Palladium-catalyzed cross-coupling reaction of functionalized aryl- and heteroarylbismuthanes with 2-halo(or 2-Triflyl)azines and -diazines

Article abstract of DOI:10.1002/ejoc.201300850

The palladium-catalyzed cross-coupling of highly functionalized organobismuthanes with 2-halo(or 2-triflyl)pyridines, -pyrimidines, -pyrazines, and -pyridazines is reported. The reaction tolerates numerous functional groups, including aldehydes. The synthesis of a shelf-stable (formylphenyl)bismuth reagent and its use in a cross-coupling reaction is also described. The palladium-catalyzed cross-coupling of highly functionalized organobismuthanes with 2-halo(or 2-triflyl)pyridines, -pyrimidines, -pyrazines, and -pyridazines is reported. The reaction tolerates numerous functional groups, including aldehydes. The synthesis of a shelf-stable (formylphenyl)bismuth reagent and its use in cross-coupling reactions is also described. Copyright

Full text of DOI:10.1002/ejoc.201300850

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201300850
Palladium-Catalyzed Cross-Coupling Reaction of Functionalized Aryl- and
Heteroarylbismuthanes with 2-Halo(or 2-Triflyl)azines and -diazines
Pauline Petiot[a] and Alexandre Gagnon*[a]
Keywords: Bismuth / Cross-coupling / Nitrogen heterocycles / Palladium / Azines
The palladium-catalyzed cross-coupling of highly function-
alized organobismuthanes with 2-halo(or 2-triflyl)pyridines,
-pyrimidines, -pyrazines, and -pyridazines is reported. The
reaction tolerates numerous functional groups, including al-
dehydes. The synthesis of a shelf-stable (formylphenyl)bis-
muth reagent and its use in a cross-coupling reaction is also
described.
organometallic species such as organomagnesium rea-
gents.[9] Although organostannanes are more tolerant to
acidic and electrophilic groups,[10] their high toxicity com-
bined with the fact that only one aryl group is usually trans-
ferred make them considerably less attractive. Coupling of
2-haloazines and -diazines with organozinc reagents offers
a great solution to issues of functional group tolerance.[11]
However, these species must imperatively be manipulated
under inert and anhydrous conditions, which complicates
their use in parallel chemistry. To the best of our knowl-
edge, the most general methods for the transfer of aryl and
heteroaryl units onto azines and diazines are those of Kno-
chel[12,13] and Quéguiner.[14] However, as these procedures
involve organomagnesium reagents, sensitive groups such as
aldehydes and ketones cannot be present on either coupling
partner.
Introduction
Azines and diazines are ubiquitous in pharmaceutical in-
dustry. Compounds that incorporate these heterocycles
have been found to possess antimicrobial, antiviral, antioxi-
dant, antitumoral, anti-inflammatory, and other activities.[1]
Azines and diazines have also been used in the preparation
of materials that show interesting electrical and optical
properties.[2] Consequently, access to efficient and general
methods that allow their preparation is of utmost impor-
tance.[3] To be applicable to the context of drug discovery,
these methods should tolerate the presence of functional
groups that can serve as handles for further transformation
of the molecule.[4] Ideally, the protocol should also involve
reagents that can be easily manipulated and should operate
under simple conditions that can be amenable to parallel
chemistry.[5]
Organobismuthanes have found increasing use in bond
formation owing to their unique properties and reac-
tivity.[15] These organometallic reagents can be easily pre-
pared,[16] chromatographed, and stored in air at room tem-
perature. In addition, their low toxicity makes them ex-
tremely attractive species for methodology development.
The low polarity of the C–Bi bond provides a moderate
reactivity for this class of reagents, which thus allows the
presence of numerous reactive or acidic functional groups
on the electrophilic partner. Cross-coupling reactions in-
volving triphenylbismuth was first reported by Barton et al.
in 1988.[17] Recently, the groups of Rao,[18] Tanaka,[19] and
others[20] have extended the scope of this reaction to include
other organobismuthanes. However, to the best of our
knowledge, the full potential of organobismuthanes in the
transfer of highly functionalized groups onto 2-halo(or 2-
triflyl)azines and -diazines has never been demonstrated.
We reported over the past years applications of tri-
valent[21,22] and pentavalent organobismuthanes[23] for the
formation of C–C and C–N bonds. Recently, we disclosed
the first palladium-mediated cross-coupling reaction of tri-
The metal-catalyzed cross-coupling reaction between ha-
logenated electrophiles and organometallic reagents has
evolved into an extremely powerful approach for the instal-
lation of aromatic and heteroaromatic units onto a variety
of scaffolds.[6] The cross-coupling of aryl- and heteroaryl-
metal compounds with 2-halo(or 2-triflyl)azines and -diaz-
ines constitutes an attractive approach to access the corre-
sponding 2-arylheterocycles. A few examples of cross-cou-
pling reactions between organometallic reagents and 2-
haloazines and -diazines have been reported.[7,8] However,
many of these methods show modest substrate scope and
require air- and moisture-sensitive reagents or complex cat-
alysts. More importantly, limited functional group tolerance
is often observed, particularly in the case of reactive
[a] Département de Chimie
Université du Québec à Montréal
C.P. 8888, Succ. Centre-Ville, Montréal, Québec H3C 3P8,
Canada
E-mail: gagnon.alexandre@uqam.ca
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300850.
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Cross-Coupling of Functionalized Aryl- and Heteroarylbismuthanes
alkylbismuth reagents with a variety of scaffolds possessing tricyclopropylbismuth[21] and other trialkylbismuthanes,[24]
reactive functional groups, including one example involving we obtained 65% yield of desired product 6 (Table 1, En-
a 2-chloropyridine.[24] We report herein our study on the try 1).
cross-coupling reaction of 2-halo(or 2-triflyl)pyridines,
-pyrazines, -pyrimidines, and -pyridazines with function-
alized aryl- and heteroarylbismuthanes.
To assure that all three aryl groups were effectively trans-
ferred, we verified that the yield of product 6 was the same
upon using 0.7 and 1.1 equiv. of triphenylbismuth (Table 1,
Entries 2 and 3). The fact that similar yields were obtained
demonstrate that all three phenyl groups were indeed trans-
ferred during the process. This well-established characteris-
tic of triarylbismuth reagents makes them more atom-eco-
nomical than other reagents such as aryltrialkyltin species.
Performing the reaction at higher temperatures under ther-
mal (Table 1, Entry 4) or microwave conditions (Table 1,
Entry 5) did not lead to any improvement in the yield of
the reaction. Doubling the catalyst loading (Table 1, En-
try 6) or changing the system to favor oxidative addition
in C–Cl bonds (Table 1, Entry 7; Cy = cyclohexyl) gave a
performance similar to that of the standard conditions. Sur-
prisingly, attempts at using Buchwald phosphanes did not
provide any improvement in the yield of the reaction.[26]
Although changing the solvent to N-methylpyrrolidone
(NMP) or toluene gave a lower yield of the coupling prod-
uct (Table 1, Entries 8 and 9), we found that the use of a
4:1 mixture of DMF/hexamethylphosphoramide (HMPA)
gave a noticeable improvement in the efficiency of the reac-
tion (Table 1, Entry 10). To evaluate the importance of the
base, we then conducted a reaction without cesium carbon-
ate and obtained the desired product in 42% yield (Table 1,
Entry 11); this suggests that – although the base is not es-
sential – it is still required to achieve optimal yields. The
results of the optimization of the reaction conditions dem-
onstrate that the cross-coupling transformation can be ac-
complished by using very simple conditions and requires
only approximately one third of an equivalent of the triaryl-
bismuth reagent.
To have high value, we aimed for a protocol that would
involve a simple catalyst, shelf-stable organometallic species
and that would permit the cross-coupling between two units
that both possess sensitive functional groups. Function-
alized organometallics are extremely valuable species in or-
ganic synthesis.[25] However, one of the major issue consists
in designing an organometallic reagent that will selectively
react at the desired position of the heterocycle without at-
tacking the functional groups present on the electrophile or
on the organometallic species (Scheme 1). We report herein
our results on the preparation of organobismuthanes that
bear functionalized groups, that are shelf-stable and that
can be used in palladium-catalyzed C–C bond-forming re-
actions.
Scheme 1. Chemoselectivity of a cross-coupling reaction between
functionalized organometallic species and 2-halopyridines. FG,
FGЈ = functional group; M = metal; X = halide or pseudohalide.
Results and Discussion
Before exploring functional group compatibility, we be-
gan by optimizing the reaction conditions for the coupling
of triphenylbismuth (0.4 equiv.) with chlorodiazine 4. Using
We next studied the substrate scope by using pyrazines
conditions that we previously reported for the coupling of 7, pyrimidines 8, pyridines 9, and pyridazines 10 (Table 2).
Table 1. Optimization of the reaction conditions.
Entry
Change from “standard conditions”
Isolated yield [%][a]
1
2
3
4
5
6
7
8
9
no change
0.7 equiv. Ph3Bi instead of 0.4 equiv.
1.1 equiv. Ph3Bi instead of 0.4 equiv.
150 °C instead of 130 °C
65
62
60
50
36
60
50
10
50
72
42
170 °C (microwave) instead of 130 °C
10 mol-% Pd(PPh3)4 instead of 5 mol-%
Pd(OAc)2 (5 mol-%)/PCy3 (10 mol-%) instead of Pd(PPh3)4
NMP instead of DMF
toluene instead of DMF
DMF/HMPA (4:1) instead of DMF
no base
10
11
[a] Yield of isolated pure product 6.
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To compare the relative reactivity of these four classes of in Table 1 (Entry 1, 2, or 10). We found that pyrazines
electrophiles, we performed all cross-coupling reactions by smoothly underwent the cross-coupling reaction with Ph3Bi
using triphenylbismuth under the optimal conditions found to provide the desired products in good to excellent yields
Table 2. Coupling of triphenylbismuth with halo(or triflyl)azines and -diazines.
[a] Conditions A: Ph3Bi (0.4 equiv.), Pd(PPh3)4 (5 mol-%), Cs2CO3 (2 equiv.), DMF, 130 °C, overnight. Conditions B: Ph3Bi (0.7 equiv.),
Pd(PPh3)4 (5 mol-%), Cs2CO3 (2 equiv.), DMF, 130 °C, overnight. Conditions C: Ph3Bi (0.4 equiv.), Pd(PPh3)4 (5 mol-%), Cs2CO3
(2 equiv.), DMF/HMPA (4:1), 130 °C, overnight. [b] Yield of isolated pure product. [c] 10 mol-% of Pd(PPh3)4 instead of 5 mol-%.
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Cross-Coupling of Functionalized Aryl- and Heteroarylbismuthanes
(Table 2, Entries 1–4). Electron-withdrawing and electron- them with 2-chloroquinoxaline (7a, Table 3). In general,
donating groups had little impact on the outcome of the similar yields were obtained for triarylbismuthanes pos-
reaction (Table 2, Entry 3 vs. 4). We next turned our atten- sessing electron-neutral (Table 3, Entries 1 and 7), electron-
tion to pyrimidines and obtained a good yield of the desired withdrawing (Table 3, Entries 3, 5, and 6), and electron-do-
product upon coupling triphenylbismuth with 2-chloro-5- nating groups (Table 3, Entries 4 and 8). Under our stan-
ethylpyrimidine (8a; Table 2, Entry 5). We demonstrated dard conditions, para- (Table 3, Entries 1, 3, 6, and 8) and
previously that 2-chloropyridines are very competent elec- meta- (Table 3, Entries 4, 5, and 7) -substituted aryl groups
trophiles in cross-coupling reactions with trialkylbismuth were efficiently transferred by using the corresponding
reagents.[24] We wanted to extend the scope of the reaction organobismuthanes. To our surprise, the coupling of ortho-
to include bromo and triflyl derivatives. Our results show substituted aryl groups proved to be more difficult than an-
that 2-bromopyridines are generally more reactive than the ticipated, as only a modest yield of the desired product was
2-chloro analogues (e.g., 9b vs. 9a, 9e vs. 9f), which is con- obtained (Table 3, Entry 2). Acid-sensitive groups such as
sistent with a palladium-mediated pathway that involves acetals were well tolerated in this protocol (Table 3, En-
oxidative addition in the C–X bond. In fact, 2-fluoropyr- tries 7 and 8). Reactive electrophilic groups such as nitriles
idines failed to react under our conditions. Gratifyingly, 2- (Table 3, Entry 5) and esters (Table 3, Entry 6) were unaf-
triflyl derivatives were found to have similar reactivity to fected during the transformation, which demonstrates the
the chloro analogues (e.g., 9i vs. 9a). These substrates can mildness of the cross-coupling reaction with organobis-
be easily accessed from the corresponding 2-hydroxypyr- muthanes. Finally, a 2-thienyl (Table 3, Entry 9) and a 3-
idines. Finally, we performed the coupling reaction on 2- quinolinyl (Table 3, Entry 10) unit were installed unevent-
chloropyridazine (10a) and obtained desired product 14a in fully on the quinoxaline by using our procedure.
excellent yield (Table 2, Entry 19).
Having established general conditions for the coupling of
These results show that a great diversity of functional functionalized organobismuthanes with 2-haloazines and
groups are tolerated in this reaction, including amines -diazines, we wanted to extend our methodology to the
(Table 2, Entry 4), esters (Table 2, Entries 8, 10, and 11), al- transfer of an aryl fragment that would bear a more reactive
dehydes (Table 2, Entry 12), nitro groups (Table 2, En- functional group such as an aldehyde. This particular func-
try 16), nitriles (Table 2, Entries 3 and 17), and trifluoro- tional group is highly reactive and is therefore incompatible
methyl groups (Table 2, Entries 13 and 15). Even acidic and with strong organometallic species such as organomagnes-
enolizable groups such as methyl ketones (Table 2, Entry 9) ium reagents. However, owing to the mild reactivity of the
and alcohols (Table 2, Entry 18) are tolerated in this reac- C–Bi bond, we postulated that the aldehyde would be toler-
tion. This is in sharp contrast to coupling reactions involv- ated during the formation and the cross-coupling reaction
ing organomagnesium reagents in which these types of of the organobismuthane. Only two examples of (form-
groups are generally incompatible with the very reactive na- ylaryl)bismuthanes have been reported in the literature, but
ture of these organometallic species.
We next studied the regioselectivity of the cross-coupling not used in subsequent coupling reactions.[27]
reaction involving 2,4-dichloro-5-methylpyrimidine (15, To test the compatibility of aldehydes with organobis-
the yields for their synthesis were low, and the species were
Scheme 2). Upon using 0.4 equiv. of triphenylbismuth, a muthanes in the context of a palladium cross-coupling reac-
mixture of mono- and diphenyl products 16 and 17 was tion, we sought to prepare a formylphenylbismuth reagent
obtained in modest yield, and there was a slight preference directly from 18g. The question we asked ourselves was how
for the compound resulting from the coupling at the 4-posi- to liberate the aldehyde without breaking the C–Bi bond.
tion (as indicated by NOE experiments). Fortunately, the To our great pleasure, tris(3-formylphenyl)bismuthane (20)
yield of monophenyl compound 16 could be considerably was obtained in 75% yield simply by exposing 18g to aque-
ameliorated, without increasing the amount of diphenyl ous acidic conditions (Scheme 3). These results show that
product 17, by using 0.7 equiv. of triphenylbismuth.
the C–Bi is strong enough to resist protic conditions. This
reaction was performed successfully on a gram scale, and
no decomposition was noticed after 1 month upon storing
the reagent at room temperature in air. A limited number
of organometallic reagents bearing formylaryl groups have
been described in the literature,[28,29] and to the best of our
knowledge, only three reports of the hydrolysis of acetals di-
rectly on the organometallic reagent could be found, those
being with germanium,[30] antimony,[31] and mercury.[32]
To unequivocally confirm the structure of this new
organometallic reagent, compound 20 was recrystallized.
X-ray diffraction analysis revealed that the compound is
pyramidal and has C–Bi–C angles of 92.02° and C–Bi bond
Scheme 2. Regioselectivity of cross-coupling between triphenylbis-
muth and 2,4-dichloro-5-methylpyrimidine (15).
To explore the full potential of organobismuthanes in the lengths of 2.266 Å (Figure 1). The structure clearly shows
transfer of highly functionalized groups, we next prepared the presence of three aryl groups each bearing a formyl
functionalized organobismuth reagents 18a–j and coupled moiety.
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P. Petiot, A. Gagnon
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Table 3. Cross-coupling of functionalized triaryl- and triheteroarylbismuthanes 18a–j with 2-chloroquinoxaline (7a).
[a] Yield of isolated pure product. [b] 10 mol-% of Pd(PPh3)4 and 0.7 equiv. of Ar3Bi were used.
We next verified the transferability of the formylphenyl
group of 20 by conducting the cross-coupling reaction with
pyrazine 7a under our standard conditions and obtained
the corresponding cross-coupling product 21 in 80% iso-
lated yield (Scheme 4).
Isolated examples of cross-coupling reactions leading to
the transfer of a formylaryl group on azines and diazines
have been reported.[33–36] However, to the best of our
knowledge, the only general methods for the coupling of
Scheme 3. Synthesis of tris(3-formylphenyl)bismuthane (20).
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Cross-Coupling of Functionalized Aryl- and Heteroarylbismuthanes
Experimental Section
Typical Procedure for the Cross-Coupling Reaction between Organo-
bismuthanes and 2-Chloro-, 2-Bromo-, and 2-Triflyl(di)azines: In a
sealed tube, the 2-halo(2-triflyl)azine or -diazine (0.30 mmol) was
dissolved in dry N,N-dimethylformamide (4.5 mL). Cesium carbon-
ate (0.60 mmol) was added, followed by tetrakis(triphenylphos-
phane)palladium (0.015 mmol) and the arylbismuth reagent
(0.12 mmol). Argon was bubbled into the reaction mixture for
5 min. The tube was sealed and heated at 130 °C overnight. The
reaction mixture was cooled to room temperature, diluted with a
saturated aqueous solution of sodium hydrogen carbonate (50 mL),
and extracted with ethyl acetate (2ϫ 50 mL). The combined
organic phases were washed with a saturated aqueous solution of
sodium hydrogen carbonate (2ϫ 50 mL) and brine (2ϫ 50 mL),
dried with sodium sulfate, filtered, and concentrated under reduced
pressure. The crude product was purified by flash column
chromatography on silica gel (hexanes/ethyl acetate) to afford the
corresponding product.
Figure 1. ORTEP diagram of compound 20. Thermal ellipsoids are
shown at the 50% probability level.
CCDC-949485 (for 20) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental details, characterization data, and copies of the
1H and 13C NMR spectra of all key intermediates and final com-
pounds.
Scheme 4. Cross-coupling reaction between (formylphenyl)bismuth
20 and 2-chloroquinoxaline (7a).
Acknowledgments
This work was supported by the Natural Sciences and Engineering
Research Council of Canada (NSERC) and the Université du
Québec à Montréal (UQAM). P. P. thanks UQAM for a FARE
scholarship. We thank Michel Simard from Université de Montréal
for the X-ray analysis of compound 20 and Dr. Alexandre Arnold
for assistance with advanced NMR studies.
highly functionalized aryl groups (including formylaryl) are
those developed by Knochel that involve organozinc[37] and
organoindium reagents.[38] Contrary to organozinc species,
organobismuthanes are not moisture-sensitive and can be
manipulated in air.
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We have developed an efficient protocol for the cross-
coupling of functionalized aryl- and heteroarylbismuth rea-
gents with 2-halo(or 2-triflyl)pyridines, -pyrimidines, -pyr-
azines, and -pyridazines bearing reactive moieties. This
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groups are transferred from the bismuthane in the course
of the coupling process. The coupling on 2,4-dichloropyr-
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phenyl product resulting from the reaction at the 4-position.
We demonstrated that functional group manipulation di-
rectly on the organobismuth species is possible and gives
access to functionalized aryl groups that are challenging to
transfer such as formylaryl groups. The cross-coupling of a
formylphenyl group was efficiently accomplished by using
our protocol. Studies on the derivatization of organobis-
muthanes and their use in cross-coupling reactions with
other electrophiles are in progress in our laboratory. Results
will be reported in due course.
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Received: June 10, 2013
Published Online: July 16, 2013
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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