen-containing compounds.³¹To further expand the

functional group diversity of our method, we tested some of

the highly functionalized organobismuthines prepared in this

F

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Table 2. Palladium-Catalyzed Cross-Coupling Reaction of Highly Functionalized Organobismuthines 1a−t and 21a−h with

Arylhalides (28), Heteroarylhalides (29), 2-Halopyridines (2), 2-Halopyrimidines (4), 2-Halopyrazines (6), and 3-

Halopyridazines (8)

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Table 2. continued

a

Method A: Ar₃Bi (0.4 equiv), Pd(PPh₃)₄(5 mol %), LiCl (2.0 equiv), K₃PO₄(2.0 equiv), DMF, 80 °C, 6 h; Method B: Ar₃Bi (0.4 equiv),

Pd(PPh₃)₄(5 mol %), LiCl (2.0 equiv), Rb₂CO₃(2.0 equiv), DMF, 80 °C, 6 h; Method C: Ar₃Bi (0.4 equiv), Pd(PPh₃)₄(5 mol %), CuI (0.4

b

equiv), Cs₂CO₃(2.0 equiv), DMF, 80 °C, 6 h. Isolated yield of pure product.

Scheme 6. N-Arylation of Indole 32, Pyrrole and Pyrazole 33, and Pyridone 16 Using Highly Functionalized

a

Organobismuthines 1a−t and 21a−h

a

b

The numbers in brackets indicate the organobismuthine used for the synthesis of each compound. Conditions: Method A: Ar₃Bi (1.0 equiv),

Cu(OAc)₂(0.1 equiv), pyridine (1.0 equiv), CH₂Cl₂, O₂, 50 °C, o.n.; Method B: Ar₃Bi (1.0 equiv), Cu(OAc)₂(1.0 equiv), pyridine (3.0 equiv),

c

CH₂Cl₂, O₂, 50 °C, o.n.; Method C: Ar₃Bi (1.0 equiv), Cu(OAc)₂(1.0 equiv), pyridine (3.0 equiv), CH₂Cl₂, air, 50 °C, o.n. ORTEP diagram at

50% ellipsoid probability of compound 17a.

work in our copper-catalyzed N-arylation reaction. The

arylations were performed at 50 °C under oxygen using 1.0

equiv of triarylbismuthine, 1.0 equiv of pyridine, and 0.1 equiv

of copper acetate (Scheme 6, Method A). Every substrate was

also arylated under more “forcing” conditions, that is, using

stoichiometric amounts of copper acetate and 3.0 equiv of

pyridine (Scheme 6, Method B). Finally, pyridones were

arylated using similar conditions, except that the reactions were

also performed under air (Scheme 6, Method C). As illustrated

in Scheme 6, indole 32, pyrrole and pyrazole 33, and pyridone

16 were N-arylated in up to 99% yield using these conditions,

demonstrating that aryl groups possessing THP-protected

phenols (34a), aldehydes (34b), benzylic alcohols (34c),

methyl ketones (34d), secondary alcohols (35a), vinyl groups

(35b), and α,β-unsaturated esters (17a) can be eﬃciently

transferred using our methods. It should be emphasized that

groups that are susceptible to elimination (secondary alcohol in

35a), oxidation (benzylic and secondary alcohols in 34c and

35a respectively), enolization (methyl ketone in 34d), or

arylation (alcohols in 34c and 35a) are also tolerated using our

protocols. The main limitation of this method, as demonstrated

previously,^11aresides in the transfer of an ortho-substituted aryl

group, as illustrated by compound 34b.

Mukaiyama reported a copper-free method to N-arylate

pyridones using pentavalent organobismuth reagents.³²We

demonstrated previously,^12bbased on IR analysis, that the

arylation of pyridones using our copper-catalyzed reaction

involving trivalent organobismuthines also leads to the N-

arylated product (as opposed to the O-arylated derivative). The

analysis of compound 17a by X-ray diﬀraction further conﬁrms

the chemoselectivity of this arylation reaction toward nitrogen.

e. Copper-Catalyzed O-Arylation of Phenols. A few

reports on the O-arylation of alcohols and phenols using

organobismuth reagents have been disclosed in the literature.³³

However, most of these methods rely on pentavalent

organobismuth compounds, which must be prepared from

their corresponding trivalent analogues. Therefore, the develop-

ment of O-arylation reactions directly from trivalent organo-

bismuthines is of high interest, as it can reduce the number of

steps required to obtain the desired O-arylated product. We

recently reported an eﬃcient and general method to prepare

diarylethers via a copper-catalyzed O-arylation of phenols using

triarylbismuthines.^12bUsing these protocols, we sought to

evaluate the applicability of the highly functionalized organo-

bismuthines in the O-arylation of methyl 3-hydroxybenzoate

36. Two sets of conditions were tested: in Method A, the

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reaction was run at 50 °C for 3 h under air using 1.0 equiv of

triarylbismuthine, triethylamine as the base, and a stoichio-

metric amount of copper acetate; in Method B, the catalyst

loading was lowered to 0.3 equiv and the reaction was

performed under oxygen for 16 h. As shown in Scheme 7, these

Table 3. Comparison of the Reactivity of Triphenylbismuth

1a and Triphenylbismuth Diacetate 38 in the N-Arylation

Reaction of Indole 32

Scheme 7. O-Arylation of Methyl 3-Hydroxybenzoate 36

Using Highly Functionalized Organobismuthines 1a−t and

21a−h

a

Entry

Bismuth reagent

Cu(OAc)₂(x equiv)

Yield (%)

1

2

3

4

Ph₃Bi (1a)

1.0

0

97

2

Ph₃Bi (1a)

Ph₃Bi(OAc)₂(38)

1.0

0

20

1

a

Yields are for isolated pure compound.

Table 4. Comparison of the Reactivity of Triphenylbismuth

1a and Triphenylbismuth Diacetate 38 in the O-Arylation

Reaction of Phenol 36

a

The numbers in brackets indicate the organobismuthine used for the

b

synthesis of each compound. Conditions: Method A: Ar₃Bi (1.0

equiv), Cu(OAc)₂(1.0 equiv), Et₃N (3.0 equiv), CH₂Cl₂, 50 °C, air, 3

h; Method B: Ar₃Bi (1.0 equiv), Cu(OAc)₂(0.3 equiv), Et₃N (3.0

equiv), CH₂Cl₂, 50 °C, O₂, 16 h.

a

Entry

Bismuth reagent

Cu(OAc)₂(x equiv)

Yield (%)

1

2

3

4

Ph₃Bi (1a)

1.0

0

70

0

Ph₃Bi (1a)

Ph₃Bi(OAc)₂(38)

1.0

0

92

4

methods allow the transfer of aryl groups bearing a variety of

groups such as acetals (37a,b), vinyl groups (37c), and α,β-

unsaturated esters (37d). Contrary to the N-arylation of

indoles, pyrroles, and pyrazoles, the O-arylation of phenols even

shows high tolerance for substitution in the ortho position, as

shown by compound 37b.

a

Yields are for isolated pure compound.

to the arylation of indole 32, in the absence of the catalyst, both

reagents were unable to arylate phenol 36, showing once again

that copper is essential for the O-arylation reaction (entries 2

and 4). The results from Table 3 and Table 4 suggest that

copper acetate is necessary for both arylation reactions and that

trivalent and pentavalent organobismuth species can both act as

arylating agents, albeit with diﬀerent eﬃciencies depending on

the substrate.

The mechanism that we propose for the copper-catalyzed N-

and O-arylation of indoles, pyrroles, pyrazoles, pyridones, and

phenols (summarized by Nu−H) using triarylbismuthines

involves the formation of an organocopper(III) species A

where the deprotonated nucleophile, the aryl group, and one

acetate are simultaneously ligated to the metal (Scheme 8).³⁴

This species would be formed by the reaction of triarylbismu-

thine Ar₃Bi and copper acetate, concomittantly with the

f. Mechanistic Investigations on the Copper-Cata-

lyzed Arylation of Indoles and Phenols Using Trivalent

and Pentavalent Organobismuth Reagents. Pentavalent

organobismuth reagents have been shown to be potent

arylating species in copper-catalyzed^8c,d,f,h,iand even metal-

free reactions.^8aBarton also proposed that, in copper-catalyzed

arylation reactions using triphenylbismuth, triphenylbismuth

diacetate is formed in situ and acts as the eﬀective arylating

agent. Therefore, to compare the arylating power of trivalent

and pentavalent organobismuth species, we performed the

arylation on indole 32 using triphenylbismuth (Ph₃Bi, 1a) and

triphenylbismuth diacetate (Ph₃Bi(OAc)₂, 38) in the presence

and absence of copper acetate (Table 3). As expected, in the

presence of copper acetate, triphenylbismuth was found to be

an excellent arylating agent, providing the N-arylindole 34e in

97% yield (entry 1). By contrast, in the presence of copper

acetate, triphenylbismuth diacetate proved to be a much less

eﬃcient arylating reagent, aﬀording 34e in only 20% yield

(entry 3). Both species were mostly inactive in the absence of

copper acetate, showing that copper is essential for the N-

arylation reaction (entries 2 and 4).

Scheme 8. Proposed Mechanism for the Copper-Catalyzed

N- and O-Arylation of Indoles, Pyrroles, Pyrazoles,

Pyridones, and Phenols Using Triarylbismuthines (Nu−H =

Indole, Pyrrole, Pyrazole, Pyridone, or Phenol)

A comparative reactivity study between triphenylbismuth and

triphenylbismuth diacetate was also performed on methyl 3-

hydroxybenzoate 36 (Table 4). Contrary to the arylation of

indoles, in the presence of copper acetate, triphenylbismuth

diacetate was found to be more reactive than triphenylbismuth

in the arylation of phenol 36 (entry 3 vs 1). However, similarly

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Article

Scheme 9. Orthogonal C-, N-Arylation and O-Arylation of 3-Iodophenol 39 and 5-Iodoindole 40 Using Tris(3-

formylphenyl)bismuthine 21b

deprotonation of the nucleophile Nu−H by the base (either

triethylamine or pyridine), leading to copper(III) intermediate

A, copper(I) acetate, and diarylbismuth acetate (Ar₂Bi(OAc)).

Reductive elimination from species A would then provide the

arylated nucleophile Nu−Ar. This mechanism is similar to that

proposed by Barton and Finet in the copper-catalyzed arylation

of amines and indoles using triphenylbismuth diacetate.^8g

Moreover, intermediate A was also proposed by Evans in the

arylation of phenols using arylboronic acids,³⁵in the Ullmann−

Goldberg copper-catalyzed N-arylation of amines using aryl

halides³⁶and in detailed mechanistic studies published by Stahl

on the Chan−Evans−Lam reaction.³⁷

g. Orthogonal C-, N-, and O-Arylation Reactions on

Iodo Phenols and Indoles. To further test the scope of our

copper- and palladium-catalyzed methods, we explored the

orthogonal transfer of aryl groups on the halogenated phenol

39 and indole 40 (Scheme 9). Using copper acetate and

organobismuthine 21b, the arylation could be directed

chemoselectively to the oxygen of 39 or the nitrogen of 40,

providing 41 and 42 in 44% and 70% yield, respectively. These

products would be diﬃcult to obtain using copper(I) or

palladium(0) catalysis since reaction at the aryl−I bond would

compete with the desired O- or N-arylation process.³⁸In

addition, the palladium-catalyzed cross-coupling reaction

between 3-iodophenol 39 and 5-iodoindole 40 with triar-

ylbismuthine 21b delivered 43 and 44, respectively, in

moderate yields. These cross-coupling reactions represent a

substantial challenge since competitive dehalogenation can

occur due to the presence of the phenol and N−H indole

functions.

additive and potassium phosphate or rubidium carbonate as a

base and require shorter reaction times and lower temperatures.

Using these protocols, highly functionalized C-arylated

compounds were obtained in good to excellent yields. The

highly functionalized organobismuthines prepared using the

functional group manipulation approach were then engaged in

a copper-catalyzed N-arylation of indoles, pyrroles, pyrazoles,

and pyridones and O-arylation of phenols to aﬀord highly

functionalized arylated products. We then demonstrated that

our palladium- and copper-catalyzed processes can be

successfully used orthogonally on halogenated indoles and

phenols. Preliminary mechanistic studies demonstrate that

copper acetate is essential for the reaction to proceed and that

the order of reactivity between the trivalent and pentavalent

species depends on the nature of the substrate. Our palladium-

and copper-catalyzed arylation reactions are simple to operate

and show high functional group tolerance. The C-, N-, and O-

arylation procedures developed in this work constitute an

eﬃcient and general portfolio of methods for the preparation of

medicinally relevant scaﬀolds.

EXPERIMENTAL SECTION

■

General Information. Unless otherwise indicated, all reactions

were run under argon in nonﬂame-dried glassware. For reactions

performed under oxygen, 99.6% extra dry oxygen was used. Unless

otherwise stated, commercial reagents were used without further

puriﬁcation. Grignard reagents were prepared by conventional

methods using metallic magnesium or via Knochel’s procedure.¹⁴

Anhydrous bismuth chloride >98% and triphenylbismuth diacetate

98% were purchased from Aldrich. Triarylbismuthines 1b, 1d, 1g, 1l,

1m, 1q, 1r, 1s, and 1t were prepared according to a procedure that we

previously reported.^10bTriarylbismuthines 1c, 1o, and 21b were

prepared according to methods previously reported by us.^12b

Triarylbismuthines 1e, 1f, 1h, 1i, 1j, 1k, 1p, 21a, 21d, and 21f were

prepared according to a procedure that we previously reported.^11a

Anhydrous solvents were obtained using an encapsulated solvent

puriﬁcation system and were further dried over 4 Å molecular sieves.

The evolution of reactions was monitored by analytical thin-layer

chromatography using silica gel 60 F254 precoated plates. Flash

chromatography was performed employing 230−400 mesh silica using

the indicated solvent system according to standard techniques. For

compounds 1n, 1o, 1p, 9b, 37a, and 37b, the silica gel was washed

with 3 volumes of 0.5% Et₃N/hexanes prior to performing the ﬂash

chromatography to avoid hydrolysis of the acetal. Melting points are

uncorrected. Nuclear magnetic resonance spectra (¹H, ¹³C) were

CONCLUSION

■

In summary, we demonstrated that highly functionalized

triarylbismuthines can be prepared by triple functional group

manipulation using acidic, nucleophilic, and reducing con-

ditions or involving organometallic reagents or ylides. Using

this approach, triarylbismuthines bearing primary, secondary,

and tertiary alcohols, aldehydes, α,β-unsaturated esters, vinyl

groups, and methyl ketones were prepared. These triarylbismu-

thines represent a class of highly functionalized and versatile

organometallic reagents that are in high demand. We then

developed improved protocols for the palladium-catalyzed

cross-coupling reaction between these highly functionalized

reagents and aryl or heteroaryl halides. These modiﬁed

procedures involve lithium chloride or copper iodide as an

1

recorded on a 300 or 600 MHz spectrometer. Chemical shifts for H

NMR spectra are recorded in parts per million from tetramethylsilane

with the solvent resonance as the internal standard (chloroform, δ 7.26

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ppm; methanol, δ 3.31 ppm). Data are reported as follows: chemical

shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, qt =

quintuplet, dd = doublet of doublet, dt = doublet of triplet, m =

multiplet), coupling constant J in Hz, and integration. Chemical shifts

for ¹³C spectra are recorded in parts per million from tetramethylsilane

using the central peak of deuterochloroform (δ 77.16 ppm) or the

central peak of tetradeuteromethanol (δ 49.00 ppm) as the internal

standard. IR spectra were recorded on an FT-IR from thin ﬁlms and

are reported in reciprocal centimeters (cm⁻¹). HRMS was performed

on a TOF LCMS analyzer using the electrospray (ESI) mode.

General Procedure for the Synthesis of Triarylbismuthines.

In a ﬂask equipped with a magnetic stir bar and a condenser, bismuth

chloride (500 mg, 1.6 mmol) was dissolved in anhydrous THF (23

mL) under argon and was cooled to −10 °C (ice/acetone bath). The

organomagnesium reagent (5.23 mmol) was slowly added dropwise

under argon. The reaction mixture was stirred at room temperature for

1 h and heated at 65 °C for 30 min. After cooling to room

temperature, the solution was diluted with sat. aq. NaHCO₃(100 mL)

and extracted with EtOAc (2 × 100 mL). The combined organic

phases were washed with sat. aq. NaHCO₃(2 × 100 mL), sat. aq.

NaCl (2 × 100 mL), dried over Na₂SO₄, ﬁltered, and concentrated

under reduced pressure. The crude product was puriﬁed by column

chromatography using the indicated solvent system to aﬀord the

desired triarylbismuthine.

(40% EtOAc/hexanes) to aﬀord tris(3-(hydroxymethyl)phenyl)-

bismuthine 21e as a white solid (392 mg, 97%): mp 107−108 °C;

1

R_f0.39 (80% EtOAc/hexanes); H NMR (300 MHz, MeOD) δ 7.77

(s, 3H), 7.63 (d, J = 6.9 Hz, 3H), 7.37−7.28 (m, 6H), 4.53 (s, 6H);

¹³C NMR (75 MHz, MeOD) δ 156.7, 144.3, 137.6, 137.2, 131.4,

127.6, 65.3; IR (neat) 3314 (br), 3038, 2923, 2869, 1563, 1412, 1203,

1012, 776; HRMS (ESI) calcd for [C₂₁H₂₁BiO₃+ Na]⁺: 553.1187,

found 553.1177.

Tris(3-vinylphenyl)bismuthine (21g). To a solution of Ph₃PCH₃I

(1.86 g, 4.58 mmol) in THF (8 mL) at −10 °C, t-BuOK was added

(606 mg, 5.4 mmol), and the solution was stirred for 30 min. To the

yellow solution, tris(3-formylphenyl)bismuthine 21b (800 mg, 1.53

mmol) was added, and the reaction was warmed up to room

temperature and stirred for 2 h. The reaction mixture was diluted with

sat. aq. NaHCO₃(50 mL) and extracted with EtOAc (2 × 50 mL).

The combined organic layers were washed with sat. aq. NaHCO₃(50

mL), sat. aq. NaCl (3 × 50 mL), dried over Na₂SO₄, ﬁltered, and

concentrated under reduced pressure. The crude material was puriﬁed

on silica gel (5% EtOAc/hexanes) to aﬀord tris(3-vinylphenyl)-

bismuthine 21g as a yellow oil (650 mg, 82%): R_f0.70 (20% EtOAc/

1

hexanes); H NMR (300 MHz, CDCl₃) 7.82 (s, 3H), 7.65−7.62 (m,

3H), 7.40−7.33 (m, 6H), 6.67 (dd, J = 17.6, 11.0 Hz, 3H), 5.66 (d, J =

17.6 Hz, 3H), 5.20 (d, J = 11.0 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃)

δ 155.4, 139.4, 137.2, 137.0, 135.5, 130.7, 125.7, 114.1; IR (neat) 3156,

3084, 3063, 3040, 3006, 2984, 2927, 1939, 1821, 1629, 1580, 1554,

1467, 1401, 1380, 991, 906, 791, 710. Anal. Calcd for C₂₄H₂₁Bi: C,

55.60; H, 4.08. Found: C, 55.87; H, 4.01.

Triphenylbismuth (1a). The general procedure was followed on a

2.27 mmol scale starting from bismuth chloride and phenylmagnesium

bromide. The crude product was puriﬁed on silica gel (2% EtOAc/

hexanes) to aﬀord triphenylbismuth 1a as a white solid (831 mg,

83%): mp 78−79 °C; R_f0.33 (2% EtOAc/hexanes). Spectral data were

identical to those of the literature compound:³⁹¹H NMR (300 MHz,

CDCl₃) δ 7.75 (d, J = 7.5 Hz, 6H), 7.42−7.30 (m, 9H); ¹³C NMR (75

MHz, CDCl₃) δ 155.3, 137.7, 130.6, 127.9; IR (neat) 3133, 3053,

3011, 2582, 1943, 1871, 1810, 1566, 1471, 1422, 1053, 992, 718, 692.

Anal. Calcd for C₁₈H₁₅Bi: C, 49.10; H, 3.43. Found: C, 49.28; H, 3.39.

Tris(2-(diethoxymethyl)phenyl)bismuthine (1n). The general

procedure was followed on a 5.33 mmol scale starting from bismuth

chloride and 2-(benzaldehydediethylacetal)magnesium bromide. The

crude product was puriﬁed on silica gel (5% EtOAc/hexanes) to aﬀord

tris(2-(diethoxymethyl)phenyl)bismuthine 1n as a white solid (3.3 g,

Tris(3-acetylphenyl)bismuthine (21h). Preparation via Dess-Martin

oxidation: A solution of tris(3-(1-hydroxyethyl)phenyl)bismuthine 21d

(50 mg, 0.09 mmol) in CH₂Cl₂(3 mL) was cooled to −10 °C

(acetone/ice bath), and pyridine (46 μL, 0.59 mmol) was added. After

5 min, Dess-Martin Periodinane (123 mg, 0.28 mmol) was added.

After 1 h, the reaction mixture was diluted with EtOAc (15 mL). The

organic layer was washed with sat. aq. NaHCO₃(15 mL), sat. aq. NaCl

(3 × 15 mL), dried over Na₂SO₄, ﬁltered, and concentrated under

reduced pressure. The crude material was puriﬁed on silica gel (20%

EtOAc/hexanes) to aﬀord tris(3-acetylphenyl)bismuthine 21h as a

white solid (30 mg, 59%). Preparation via Swern oxidation: A solution

of oxalyl chloride (67 μL, 0.79 mmol) in anhydrous CH₂Cl₂(2.0 mL)

was put under argon and cooled to −78 °C (acetone/ice bath).

Anhydrous DMSO (112 μL, 1.57 mmol) was added dropwise to the

reaction mixture and stirred for 30 min at −78 °C. Tris(3-(1-

hydroxyethyl)phenyl)bismuthine 21d (100 mg, 0.17 mmol) was

dissolved in anhydrous CH₂Cl₂(10 mL) and added dropwise to the

reaction mixture and stirred for 1 h at −78 °C. Et₃N (219 μL, 1.57

mmol) was added, and the reaction mixture was warmed to room

temperature and stirred for 30 min. The reaction mixture was diluted

with sat. aq. NaHCO₃(50 mL) and extracted with CH₂Cl₂(2 × 50

mL). The combined organic phases were washed with sat. aq.

NaHCO₃(2 × 50 mL), sat. aq. NaCl (2 × 50 mL), dried over Na₂SO₄,

ﬁltered, and concentrated under reduced pressure. The crude material

was puriﬁed on silica gel (20% EtOAc/hexanes) to aﬀord tris(3-

acetylphenyl)bismuthine 21h as a white solid (61 mg, 63%): mp 85−

86 °C; R_f0.17 (20% EtOAc/hexanes). Spectral data were identical to

those of the literature compound:⁴⁰¹H NMR (300 MHz, CDCl₃) δ

8.36−8.35 (m, 3H), 7.90−7.88 (m, 6H), 7.49 (t, J = 7.5 Hz, 3H), 2.49

(s, 9H); ¹³C NMR (75 MHz, CDCl₃) δ 198.4, 156.0, 142.2, 138.8,

137.1, 131.1, 128.3, 26.8; IR (neat) 3344, 3051, 3008, 2923, 1678,

1578, 1559, 1404, 1356, 1255; HRMS (ESI) calcd for [C₂₄H₂₁BiO₃+

H]⁺: 567.1367, found 567.1400.

1

82%): mp 78−79 °C; R_f0.81 (20% EtOAc/hexanes); H NMR (300

MHz, CDCl₃) δ 7.70 (dd, J = 6.5, 1.4 Hz, 3H), 7.60 (dd, J = 7.3, 1.4

Hz, 3H), 7.30 (dt, J = 7.2, 1.4 Hz, 3H), 7.13 (dt, J = 7.3, 1.5 Hz, 3H),

5.53 (s, 3H), 3.55−3.34 (m, 12H), 1.01 (t, J = 7.0 Hz, 18H); ¹³C

NMR (75 MHz, CDCl₃) δ 162.6, 144.5, 140.6, 131.0, 127.5, 126.8,

104.4, 61.4, 15.1; IR (neat) 3049, 2973, 2928, 2871, 1438, 1336, 1204,

1108, 1090, 1050, 757; HRMS (ESI) calcd for [C₃₃H₄₅BiO₆+ Na]⁺:

769.2912, found 769.2868.

Tris(2-formylphenyl)bismuthine (21c). H₂O (10 mL) and HCl

12N (0.90 mL) were added at room temperature to a stirred solution

of 1n (1.0 g, 1.3 mmol) in THF (30 mL). The reaction mixture was

stirred overnight and then diluted with EtOAc (20 mL). The organic

layer was washed with sat. aq. NaHCO₃(100 mL mL), sat. aq. NaCl

(3 × 20 mL), dried over Na₂SO₄, ﬁltered, and concentrated under

reduced pressure. The crude material was puriﬁed on silica gel (5%

EtOAc/hexanes) to aﬀord tris(2-formylphenyl)bismuthine 21c as a

yellow solid (213 mg, 31%): mp 179−180 °C; R_f0.46 (20% EtOAc/

hexanes); ¹H NMR (300 MHz, CDCl₃) δ 10.23 (s, 3H), 8.02 (dd, J =

7.5, 1.4 Hz, 3H), 7.59−7.54 (m, 6H), 7.34 (td, J = 7.5, 1.5 Hz, 3H);

¹³C NMR (150 MHz, CDCl₃) δ 196.0, 171.2, 142.3, 140.9, 136.9,

136.4, 127.7; IR (neat) 3042, 2977, 2806, 2724, 1690, 1671, 1571,

1556, 1197, 835, 759; HRMS (ESI) calcd for [C₂₁H₁₅BiO₃+ H]⁺:

525.0898, found 525.0896.

Tris(3-(hydroxymethyl)phenyl)bismuthine (21e). A solution of

tris(3-formylphenyl)bismuthine 21b (400 mg, 0.76 mmol) in MeOH

(10 mL) was cooled to 0 °C (acetone/ice bath), and NaBH₄(90 mg,

2.4 mmol) was added. After 30 min, the reaction mixture was diluted

with sat. aq. NaHCO₃(15 mL) and extracted with EtOAc (15 mL).

The organic layer was washed with sat. aq. NaHCO₃(15 mL) and sat.

aq. NaCl (3 × 15 mL), dried over Na₂SO₄, ﬁltered, and concentrated

under reduced pressure. The crude material was puriﬁed on silica gel

General Procedure for the Crystallization of Triarylbismu-

thines 1f, 1i, 1k, 1n, 1s, 1t, 21b, 21c, 21e and Pyridone 17a.

Compounds 1f, 1i, 1k, 1n, 1s, 1t, 21b, 21c, 21e, and 17a were

crystallized by the solvent diﬀusion technique according to the

following procedure: 10 mg of the corresponding compound was

dissolved in a minimal amount of dichloromethane in an open vial.

The vial was then placed in a bigger vial ﬁlled with hexanes with a

loosely tightened cap. The vials were kept at room temperature until

crystals were obtained.

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General Procedures for the Palladium-Catalyzed Cross-

Coupling Reactions. Compounds 3a,b, 5a, 7a, 9a,b, 27, 30a−d,

31a, 43, and 44 were prepared according to the following procedures:

Method A (Table 1, entry 13): In a sealed tube, the aryl or heteroaryl

chloride, bromide, or iodide (1.0 equiv) was dissolved in N,N-

dimethylformamide (4.0 mL). Potassium phosphate (2.0 equiv) was

added, followed by tetrakis(triphenylphosphine)palladium (5 mol %),

lithium chloride (2.0 equiv), and triarylbismuth reagent (0.4 equiv).

Argon was bubbled in the reaction mixture for 1 min. The tube was

sealed and heated at 80 °C for 6 h. The reaction mixture was cooled to

room temperature, diluted with sat. aq. NaHCO₃(20 mL), and

extracted with EtOAc (2 × 20 mL). The combined organic phases

were washed with sat. aq. NaHCO₃(2 × 20 mL), sat. aq. NaCl (2 ×

20 mL), dried over Na₂SO₄, ﬁltered, and concentrated under reduced

pressure. The crude product was puriﬁed by ﬂash column

chromatography on silica gel using EtOAc/hexanes as the eluent to

aﬀord the corresponding product. Method B (Table 1, entry 14):

Same as conditions A except that rubidium carbonate was used instead

of potassium phosphate. Method C (Table 1, entry 18): Same as

conditions A except that cesium carbonate was used instead of

potassium phosphate and 0.4 equiv of cuprous iodide was used instead

of lithium chloride.

6-(3-Formylphenyl)nicotinaldehyde (3a). Method B was followed

on a 0.095 mmol scale starting from 6-chloronicotinaldehyde 2a and

organobismuthine 21b. The crude material was puriﬁed on silica gel

(15% EtOAc/hexanes) to aﬀord 3a as a white solid (13 mg, 64%): mp

117−118 °C; R_f0.29 (20% EtOAc/hexanes). Spectral data were

identical to those of the literature compound:⁴¹¹H NMR (300 MHz,

CDCl₃) δ 10.15 (s, 1H), 10.12 (s, 1H), 9.15 (d, J = 1.4 Hz, 1H), 8.58

(s, 1H), 8.37 (dt, J = 7.7, 1.2 Hz, 1H), 8.26 (dd, J = 8.2, 2.1 Hz, 1H),

8.01−7.96 (m, 2H), 7.68 (t, J = 7.7 Hz, 1H); ¹³C NMR (75 MHz,

CDCl₃) δ 192.0, 190.4, 160.6, 152.4, 139.0, 137.2, 137.1, 133.3, 131.3,

130.5, 129.9, 128.9, 120.8; IR (neat) 3053, 2852, 2745, 1689, 1587,

1359, 1212, 1183, 1166, 835, 795, 740; HRMS (ESI) calcd for

[C₁₃H₉NO₂+ H]⁺: 212.0706, found 212.0708.

150.5, 149.2, 136.0, 128.4, 127.9, 126.8, 125.0, 72.6, 37.6, 31.9; IR

(neat) 3371 (br), 3059, 2971, 2923, 2869, 1583, 1566, 1527, 1425,

1402, 1372, 1186, 1151, 996, 831; HRMS (ESI) calcd for [C₁₅H₁₉N₃O

+ H]⁺: 258.1601, found 258.1603.

1-(3-(6-Phenylpyridazin-3-yl)phenyl)ethanone (9a). Method A

was followed on a 0.26 mmol scale starting from 3-chloro-6-

phenylpyridazine 8a and organobismuthine 21h. The crude material

was puriﬁed on silica gel (20% EtOAc/hexanes) to aﬀord 9a as a

yellow solid (18 mg, 25%): mp 130−131 °C; R_f0.25 (20% EtOAc/

1

hexanes); H NMR (300 MHz, CDCl₃) δ 8.77 (t, J = 1.9 Hz, 1H),

8.41 (dt, J = 7.9, 1.4 Hz, 1H), 8.18 (dd, J = 8.1, 1.9 Hz, 2H), 8.11 (dt, J

= 6.5, 1.5 Hz, 1H), 8.05−7.97 (m, 2H), 7.67 (t, J = 7.8 Hz, 1H), 7.60−

7.52 (m, 3H), 2.72 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 198.0,

158.1, 156.8, 137.9, 136.7, 135.9, 131.4, 130.4, 129.8, 129.5, 129.2,

127.1, 126.9, 124.5, 124.4, 27.0; IR (neat) 3061, 3000, 2932, 1683,

1601, 1585, 1432, 1398, 1358, 1236, 689; HRMS (ESI) calcd for

[C₁₈H₁₄N₂O + H]⁺: 275.1179, found 275.1191.

3-(3-(Diethoxymethyl)phenyl)-6-phenylpyridazine (9b). Method

B was followed on a 0.10 mmol scale starting from 3-chloro-6-

phenylpyridazine 8a and organobismuthine 1o. The crude material

was puriﬁed on silica gel (20% EtOAc/hexanes) to aﬀord 9b as a beige

solid (15 mg, 45%): mp 88−89 °C; R_f0.36 (20% EtOAc/hexanes); ¹H

NMR (300 MHz, CDCl₃) δ 8.25 (t, J = 1.8 Hz, 1H), 8.19−8.14 (m,

3H), 7.95 (dd, J = 11.3, 9.0 Hz, 2H), 7.63 (dt, J = 7.7, 1.5 Hz, 1H),

7.58−7.51 (m, 4H), 5.61 (s, 1H), 3.73−3.54 (m, 4H), 1.27 (t, J = 7.1

Hz, 6H); ¹³C NMR (75 MHz, CDCl₃) δ 157.8, 157.7, 140.3, 136.3,

130.2, 129.2, 129.1, 128.5, 127.1, 125.4, 124.5, 124.3, 101.5, 61.4, 15.4;

IR (neat) 3052, 2974, 2917, 2848, 1704, 1450, 1397, 1328, 1095, 1050,

997, 780, 690; HRMS (ESI): calcd for [C₂₁H₂₂N₂O₂+ H]⁺: 335.1754,

found 335.1767.

3′-(1-Hydroxyethyl)-[1,1′-biphenyl]-4-carbaldehyde (27). Method

C was followed on a 0.27 mmol scale starting from 4-bromo-

benzaldehyde 26 and organobismuthine 21d. The crude material was

puriﬁed on silica gel (25% EtOAc/hexanes) to aﬀord 27 as a yellow oil

1

(51 mg, 83%): R_f0.22 (20% EtOAc/hexanes); H NMR (300 MHz,

1-(6-(4-((Tetrahydro-2H-pyran-2-yl)oxy)phenyl)pyridine-2-yl)-

ethanone (3b). Method B was followed on a 0.21 mmol scale starting

from 2-acetyl-6-bromopyridine 2b and organobismuthine 1m. The

crude material was puriﬁed on silica gel (10% EtOAc/hexanes) to

aﬀord 3b as a light pink solid (50 mg, 80%): mp 90−91 °C; R_f0.47

CDCl₃) δ 10.05 (s, 1H), 7.97−7.93 (m, 2H), 7.78−7.74 (m, 2H),

7.67−7.66 (m, 1H), 7.55 (td, J = 7.1, 1.9 Hz, 1H), 7.49−7.41 (m, 2H)

4.99 (q, J = 6.5 Hz, 1H), 1.82 (s(br), 1H), 1.56 (d, J = 6.4 Hz, 3H);

¹³C NMR (75 MHz, CDCl₃) δ 192.1, 147.2, 146.8, 139.9, 135.3, 130.3,

129.2, 127.8, 126.5, 125.6, 124.5, 70.3, 25.4; IR (neat) 3422 (br), 3059,

3032, 2971, 2923, 2836, 2731, 1689, 1603, 1567, 1170, 1077, 794, 703;

HRMS (ESI) calcd for [C₁₅H₁₄O₂+ H]⁺: 227.1067, found 227.1068.

(E)-Ethyl 3-(4′-(2-((tert-Butoxycarbonyl)amino)ethyl)-[1,1′-bi-

phenyl]-3-yl)acrylate (30a). Method A was followed on a 0.17

mmol scale starting from tert-butyl 4-bromophenethylcarbamate 28a

and organobismuthine 21f. The crude material was puriﬁed on silica

gel (15% EtOAc/hexanes) to aﬀord 30a as a yellow solid (60 mg,

1

(20% EtOAc/hexanes); H NMR (300 MHz, CDCl₃) δ 8.07−8.02

(m, 2H), 7.93−7.90 (m, 1H), 7.89−7.84 (m, 2H), 7.21−7.16 (m, 2H),

5.52 (t, J = 3.3 Hz, 1H), 3.97−3.89 (m, 1H), 3.67−3.60 (m, 1H), 2.82

(s, 3H), 2.10−2.00 (m, 1H), 1.93−1.89 (m, 2H), 1.88−1.60 (m, 3H);

¹³C NMR (75 MHz, CDCl₃) δ 200.9, 158.5, 156.4, 153.4, 137.6, 132.0,

128.3, 122.9, 119.3, 116.8, 96.4, 62.2, 30.4, 25.9, 25.3, 18.8; IR (neat)

3060, 2943, 2872, 2840, 1696, 1606, 1513, 1449, 1355, 1239, 1177,

1036, 960, 919, 845, 806, 739, 613, 593; HRMS (ESI): calcd for

[C₁₈H₁₉NO₃+ H]⁺: 298.1438, found 298.1426.

1

89%): mp 111−112 °C; R_f0.52 (20% EtOAc/hexanes); H NMR

(300 MHz, CDCl₃) δ 7.75 (d, J = 16.0 Hz, 1H), 7.73 (s, 1H), 7.61−

7.59 (m, 1H), 7.55−7.53 (m, 1H), 7.48 (d, J = 7.5 Hz, 1H), 7.45−7.40

(m, 2H), 7.06 (d, J = 8.2 Hz, 2H), 6.52 (d, J = 16.0 Hz, 1H), 4.53

(s(br), 1H), 4.28 (q, J = 7.1 Hz, 2H), 3.34 (q, J = 6.4 Hz, 2H), 2.75 (t,

J = 6.9 Hz, 2H), 1.43 (s, 9H), 1.35 (t, J = 7.1 Hz, 3H); ¹³C NMR (75

MHz, CDCl₃) δ 170.0, 155.9, 144.3, 141.3, 138.1, 135.2, 131.7, 130.6,

129.6, 129.0, 127.3, 126.9, 120.3, 119.0, 79.4, 60.7, 41.7, 35.8, 28.5,

14.4; IR (neat) 3437, 3363, 2977, 2931, 2866, 1703, 1637, 1508, 1488,

1365, 1307, 1267, 1248, 1163, 1036, 1011, 789. Anal. Calcd for

C₂₄H₂₉NO₄: C, 72,89; H, 7.39; N, 3.54. Found: C, 72.90; H, 7.41; N,

3.52.

4-Methyl-2-(3-vinylphenyl)pyrimidine (5a). Method A was fol-

lowed on a 0.40 mmol scale starting from 2-chloro-4-methylpyrimidine

4a and organobismuthine 21g. The crude material was puriﬁed on

silica gel (10% EtOAc/hexanes) to aﬀord 5a as a yellow oil (16 mg,

20%): R_f0.60 (20% EtOAc/hexanes); ¹H NMR (300 MHz, CDCl₃) δ

8.65 (d, J = 5.1 Hz, 1H), 8.48 (t, J = 1.9 Hz, 1H), 8.34 (dt, J = 7.7, 1.5

Hz, 1H), 7.54 (dt, J = 7.7, 1.6 Hz, 1H), 7.45 (t, J = 7.7 Hz, 1H), 7.05

(d, J = 5.0 Hz, 1H), 6.82 (dd, J = 17.6, 10.9 Hz, 1H), 5.87 (dd, J =

17.4, 0.9 Hz, 1H), 5.30 (dd, J = 10.8, 0.9 Hz, 1H), 2.60 (s, 3H); ¹³C

NMR (75 MHz, CDCl₃) δ 167.5, 164.3, 156.9, 138.2, 138.0, 136.8,

128.9, 128.3, 127.8, 126.3, 118.8, 114.4, 24.6; IR (neat) 3061, 3038,

2954, 2928, 2867, 1692, 1572, 1555, 1431, 1384, 1364, 912, 789;

HRMS (ESI) calcd for [C₁₃H₁₂N₂+ H]⁺: 197.1073, found 197.1080.

2-(4-(6-(Dimethylamino)pyrazin-2-yl)phenyl)propan-2-ol (7a).

Method A was followed on a 0.32 mmol scale starting from 6-

chloro-N,N-dimethylpyrazin-2-amine 6a and organobismuthine 21a.

The crude material was puriﬁed on silica gel (40% EtOAc/hexanes) to

aﬀord 7a as a yellow solid (34 mg, 41%): mp 158−159 °C; R_f0.20

Methyl 3′-Methoxy-[1,1′-biphenyl]-4-carboxylate (30b). Starting

from methyl 4-iodobenzoate 28b: Method C was followed on a 0.19

mmol scale starting from methyl 4-iodobenzoate 28b and organo-

bismuthine 1l. The crude material was puriﬁed on silica gel (10%

EtOAc/hexanes) to aﬀord 30b as a white solid (45 mg, 98%). Starting

from methyl 4-bromobenzoate 28c: Method B was followed on a 0.30

mmol scale starting from methyl 4-bromobenzoate 28c and organo-

bismuthine 1l. The crude material was puriﬁed on silica gel (10%

EtOAc/hexanes) to aﬀord 30b as a white solid (57 mg, 78%): mp 55−

56 °C; R_f0.50 (10% EtOAc/hexanes). Spectral data were identical to

those of the literature compound:⁴²¹H NMR (600 MHz, CDCl₃) δ

1

(40% EtOAc/hexanes); H NMR (300 MHz, CDCl₃) δ 8.21 (s, 1H),

7.99−7.94 (m, 2H), 7.91 (s, 1H), 7.60−7.56 (m, 2H), 3.17 (s, 6H),

2.37 (s(br), 1H), 1.61 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ 154.4,

L

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J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

8.10 (d, J = 4.2 Hz, 2H), 7.65 (d, J = 4.2 Hz, 2H), 7.38 (t, J = 3.9 Hz,

1H), 7.20 (d, J = 3.8 Hz, 1H), 7.16−7.15 (m, 1H), 6.94 (dd, J = 4.1,

1.0 Hz, 1H) 3.94 (s, 3H), 3.87 (s, 3H); ¹³C NMR (150 MHz, CDCl₃)

δ 167.1, 160.1, 145.6, 141.6, 130.2, 130.1, 129.1, 127.2, 119.9, 113.6,

113.1, 55.5, 52.2; IR (neat) 3064, 2999, 2950, 2835, 1932, 1716, 1605,

1434, 1270, 1103, 1017, 849, 764, 694; HRMS (ESI): calcd for

[C₁₅H₁₄O₃+ H]⁺: 243.1016, found 243.1016.

Methyl 3′-Cyano-[1,1′-biphenyl]-4-carboxylate (30c). Method B

was followed on a 0.30 mmol scale starting from methyl 4-

iodobenzoate 28b and organobismuthine 1s. The crude material was

puriﬁed on silica gel (10% EtOAc/hexanes) to aﬀord 30c as a white

solid (62 mg, 87%): mp 137−138 °C; R_f0.60 (20% EtOAc/hexanes).

Spectral data were identical to those of the literature compound:⁴³¹H

NMR (300 MHz, CDCl₃) δ 8.14−8.10 (m, 2H), 7.88−7.87 (m, 1H),

7.85−7.81 (m, 1H), 7.68−7.54 (m, 4H) 3.94 (s, 3H); ¹³C NMR (75

MHz, CDCl₃) δ 166.7, 143.2, 141.3, 131.7, 131.6, 130.9, 130.5, 130.1,

129.9, 127.2, 118.6, 113.3, 52.4; IR (neat) 3411, 3068, 2954, 2836,

2232, 1608, 1429, 1281, 1186, 1102, 764, 684; HRMS (ESI): calcd for

[C₁₅H₁₁NO₂+ H]⁺: 238.0863, found 238.0870.

General Procedure for the N-Arylation of Indoles, Pyrroles,

Pyrazoles, and Pyridones. Compounds 17a, 34a−e, 35a,b, and 42

were prepared according to the following procedures: Method A: In a

sealed tube, the triarylbismuthine (1.0 equiv) was added, followed by

copper(II) acetate (0.1 equiv) and the indole, pyrrole, pyrazole, or

pyridone (1.0 equiv). The reagents were dissolved in anhydrous

dichloromethane (4 mL), and pyridine (1.0 equiv) was added to the

mixture. The reaction tube was purged with dry oxygen for 30 s,

sealed, and heated at 50 °C overnight. The reaction mixture was

cooled to room temperature, transferred, and rinsed with EtOAc in a

round-bottom ﬂask. Silica gel was added, and the mixture was

concentrated under reduced pressure. The crude product was puriﬁed

by ﬂash column chromatography on silica gel using the indicated

solvent system as the eluent to give the corresponding product.

Method B: Same as method A except for copper(II) acetate (1.0 equiv

instead of 0.1 equiv) and pyridine (3.0 equiv instead of 1.0 equiv).

Method C: Same as method A except that 1.0 equiv of copper(II)

acetate and 3.0 equiv of pyridine were used and the reaction was

performed at 50 °C under air in a sealed tube overnight.

(E)-Ethyl 3-(3-(3-Cyano-2-oxopyridin-1(2H)-yl)phenyl)acrylate

(17a). Method B was followed on a 0.21 mmol scale starting from

2-oxo-1,2-dihydropyridine-3-carbonitrile and organobismuthine 21f.

The crude product was puriﬁed on silica gel (50% EtOAc/hexanes) to

aﬀord 17a as a white solid (52 mg, 84%): mp 173−174 °C; R_f0.37

3′-Vinyl-[1,1′-biphenyl]-4-carbaldehyde (30d). Method C was

followed on a 0.17 mmol scale starting from 4-bromobenzaldehyde

28d and organobismuthine 21g. The crude material was puriﬁed on

silica gel (5% EtOAc/hexanes) to aﬀord 30d as a colorless oil (27 mg,

1

76%): R_f0.30 (5% EtOAc/hexanes); H NMR (300 MHz, CDCl₃) δ

1

(60% EtOAc/hexanes); H NMR (300 MHz, CDCl₃) δ 7.91 (dd, J =

10.07 (s, 1H), 7.98−7.94 (m, 2H), 7.79−7.74 (m, 2H), 7.66−7.65 (m,

1H), 7.55−7.51 (m, 1H), 7.49−7.42 (m, 2H), 6.80 (dd, J = 17.6, 10.8

Hz, 1H), 5.84 (d, J = 17.6 Hz, 1H), 5.33 (d, J = 10.9 Hz, 1H); ¹³C

NMR (75 MHz, CDCl₃) δ 192.0, 147.2, 140.2, 138.5, 136.6, 135.4,

130.4, 129.3, 127.9, 126.9, 126.3, 125.5, 114.9; IR (neat) 3407 (br),

3057, 2916, 2844, 2734, 1692, 1601, 1384, 1209, 1167, 988, 836, 791,

699; HRMS (ESI): calcd for [C₁₅H₁₂O + H]⁺: 209.0961, found

209.0965.

7.1, 2.1 Hz, 1H), 7.66 (d, J = 16.1 Hz, 1H), 7.63−7.59 (m, 2H), 7.54

(d, J = 7.7 Hz, 1H), 7.52−7.51 (m, 1H), 7.38 (dt, J = 7.9, 1.6 Hz, 1H),

6.45 (d, J = 16.1 Hz, 1H), 6.38 (t, J = 7.0 Hz, 1H), 4.26 (q, J = 7.1 Hz,

2H), 1.33 (t, J = 7.1 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 166.5,

159.3, 148.0, 142.9, 142.6, 140.1, 136.4, 130.3, 129.0, 127.7, 125.6,

120.5, 115.3, 107.0, 105.8, 60.9, 14.4; IR (neat) 3080, 2977, 2924,

2905, 2228, 1707, 1662, 1640, 1542, 1269, 1181; HRMS (ESI) calcd

for [C₁₇H₁₄N₂O₃+ H]⁺: 295.1077, found 295.1099.

1-(4-((Tetrahydro-2H-pyran-2-yl)oxy)phenyl)-1H-indole-5-carb-

aldehyde (34a). Method B was followed on a 0.17 mmol scale starting

from 1H-indole-5-carbaldehyde 32 and organobismuthine 1m. The

crude product was puriﬁed on silica gel (15% EtOAc/hexanes) to

aﬀord 34a as a yellow solid (43 mg, 79%): mp 105−106 °C; R_f0.52

(20% EtOAc/hexanes); ¹H NMR (300 MHz, CDCl₃) δ 10.04 (s, 1H),

8.20 (s, 1H), 7.76 (d, J = 8.6 Hz, 1H), 7.53−7.46 (m, 1H), 7.41−7.30

(m, 3H), 7.26−7.20 (m, 2H), 6.80 (d, J = 3.2 Hz, 1H), 5.49 (t, J = 3.3

Hz, 1H), 3.99−3.91 (m, 1H), 3.70−3.63 (m, 1H), 2.08−1.99 (m, 1H),

1.94−1.89 (m, 2H), 1.78−1.62 (m, 3H); ¹³C NMR (75 MHz, CDCl₃)

δ 192.5, 156.5, 139.7, 132.7, 130.5, 130.0, 128.8, 126.5, 126.2, 122.6,

117.6, 111.2, 104.8, 96.7, 62.3, 30.4, 25.3, 18.8; IR (neat) 3101, 3039,

2943, 2873, 2850, 2715, 1683, 1615, 1509, 1330, 1237, 1221, 1201,

1102, 1044, 921, 731; HRMS (ESI) calcd for [C₂₀H₁₉NO₃+ H]⁺:

322.1438, found 322.1430.

1-(2-Formylphenyl)-1H-indole-5-carbaldehyde (34b). Method B

was followed on a 0.17 mmol scale starting from 1H-indole-5-

carbaldehyde 32 and organobismuthine 21c. The crude product was

puriﬁed on silica gel (20% EtOAc/hexanes) to aﬀord 34b as a yellow

oil (15 mg, 35%): R_f0.44 (20% EtOAc/hexanes); ¹H NMR (300

MHz, CDCl₃) δ 10.07 (s, 1H), 9.63 (s, 1H), 8.25 (d, J = 0.9 Hz, 1H),

8.13 (dd, J = 7.7, 1.5 Hz, 1H), 7.83−7.77 (m, 2H), 7.65 (t, J = 7.6 Hz,

1H), 7.51 (dd, J = 7.9, 0.8 Hz, 1H), 7.39 (d, J = 3.3 Hz, 1H), 7.24 (d, J

= 8.2 Hz, 1H), 6.91 (dd, J = 3.3, 0.9 Hz, 1H); ¹³C NMR (75 MHz,

CDCl₃) δ 192.3, 189.1, 141.5, 141.0, 135.4, 132.3, 131.9, 131.7, 130.7,

129.2, 128.7, 128.4, 126.4, 123.6, 110.9, 106.0; IR (neat) 3357, 3106,

3065, 2977, 2920, 2867, 2745, 1687, 1597, 1490, 1331, 1195; HRMS

(ESI) calcd for [C₁₆H₁₁NO₂+ H]⁺: 250.0868, found 250.0873.

1-(3-(Hydroxymethyl)phenyl)-1H-indole-5-carbaldehyde (34c).

Method B was followed on a 0.09 mmol scale starting from 1H-

indole-5-carbaldehyde 32 and organobismuthine 21e. The crude

product was puriﬁed on silica gel (30% EtOAc/hexanes) to aﬀord 34c

as a yellow oil (17 mg, 75%): R_f0.15 (20% EtOAc/hexanes); ¹H NMR

(300 MHz, CDCl₃) δ 10.06 (s, 1H), 8.22 (d, J = 1.1 Hz, 1H), 7.78

(dd, J = 8.7, 1.5 Hz, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.55−7.53 (m, 2H),

7.44−7.41 (m, 3H), 6.84 (d, J = 3.3 Hz, 1H), 4.83 (d, J = 4.0 Hz, 2H),

1.84 (t, J = 5.0 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 192.5, 143.2,

5-(3-(1-Hydroxyethyl)phenyl)furan-2-carbaldehyde (31a). Meth-

od A was followed on a 0.23 mmol scale starting from 5-iodofuran-2-

carbaldehyde 29a and organobismuthine 21d. The crude material was

puriﬁed on silica gel (30% EtOAc/hexanes) to aﬀord 31a as a yellow

1

oil (41 mg, 82%): R_f0.25 (40% EtOAc/hexanes); H NMR (300

MHz, CDCl₃) δ 9.65 (s, 1H), 7.85 (s, 1H), 7.74−7.71 (m, 1H), 7.43−

7.41 (m, 2H), 7.32 (d, J = 3.7 Hz, 1H), 6.86 (d, J = 3.7 Hz, 1H), 4.97

(q, J = 6.5 Hz, 1H), 1.96 (s(br), 1H), 1.53 (d, J = 6.5 Hz, 3H); ¹³C

NMR (75 MHz, CDCl₃) δ 177.4, 159.5, 151.9, 146.9, 129.2, 129.1,

126.8, 124.4, 123.8, 122.3, 107.9, 70.1, 25.4; IR (neat) 3416 (br), 3103,

2972, 2916, 2871, 2821, 1663, 1516, 1468, 1426, 1265, 1071, 1028,

792; HRMS (ESI) calcd for [C₁₃H₁₂O₃+ H]⁺: 217.0859, found

217.0867.

3′-Hydroxy-[1,1′-biphenyl]-3-carbaldehyde (43). Method A was

followed on a 0.23 mmol scale starting from 3-iodophenol 39 and

organobismuthine 21b. The crude material was puriﬁed on silica gel

(20% EtOAc/hexanes) to aﬀord 43 as a white solid (23 mg, 50%): mp

88−89 °C; R_f0.38 (20% EtOAc/hexanes); ¹H NMR (300 MHz,

CDCl₃) δ 10.09 (s, 1H), 8.08 (t, J = 1.6 Hz, 1H), 7.86 (dt, J = 7.4, 1.4

Hz, 2H), 7.61 (t, J = 7.7 Hz, 1H), 7.34 (t, J = 7.9 Hz, 1H), 7.20 (dt, J =

7.6, 1.4 Hz, 1H), 7.11 (t, J = 2.2 Hz, 1H), 6.87 (ddd, J = 8.1, 2.5, 0.8

Hz, 1H), 4.97 (s(br), 1H); ¹³C NMR (75 MHz, CDCl₃) δ 192.7,

156.3, 141.9, 141.5, 137.0, 133.3, 130.4, 129.7, 129.1, 128.3, 119.8,

115.2, 114.3; IR (neat) 3363 (br), 3062, 2927, 2831, 2734, 1686, 1599,

1588, 1458, 1308, 1212, 1169, 779, 690; HRMS (ESI) calcd for

[C₁₃H₁₀O₂+ H]⁺: 199.0754, found 199.0750.

3-(1H-Indol-5-yl)benzaldehyde (44). Method A was followed on

0.21 mmol scale starting from 5-iodo-1H-indole 40 and organo-

bismuthine 21b. The crude material was puriﬁed on silica gel (20%

EtOAc/hexanes) to aﬀord 44 as a yellow oil (18 mg, 39%): R_f0.43

(20% EtOAc/hexanes); ¹H NMR (300 MHz, CDCl₃) δ 10.11 (s, 1H),

8.26 (s(br), 1H), 8.17 (t, J = 1.8 Hz, 1H), 7.95−7.91 (m, 1H), 7.91 (s,

1H), 7.82 (dt, J = 7.6, 1.4 Hz, 1H), 7.60 (t, J = 7.6 Hz, 1H), 7.49 (s,

2H), 7.28 (t, J = 2.9 Hz, 1H), 6.64 (dd, J = 3.1, 1.9 Hz, 1H); ¹³C NMR

(75 MHz, CDCl₃) δ 192.8, 143.6, 137.0, 135.8, 133.4, 132.0, 129.5,

128.6, 127.8, 125.3, 121.8, 119.6, 111.6, 103.1; IR (neat) 3414 (br),

3057, 2825, 2738, 1689, 1599, 1578, 1466, 1424, 1316, 1197, 792;

HRMS (ESI) calcd for [C₁₅H₁₁NO + H]⁺: 222.0913, found 222.0924.

M

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Article

139.3, 130.2, 130.1, 130.0, 129.2, 126.5, 125.8, 123.8, 123.1, 122.8,

111.2, 105.4, 105.4, 64.8; IR (neat) 3411 (br), 3105, 3055, 2920, 2858,

2815, 2727, 1682, 1601, 1589, 1565, 1493, 1449, 1331, 1223, 1103,

1032, 894, 726, 698; HRMS (ESI) calcd for [C₁₆H₁₃NO₂+ H]⁺:

252.1019, found 252.1012.

General Procedure for the O-Arylation of Phenols. Com-

pounds 37a−e and 41 were prepared according to the following

procedures: Method A: In a sealed tube, the phenol (1.0 equiv) was

dissolved in nonanhydrous solvent grade dichloromethane (3 mL).

The organobismuthine (1.0 equiv) was added followed by copper(II)

acetate (1.0 equiv) and Et₃N (3.0 equiv). The tube was sealed and

heated at 50 °C for 3 h under air. The reaction mixture was cooled to

room temperature, and silica gel was added. The mixture was

concentrated under reduced pressure, and the crude product was

puriﬁed by ﬂash column chromatography using the indicated solvent

system to aﬀord the corresponding product. Method B: Same as

method A except that 0.3 equiv of Cu(OAc)₂was used and the

reaction was performed under O₂for 16 h.

1-(3-Acetylphenyl)-1H-indole-5-carbaldehyde (34d). Method B

was followed on a 0.17 mmol scale starting from 1H-indole-5-

carbaldehyde 32 and organobismuthine 21h. The crude product was

puriﬁed on silica gel (30% EtOAc/hexanes) to aﬀord 34d as a yellow

1

oil (27 mg, 60%): R_f0.34 (20% EtOAc/hexanes); H NMR (300

MHz, CDCl₃) δ 10.07 (s, 1H), 8.23 (d, J = 1.5 Hz, 1H), 8.09 (t, J = 1.8

Hz, 1H), 8.00 (dt, J = 7.4, 1.6 Hz, 1H), 7.81 (dd, J = 8.7, 1.6 Hz, 1H),

7.73 (dt, J = 8.0, 1.7 Hz, 1H), 7.70−7.65 (m, 1H), 7.57 (d, J = 8.7 Hz,

1H) 7.45 (d, J = 3.3 Hz, 1H), 6.87 (d, J = 3.3 Hz, 1H), 2.68 (s, 3H);

¹³C NMR (75 MHz, CDCl₃) δ 197.1, 192.3, 139.6, 139.2, 139.0, 130.5,

130.4, 129.9, 129.3, 129.1, 127.3, 126.5, 124.3, 123.2, 111.0, 106.0,

26.9; IR (neat) 3357, 3103, 3057, 2924, 2825, 2741, 1682, 1599, 1586,

1491, 1445, 1330, 1236, 1105, 769; HRMS (ESI) calcd for

[C₁₇H₁₃NO₂+ H]⁺: 264.1019, found 264.1012.

1-Phenyl-1H-indole-5-carbaldehyde (34e). Method B was fol-

lowed on a 0.29 mmol scale starting from 1H-indole-5-carbaldehyde

32 and organobismuthine 1a. The crude material was puriﬁed on silica

gel (20% EtOAc/hexanes) to aﬀord 34e as a yellow oil (62 mg, 97%):

R_f0.14 (10% EtOAc/hexanes). Spectral data were identical to those of

the literature compound:⁴⁴¹H NMR (300 MHz, CDCl₃) δ 10.06 (s,

1H), 8.22 (s, 1H), 7.57 (d, J = 8.7 Hz, 1H), 7.61−7.54 (m, 3H), 7.52−

7.49 (m, 2H), 7.46−7.41 (m, 2H), 6.84 (d, J = 3.2 Hz, 1H); ¹³C NMR

(75 MHz, CDCl₃) δ 192.4, 139.4, 139.1, 130.3, 130.2, 130.0, 129.2,

127.6, 126.5, 124.9, 122.8, 111.2, 105.4; IR (neat) 3060, 2962, 2921,

2815, 2778, 2709, 1683, 1593, 1498, 1448, 1338, 1222, 1103, 886, 755,

695; HRMS (ESI): calcd for [C₁₅H₁₁NO + H]⁺: 222.0913, found

222.0919.

Methyl 3-(3-(Diethoxymethyl)phenoxy)benzoate (37a). Method

A was followed on a 0.26 mmol scale starting from methyl 3-

hydroxybenzoate 36 and organobismuthine 1o. The crude material

was puriﬁed on silica gel (15% EtOAc/hexanes) to aﬀord 37a as a

1

colorless oil (75 mg, 87%): R_f0.62 (20% EtOAc/hexanes); H NMR

(300 MHz, CDCl₃) δ 7.77 (dt, J = 7.7, 1.3 Hz, 1H), 7.65 (dd, J = 2.6,

1.5 Hz, 1H), 7.42−7.31 (m, 2H), 7.27−7.24 (m, 1H), 7.20 (ddd, J =

8.2, 2.6, 1.1 Hz, 1H), 7.16 (t, J = 2.1 Hz, 1H), 6.97 (ddd, J = 7.9, 2.6,

1.2 Hz, 1H), 5.48 (s, 1H), 3.88 (s, 3H), 3.67−3.48 (m, 4H), 1.22 (t, J

= 7.0 Hz, 6H); ¹³C NMR (75 MHz, CDCl₃) δ 166.6, 157.5, 156.8,

141.6, 132.0, 129.9, 129.8, 124.4, 123.4, 122.2, 119.6, 119.0, 117.6,

101.1, 61.2, 52.4, 15.3; IR (neat) 3068, 2973, 2920, 2878, 1726, 1684,

1582, 1483, 1441, 1357, 1270, 1049, 901, 794, 753, 696; HRMS (ESI)

calcd for [C₁₉H₂₂O₅+ Na]⁺: 353.1359, found 353.1369.

Methyl 3-(2-(Diethoxymethyl)phenoxy)benzoate (37b). Method

B was followed on a 0.16 mmol scale starting from methyl 3-

hydroxybenzoate 36 and organobismuthine 1n. The crude material

was puriﬁed on silica gel (15% EtOAc/hexanes) to aﬀord 37b as a

1

colorless oil (39 mg, 74%): R_f0.73 (20% EtOAc/hexanes); H NMR

(300 MHz, CDCl₃) δ 7.78−7.73 (m, 1H), 7.70 (dd, J = 7.6, 1.8 Hz,

1H), 7.64 (dd, J = 2.6, 1.5 Hz, 1H), 7.37 (t, J = 7.9 Hz, 1H), 7.28 (dt, J

= 7.4, 1.8 Hz, 1H), 7.20 (td, J = 7.5, 1.3 Hz, 1H), 7.14 (ddd, J = 8.3,

2.6, 1.1 Hz, 1H), 6.88 (dd, J = 8.2, 1.5 Hz, 1H), 5.73 (s, 1H), 3.89 (s,

3H), 3.70−3.60 (m, 2H), 3.56−3.49 (m, 2H), 1.16 (t, J = 7.1 Hz, 6H);

¹³C NMR (75 MHz, CDCl₃) δ 166.6, 158.2, 153.8, 131.9, 131.2, 129.9,

129.7, 128.0, 124.4, 124.0, 122.6, 119.7, 119.0, 97.6, 62.4, 52.3, 15.2; IR

(neat) 3066, 2975, 2877, 1724, 1580, 1482, 1444, 1271, 1230, 1202,

1052, 994, 905, 754; HRMS (ESI) calcd for [C₁₉H₂₂O₅+ Na]⁺:

353.1359, found 353.1363.

1-(1-(3-(1-Hydroxyethyl)phenyl)-1H-pyrrol-2-yl)ethanone (35a).

Method A was followed on a 0.13 mmol scale starting from 1-(1H-

pyrrol-2-yl)ethanone and organobismuthine 21d. The crude product

was puriﬁed on silica gel (35% EtOAc/hexanes) to aﬀord 35a as a

1

yellow oil (30 mg, 99%): R_f0.19 (20% EtOAc/hexanes); H NMR

(300 MHz, CDCl₃) δ 7.34−7.32 (m, 2H), 7.26 (s, 1H), 7.13−7.08 (m,

2H), 6.94 (dd, J = 2.4, 1.8 Hz, 1H), 6.28 (dd, J = 4.1, 2.6 Hz, 1H), 4.84

(q, J = 6.4 Hz, 1H), 3.51 (s(br), 1H), 2.38 (s, 3H), 1.45 (d, J = 6.5 Hz,

3H); ¹³C NMR (75 MHz, CDCl₃) δ 187.5, 147.1, 140.8, 131.5, 131.4,

128.6, 124.8, 124.7, 123.4, 120.9, 109.3, 69.6, 27.2, 25.0; IR (neat)

3409 (br), 3114, 3057, 2973, 2920, 2867, 1644, 1489, 1405, 1366,

1348, 1110, 1084, 1050, 940, 793, 738, 654; HRMS (ESI) calcd for

[C₁₄H₁₅NO₂+ H]⁺: 230.1176, found 230.1178.

Methyl 3-(3-Vinylphenoxy)benzoate (37c). Method B was

followed on a 0.13 mmol scale starting from methyl 3-hydrox-

ybenzoate 36 and organobismuthine 21g. The crude material was

puriﬁed on silica gel (10% EtOAc/hexanes) to aﬀord 37c as a yellow

oil (27 mg, 82%): R_f0.74 (20% EtOAc/hexanes); ¹H NMR (300

MHz, CDCl₃) δ 7.78 (dt, J = 7.7, 1.3 Hz, 1H), 7.66 (dd, J = 2.6, 1.6

Hz, 1H), 7.41 (t, J = 8.0 Hz, 1H), 7.31 (t, J = 7.8 Hz, 1H), 7.23−7.17

(m, 2H), 7.07 (t, J = 2.0 Hz, 1H), 6.90 (ddd, J = 8.1, 2.4, 1.0 Hz, 1H),

6.67 (dd, J = 17.6, 10.9 Hz, 1H), 5.70 (dd, J = 17.6, 0.8 Hz, 1H), 5.27

(d, J = 10.9 Hz, 1H), 3.90 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ

166.6, 157.5, 157.1, 139.8, 136.3, 132.1, 130.1, 129.9, 124.5, 123.4,

122.0, 119.7, 118.6, 116.8, 115.0, 52.4; IR (neat) 3076, 3008, 2952,

2928, 2844, 1724, 1573, 1485, 1442, 1275, 1250, 1208, 1143, 1098,

991; HRMS (ESI) calcd for [C₁₆H₁₄O₃+ H]⁺: 255.1016, found

255.1020.

(E)-Methyl 3-(3-(3-Ethoxy-3-oxoprop-1-en-1-yl)phenoxy)-

benzoate (37d). Method A was followed on a 0.25 mmol scale

starting from methyl 3-hydroxybenzoate 36 and organobismuthine

21f. The crude material was puriﬁed on silica gel (15% EtOAc/

hexanes) to aﬀord 37d as a yellow oil (43 mg, 53%): R_f0.61 (20%

EtOAc/hexanes); ¹H NMR (300 MHz, CDCl₃) δ 7.81 (td, J = 7.8, 1.3

Hz, 1H), 7.67−7.66 (m, 1H), 7.62 (d, J = 16.0 Hz, 1H), 7.46−7.40

(m, 1H), 7.39−7.34 (m, 1H), 7.30−7.27 (m, 1H), 7.22 (ddd, J = 8.2,

2.6, 1.1 Hz, 1H), 7.14 (t, J = 2.1 Hz, 1H), 7.02 (ddd, J = 8.0, 1.9, 1.2

Hz, 1H), 6.37 (d, J = 16.0 Hz, 1H), 4.25 (q, J = 7.1 Hz, 2H), 3.90 (s,

3H), 1.32 (t, J = 7.1 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 166.9,

166.5, 157.5, 157.0, 143.8, 136.6, 132.2, 130.5, 130.1, 124.9, 123.7,

123.6, 120.7, 120.0, 119.3, 118.0, 60.7, 52.4, 14.4; IR (neat) 3065,

4-Methyl-1-(3-vinylphenyl)-1H-pyrazole (35b). Method B was

followed on a 0.43 mmol scale starting from 4-methyl-1H-pyrazole

and organobismuthine 21g. The crude product was puriﬁed on silica

gel (20% EtOAc/hexanes) to aﬀord 35b as a yellow oil (70 mg, 88%):

1

R_f0.53 (20% EtOAc/hexanes); H NMR (300 MHz, CDCl₃) δ 7.72

(t, J = 2.0 Hz, 1H), 7.70−7.69 (m, 1H), 7.53 (s, 1H), 7.51−7.48 (m,

1H), 7.35 (t, J = 7.7 Hz, 1H), 7.27 (dt, J = 7.7, 1.5 Hz, 1H), 6.73 (dd, J

= 17.6, 10.8 Hz, 1H), 5.82 (d, J = 17.6 Hz, 1H), 5.31 (d, J = 10.9 Hz,

1H), 2.14 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 141.9, 140.6, 139.1,

136.3, 129.6, 125.5, 123.9, 118.4, 118.0, 116.6, 115.1, 9.1; IR (neat)

3141, 3118, 3065, 2926, 2863, 1695, 1606, 1585, 1533, 1489, 1454,

1399, 1362, 1047, 791, 755, 697; HRMS (ESI) calcd for [C₁₂H₁₂N₂+

H]⁺: 185.1073, found 185.1078.

3-(5-Iodo-1H-indol-1-yl)benzaldehyde (42). Method B was

followed on 0.12 mmol scale starting from 5-iodo-1H-indole 40 and

organobismuthine 21b. The crude material was puriﬁed on silica gel

(20% EtOAc/hexanes) to aﬀord 42 as a yellow oil (29 mg, 70%): R_f

0.54 (20% EtOAc/hexanes); ¹H NMR (300 MHz, CDCl₃) δ 10.10 (s,

1H), 8.03 (d, J = 1.5 Hz, 1H), 7.98−7.97 (m, 1H), 7.87 (dt, J = 7.0, 1.6

Hz, 1H), 7.76−7.68 (m, 2H), 7.49 (dd, J = 8.7, 1.6 Hz, 1H), 7.33 (s,

1H), 7.31 (d, J = 5.2 Hz, 1H), 6.65 (d, J = 3.3 Hz, 1H); ¹³C NMR (75

MHz, CDCl₃) δ 191.4, 140.3, 138.0, 134.9, 132.1, 131.2, 130.7, 130.3,

129.9, 128.5, 128.4, 124.3, 112.3, 103.8, 84.4; IR (neat) 3106, 3068,

2958, 2920, 2829, 2734, 1698, 1588, 1513, 1487, 1459, 1237, 793;

HRMS (ESI) calcd for [C₁₅H₁₀INO + H]⁺: 347.9880, found 347.9896.

N

DOI: 10.1021/acs.joc.6b00767

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

2980, 2953, 2901, 1709, 1639, 1575, 1484, 1442, 1269, 1230, 1177,

1097, 1036, 983, 756; HRMS (ESI) calcd for [C₁₉H₁₈O₅+ H]⁺:

327.1227, found 327.1224.

(3) For selected examples of applications of organobismuth reagents

in methodology development, see: (a) Kobiki, Y.; Kawaguchi, S.-i.;

Ogawa, A. Org. Lett. 2015, 17, 3490−3493. (b) Wang, T.; Sang, S.; Liu,

L.; Qiao, H.; Gao, Y.; Zhao, Y. J. Org. Chem. 2014, 79, 608−617.

(c) Sueda, T.; Oshima, A.; Teno, N. Org. Lett. 2011, 13, 3996−3999.

(d) Sato, I.; Toyota, Y.; Asakura, N. Eur. J. Org. Chem. 2007, 2007,

2608−2610. (e) Ikegai, K.; Fukumoto, K.; Mukaiyama, T. Chem. Lett.

2006, 35, 612−613. (f) Mukaiyama, T.; Sakurai, N.; Ikegai, K. Chem.

Lett. 2006, 35, 1140−1141. (g) Koech, P. K.; Krische, M. J. J. Am.

Chem. Soc. 2004, 126, 5350−5351. (h) Ooi, T.; Goto, R.; Maruoka, K.

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Y.; Uemura, S. Bull. Chem. Soc. Jpn. 1995, 68, 950−957.

Methyl 3-Phenoxybenzoate (37e). A modiﬁed method B using 1.0

equiv of Cu(OAc)₂instead of 0.3 equiv and pyridine instead of

triethylamine was followed on a 0.33 mmol scale starting from methyl

3-hydroxybenzoate 36 and organobismuthine 1a. The crude material

was puriﬁed on silica gel (5% EtOAc/hexanes) to aﬀord 37e as a pale

yellow oil (53 mg, 70%): R_f0.43 (10% EtOAc/hexanes). Spectral data

were identical to those of the literature compound:⁴⁵¹H NMR (300

MHz, CDCl₃) δ 7.79 (td, J = 7.7, 1.3 Hz, 1H), 7.68 (t, J = 2.1 Hz, 1H),

7.43−7.32 (m, 3H), 7.21 (dd, J = 8.2, 2.5 Hz, 1H), 7.14 (t, J = 7.4 Hz,

1H), 7.02 (d, J = 8.2 Hz, 2H), 3.89 (s, 3H); ¹³C NMR (75 MHz,

CDCl₃) δ 166.5, 157.5, 156.7, 131.9, 129.9, 129.8, 124.3, 123.8, 123.3,

119.6, 119.1, 52.2; IR (neat) 3068, 2947, 2840, 1722, 1582, 1479,

1437, 1266, 1228, 1091, 988, 904, 749, 688; HRMS (ESI): calcd for

[C₁₄H₁₂O₃+ H]⁺: 229.0859, found 229.0863.

(4) For examples of applications of organobismuth reagents in total

synthesis, see: (a) Nicolaou, K. C.; Sarlah, D.; Wu, T. R.; Zhan, W.

Angew. Chem., Int. Ed. 2009, 48, 6870−6874. (b) Krawczuk, P. J.;

Schone, N.; Baran, P. S. Org. Lett. 2009, 11, 4774−4776.

̈

(5) For reviews on organobismuth compounds as ligands in

transition metal complexes, see: (a) Benjamin, S. L.; Reid, G. Coord.

Chem. Rev. 2015, 297−298, 168−180. (b) Braunschweig, H.;

Cogswell, P.; Schwab, K. Coord. Chem. Rev. 2011, 255, 101−117.

(6) For reviews on polymerization reactions using organobismuth

reagents, see: Yamago, S. Chem. Rev. 2009, 109, 5051−5068 and

references cited therein.

3-(3-Iodophenoxy)benzaldehyde (41). Method B was followed on

a 0.23 mmol scale starting from 3-iodophenol 39 and organo-

bismuthine 21b. The crude material was puriﬁed on silica gel (15%

EtOAc/hexanes) to aﬀord 41 as a yellow oil (33 mg, 44%): R_f0.69

1

(20% EtOAc/hexanes); H NMR (300 MHz, CDCl₃) δ 9.97 (s, 1H),

7.64 (dt, J = 7.4, 1.1 Hz, 1H), 7.52−7.46 (m, 3H), 7.37 (t, J = 2.0 Hz,

1H), 7.28 (ddd, J = 8.1, 2.5, 1.0 Hz, 1H), 7.09 (t, J = 8.1 Hz, 1H), 6.99

(ddd, J = 8.2, 2.3, 0.9 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 191.5,

157.7, 157.1, 138.3, 133.3, 131.4, 130.8, 128.4, 125.5, 125.0, 118.7,

118.6, 94.5; IR (neat) 3059, 2923, 2827, 2734, 1697, 1572, 1465, 1450,

1243, 1208, 846, 781; HRMS (ESI) calcd for [C₁₃H₉IO₂+ H]⁺:

324.9720, found 324.9714.

(7) For reviews on the application of organobismuth compounds in

medicinal chemistry, see: (a) Yang, Y.; Ouyang, R.; Xu, L.; Guo, N.; Li,

W.; Feng, K.; Ouyang, L.; Yang, Z.; Zhou, S.; Miao, Y. J. Coord. Chem.

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99, 2601−2657.

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(c) Combes, S.; Finet, J.-P. Tetrahedron 1998, 54, 4313−4318.

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4137−4144. (e) Abramovitch, R. A.; Barton, D. H. R.; Finet, J.-P.

Tetrahedron 1988, 44, 3039−3071. (f) Barton, D. H. R.; Finet, J.-P.;

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RSC Adv. 2016, 6, 1012−1017. (b) Rao, M. L. N.; Dhanorkar, R. J.

Eur. J. Org. Chem. 2014, 2014, 5214−5228. (c) Rao, M. L. N.;

Dhanorkar, R. J. RSC Adv. 2014, 4, 13134−13144. (d) Rao, M. L. N.;

Dhanorkar, R. J. Tetrahedron 2014, 70, 8067−8078. (e) Rao, M. L. N.;

Jadhav, D. N.; Dasgupta, P. Eur. J. Org. Chem. 2013, 2013, 781−788.

(f) Rao, M. L. N.; Banerjee, D.; Giri, S. J. Organomet. Chem. 2010, 695,

1518−1525. (g) Rao, M. L. N.; Jadhav, D. N.; Dasgupta, P. Org. Lett.

2010, 12, 2048−2051. (h) Rao, M. L. N.; Venkatesh, V.; Dasgupta, P.

Tetrahedron Lett. 2010, 51, 4975−4980.

ASSOCIATED CONTENT

* Supporting Information

The Supporting Information is available free of charge on the

ACS Publications website at DOI: 10.1021/acs.joc.6b00767.

■

S

Crystallographic data for 1f, 1i, 1k, 1n, 1s, 1t, 17a, 21c,

and 21e (ZIP)

1

Copies of H, ¹³C, and IR spectra (PDF)

AUTHOR INFORMATION

Corresponding Author

*E-mail: gagnon.alexandre@uqam.ca.

Notes

■

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

This work was supported by the Natural Sciences and

Engineering Research Council of Canada (NSERC), the

(10) (a) Petiot, P.; Gagnon, A. Heterocycles 2014, 88, 1615−1624.

(b) Petiot, P.; Gagnon, A. Eur. J. Org. Chem. 2013, 2013, 5282−5289.

(c) Gagnon, A.; Albert, V.; Duplessis, M. Synlett 2010, 2010, 2936−

2940. (d) Gagnon, A.; Duplessis, M.; Fader, L. Org. Prep. Proced. Int.

̀

́ ́ ̀ ́

Universite du Quebec a Montreal (UQAM) and the Centre

in Green Chemistry and Catalysis. M.H. thanks NSERC and

̀

FRQNT for graduate scholarships. P.P. and J.D. thank UQAM

for a FARE scholarship.

́

2010, 42, 1−69. (e) Gagnon, A.; Duplessis, M.; Alsabeh, P.; Barabe, F.

J. Org. Chem. 2008, 73, 3604−3607.

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P

DOI: 10.1021/acs.joc.6b00767

J. Org. Chem. XXXX, XXX, XXX−XXX

Article Doi

Synthesis of highly functionalized triarylbismuthines by functional group manipulation and use in palladium- and copper-catalyzed arylation reactions

DOI: 10.1021/acs.joc.6b00767

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