Synthesis of conjugated tri(hetero)aryl derivatives based on one-pot double Suzuki-miyaura couplings using bifunctional dipotassium phenylene-1,4- bis(trifluoroborate)

Article abstract of DOI:10.1055/s-0030-1260581

An efficient one-pot double Suzuki-Miyaura cross--coupling reaction between bifunctional phenylene-1,4-bis(potassium trifluoroborate) and aryl and heteroaryl bromides is described. The scope and limitations of this methodology that enables the synthesis o

Full text of DOI:10.1055/s-0030-1260581

LETTER
1761
Synthesis of Conjugated Tri(hetero)aryl Derivatives Based on One-Pot Double
Suzuki–Miyaura Couplings Using Bifunctional Dipotassium Phenylene-1,4-
Bis(Trifluoroborate)
S
ynthesis of Conju
n
gate
d
T
ri(he
t
tero)ar
o
yl Derivative
n
s
io Salomone, Marilena Petrera, Donato Ivan Coppi, Filippo Maria Perna, Saverio Florio, Vito Capriati*
Dipartimento Farmaco-Chimico, Università di Bari ‘A. Moro’, Consorzio Interuniversitario Nazionale ‘Metodologie e Processi Innovativi
di Sintesi’ C.I.N.M.P.I.S., Via E. Orabona 4, 70125 Bari, Italy
Fax +39(080)5442539; E-mail: capriati@farmchim.uniba.it
Received 4 April 2011
This paper is dedicated to Professor Alfredo Ricci on the occasion of his retirement.
employing bifunctional organotrifluoroborates are still
Abstract: An efficient one-pot double Suzuki–Miyaura cross-
quite limited.10 Herein, we wish to report an efficient pro-
tocol for one-pot double SM couplings exploiting dipotas-
sium phenylene-1,4-bis(trifluoroborate) (2; Scheme 1) as
coupling reaction between bifunctional phenylene-1,4-bis(potassi-
um trifluoroborate) and aryl and heteroaryl bromides is described.
The scope and limitations of this methodology that enables the syn-
thesis of tri(hetero)aryl derivatives, potentially useful as drugs and the starting material; the scope and limitations of such a
in the field of materials science, have also been probed.
synthetic procedure have been probed as well.
Key words: terphenyls, arylation, cross-coupling, epoxides,
Suzuki–Miyaura reaction
Bistrifluoroborate 2 was conveniently prepared in 92%
yield by treatment of a methanol solution of the corre-
sponding commercially available bis(boronic acid) 1 with
a saturated aqueous solution of KHF2 (see Scheme 1 and
the Supporting Information).11
The development of efficient methods for the synthesis of
poly(hetero)aryl systems is currently being pursued by or-
ganic chemists as these compounds are essential to medic-
inal chemistry1 and materials science.2 The synthesis, in
particular of functionalized terphenyl derivatives is also
challenging as these molecules are nearly ubiquitous in
nature3 and display a variety of intriguing biological activ-
ities, which also serve as the basis for the synthesis of
powerful new therapeutic agents.4 Among the many syn-
thetic protocols available, the Suzuki–Miyaura (SM)
cross-coupling reaction5 has recently emerged as one of
the most powerful and attractive carbon–carbon bond-
forming methodologies for the synthesis of conjugated or-
ganic molecules. In this context, organotrifluoroborates
have often proven largely superior and more versatile
compared to their boronic acid and boronate ester ana-
logues in terms of stability, efficiency, favorable physical
properties, atom economy and scalability.6 Recently, en-
dogenous aryl boronic acid and fluoride, both derived
from the hydrolysis of organotrifluoroborates, have also
been shown to play key roles in improving the perfor-
mance of the coupling reaction and in suppressing side
reactions such as protodeboronation and oxidative homo-
coupling reactions.7 The simultaneous introduction of two
aryl substituents onto a central phenylene core may in
principle be carried out either starting from a dihalogenat-
ed aryl precursor or from an organodimetallic reagent.8 To
the best of our knowledge, while the use of trifluoro-
borates in biaryl synthesis is well documented,9 examples
of straightforward assembly of triaryl aromatic moieties
KHF2
(HO)2B
B(OH)2
KF3B
BF3K
MeOH–H2O
r.t.
1
2
92%
Scheme 1
The white free-flowing powder initially obtained was suc-
cessfully recrystallized from acetone–water (2:1) as color-
less needle-shaped crystals indefinitely stable to moisture
and air. In contrast to bifunctional dipotassium perfluo-
rophenylene-1,2-bis(trifluoroborate), which was shown to
exist in solution as a mixture of two equilibrating fluoro-
borate species,12 in the case of compound 2, 1H NMR, 13C
NMR, 11B NMR and 19F NMR spectra each showed a sin-
gle set of signals.13
With compound 2 in hand, we were initially interested in
developing an optimum set of reaction conditions for the
SM palladium-catalyzed cross-coupling reaction employ-
ing such a salt and ortho-bromostyrene oxide (3a) as cou-
pling partners. This is because the epoxide ring is one of
the most widely used functional groups in organic synthe-
sis and regioselective nucleophile-promoted intermolecu-
lar or intramolecular ring-opening reactions can allow the
introduction of different moieties on the original organic
skeleton, thereby leading to useful building blocks or
ligands.14 Additionally, as oxiranyllithiums, they may
also act as key synthons for the asymmetric synthesis of
more substituted epoxides and products that can be de-
rived from them.15 Examples of SM reactions wherein an
epoxide resides in one of the two coupling partners are
still rare and not well documented in the literature.16
To date, the application of Buchwald conditions
SYNLETT 2011, No. 12, pp 1761–1765
x
x
.x
x
.2
0
1
1
Advanced online publication: 05.07.2011
DOI: 10.1055/s-0030-1260581; Art ID: S02911ST
© Georg Thieme Verlag Stuttgart · New York

1762
A. Salomone et al.
LETTER
[Pd2(dba)2·C6H6 (1 mol%), S-Phos (4 mol%), toluene, 100
°C, Cs2CO3 (2 equiv)] has successfully allowed cross-
couplings between different boronic acids and enantio-
merically enriched bromoarylglycidyl ethers.16a In addi-
tion, just two examples of Ag(I)-promoted SM cross-
couplings of n-alkylboronic acids with stereodefined ep-
oxy vinyl iodides have been described.16b,c Problems to be
circumvented in such types of arylations are related to
possible isomerization of the epoxide in the final cross-
coupled product due to the intervention of a palladium-
catalyzed 1,2-H shift reaction16a or the formation of ring-
opening products as in the case, for example, of competi-
tive hydrolyses.16d Interestingly, Molander succeeded in
performing the first SM cross-coupling reaction involving
an epoxyalkyltrifluoroborate derivative simply by de-
creasing the amount of water in the solvent mixture THF–
water from 10:1 to 40:1, such that the epoxide ring was
still retained in the final product after refluxing the reac-
tion mixture for three days in the presence of PdCl2(dppf)
·CH2Cl2 (9 mol%) and Cs2CO3 (3 equiv) as the base. We
were pleased to find that by employing the same precata-
lyst [PdCl2(dppf) ·CH2Cl2 (5 mol%)] and K2CO3 (3 equiv)
as a base, ortho-bromostyrene oxide (3a; 2.1 equiv) clean-
ly underwent a cross-coupling reaction with the bifunc-
tional salt 2 (1 equiv) and the desired p-terphenyl 4a
(Scheme 2) was isolated in 80% yield after warming the
reaction mixture, under an argon atmosphere, at 50 °C for
24 hours and with a THF–water ratio of only 5:1.17
O
O
O
PdCl2(dppf)⋅CH2Cl2
K2CO3
2 +
Br
THF–H2O (5:1)
50 °C, 24 h
3a
4a (80%)
Scheme 2
Table 1, entries 8 and 9). Bromo heterocyclic substrates
could also participate in the coupling process. Using elec-
tron-rich five-membered ring heterocycles such as 2-bro-
mothiophene (3k), 2-bromo-5-chlorothiophene (3l), 2-
bromothiazole (3m), and 3-bromofuran (3n), 40–75%
yields of the expected symmetrically substituted products
4k–n were obtained (Table 1, entries 10–13). An interest-
ing tetraazaterphenyl derivative 4o was also synthesized
in 60% yield from readily available 5-bromopyrimidine
(3o; Table 1, entry 14). Electron-deficient 4-bromoiso-
quinoline (3p) could also be successfully coupled to af-
ford bis(4-isoquinolyl)-substituted benzene 4p in 80%
yield (Table 1, entry 15). Terphenyl and oligoazaterphe-
nyl derivatives exhibit attractive optical properties that
can be tuned over a wide spectral range by simply varying
the nature and position of substituents (or of N atoms in
the case of oligoaza derivatives) on the conjugated sys-
tem.20 In our case, compounds 4a,b show absorption max-
ima at lmax = 259 and 257 nm (CHCl3) and emission
maxima at lmax = 346 and 347 nm, respectively. Interest-
ingly, the coupled product 4p, with the absorption maxi-
mum at lmax = 336 nm (CHCl3), shows blue fluorescence
with lmax = 432 nm (see the Supporting Information).21
Bis(trifluoroborate) 2 could also be successfully partnered
either with the functionalized alkenyl bromide 3q or with
benzyl bromide (3r) to give the corresponding bis(alke-
nyl)- and bis(benzyl)-coupled products 4q,r in good to ex-
cellent yields (60–95%; Scheme 3). Of note, the coupling
reaction with alkenyl bromide 3q was completely ste-
reospecific with regard to olefin geometry.22
The scope of the reaction was then extended to a series of
different (hetero)aryl bromides bearing electron-donating,
‘neutral’ and electron-withdrawing substituents in order
to prepare symmetrical tri(hetero)aryl derivatives accord-
ing to a one-pot strategy. By using the optimal conditions
found for compound 4a, the relatively higher yields (80–
91%) in the desired coupled products (4b–e) were ob-
tained when aryl bromides with a ‘neutral’ substituent
(3b) or with a carbonyl functional group (3c–e) participat-
ed in the process (Table 1, entries 1–4). Aryl bromides
bearing electron-rich groups at the ortho or para posi-
tions, such as hydroxyl and amino groups (3g,h), also un-
derwent cross-coupling with salt 2 to give terphenyls
4g,h, albeit in moderate yields (40–49%; Table 1, entries
6 and 7).
Br
O
O
O
Ph
3q
PdCl2(dppf)⋅CH2Cl2
Ph
Ph
4q (60%)
K2CO3
Of particular note, coupling module 3f, which has iodine
and fluorine atoms on the aromatic ring, afforded sym-
metrical halogenated terphenyl 4f in 61% yield (Table 1,
entry 5), thus chemoselectively introducing aromatic
components onto the central phenylene core in the place
of iodine atoms.18 In principle, the availability in the final
product (4f) of two additional bromine atoms may allow
iteration of the above cross-coupling methodology for the
synthesis of fluorinated oligophenylenes which are of in-
terest in materials science.19
2
THF–H2O (5:1)
50 °C, 24 h
Ph
Ph
Br
Ph
4r (95%)
3r
Scheme 3
With the aim of extending further the scope of such dou-
ble SM couplings, we decided to investigate the possibil-
ity of performing an unprecedented one-pot three-
component palladium-catalyzed cross-coupling reaction
by means of a chemoselective introduction of two differ-
ent aromatic moieties onto the central phenylene unit.
Aryl bromides bearing electron-withdrawing substituents
at the para position, such as ester (3i) and nitro (3j)
groups, were also efficiently cross-coupled with 2 to give
the desired terphenyls 4i,j in good yields (64–75%;
Synlett 2011, No. 12, 1761–1765 © Thieme Stuttgart · New York

LETTER
Synthesis of Conjugated Tri(hetero)aryl Derivatives
1763
Table 1 Suzuki–Miyaura One-Pot Double Coupling between Bifunctional Salt 2 and (Hetero)aryl Bromides 3a
PdCl2(dppf)⋅CH2Cl2
+
KF3B
BF3K
(Het)ArBr
(Het)Ar
Ar(Het)
K2CO3, THF–H2O (5:1)
50 °C, 24 h
3b–p
2
4b–p
Entry (Het)ArBr
Product [Yield (%)]b
Entry (Het)ArBr
Product [Yield(%)]b
Br
NO2
O2N
NO2
1
9
Et
Br
3j
4j (75)
3b
4b (80)
Br
O
O
O
O
2
10
11
12
Br
S
S
S
COMe
3k
4k (60)
3c
4c (89)
Br
3
4
Br
Cl
S
S
S
Cl
Cl
CHO
3l
4l (40)
3d
4d (91)
CHO
O
O
N
N
S
N
S
Br
S
Br
3m
4m (63)
4e (80)
3e
F
F
Br
I
O
O
5
6
13
14
Br
Br
Br
F
O
4n (75)
3f
4f (61)
3n
NH2
H2N
Br
N
N
N
Br
N
N
N
N
NH2
3o
4o (60)
3g
4g (40)
N
Br
Cl
Cl
OH
Cl
7
8
15
HO
OH
Br
N
3h
4h (49)
3p
4p (80)
EtO2C
EtO2C
CO2Et
Br
4i (64)
3i
a Reagents and conditions: 2 (1 equiv), 3b–p (2.1 equiv), PdCl2(dppf)·CH2Cl2 (5 mol%), K2CO3 (3 equiv), THF–H2O (5:1), 50 °C, 24 h, Ar
atmosphere.
b Isolated yields after silica gel flash chromatography.
To date, such a challenging task has been successfully ac- In principle, in order to achieve a chemoselective aromat-
complished either by exploiting the different reactivities ic substitution in the highly symmetrical salt 2, the two
of the electrophilic sites23 or by modulating the reactivity borate functions should undergo hydrolysis, in the basic
(e.g., changing the electron density and/or the hybridiza- reaction medium, at a different rate, before coupling reac-
tion state) of the boron reagents, generally according to tion occurs. To this end, hydrolysis of 2 was investigated
consecutive SM couplings.24 Of note, a one-pot double by 1H NMR spectroscopy (room temperature) in a solely
SM coupling of symmetrical dibromoaryl and hetero- deuterated aqueous medium in the presence of K2CO3 (3
cyclic substrates with two different aryl boronic acids, si- equiv) as a function of time. After five minutes of reaction
multaneously present in the reaction mixture, has recently time, the percentage of the tetradeuterated salt 2-D4 (39%)
been accomplished by taking advantage of the difference was already as high as that of the dideuterated salt 2-D2
in reactivity of each boronic acid.25
(31%), with 30% remaining of the starting bis(trifluoro-
Synlett 2011, No. 12, 1761–1765 © Thieme Stuttgart · New York

1764
A. Salomone et al.
LETTER
borate) 2, instead (see Scheme 4 and the Supporting Infor- Supporting Information for this article is available online at
mation).
http://www.thieme-connect.com/ejournals/toc/synlett.
At a longer reaction time, formation of 2-D4 was even
more sped up to the detriment of 2-D2, with 66% and 23%
as the percentages of 2-D4 and 2-D2, respectively, after 10
minutes vs. 84% and 12% after 15 minutes. The rapid for-
mation of 2-D4 is, therefore, a limit for the selective and
sequential in situ installation of each aromatic moiety onto
the central phenylene core.
Acknowledgment
This work was carried out under the framework of the National Pro-
jects PRIN ‘Stereoselezione in Sintesi Organica. Metodologie ed
Applicazioni’ (Code: 2007FJC4SF_002) and FIRB ‘Futuro in
Ricerca’ (Code: CINECA RBF12083M5N) and financially suppor-
ted also by the University of Bari and by the Interuniversities
Consortium C.I.N.M.P.I.S. The authors would like to acknowledge
Dr. Valeria Volpe for her contribution to the Experimental Section
and are also indebted to Dr. Konrad Koszinowski (Ludwig Maximi-
lians Universität, München, Germany) for providing HRMS data.
Thus, to better discriminate between the two trifluoro-
borate sites in salt 2, we envisaged that the employment of
two electrophilic partners with complementary electronic
properties might be a suitable strategy to pursue.
References and Notes
K2CO3
K2CO3
2
KF3B
B(OD)2
(OD)2B
B(OD)2
(1) Arafa, R. K.; Ismail, M. A.; Munde, M.; Wison, W. D.;
Wenzler, T.; Brun, R.; Boykin, D. W. Eur. J. Med. Chem.
2008, 43, 2901.
(2) (a) Sharmoukh, W.; Ko, K. C.; Park, S. Y.; Ko, J. H.; Lee, J.
M.; Noh, C.; Lee, J. Y.; Son, S. U. Org. Lett. 2008, 10, 5365.
(b) Umemoto, Y.; Ie, Y.; Saeki, A.; Seki, S.; Tagawa, S.;
Aso, Y. Org. Lett. 2008, 10, 1095. (c) Lee, W.; Kang, Y.;
Lee, P. H. J. Org. Chem. 2008, 73, 4326. (d) Karsten, B. P.;
Janssen, R. A. J. Org. Lett. 2008, 10, 3513.
D2O
r.t.
D2O
r.t.
2-D2
2-D4
Scheme 4
By applying the general conditions set up for the synthesis
of symmetrical terphenyl derivatives, it was gratifying to
find that the one-pot coupling reaction of bifunctional salt
2 (1 equiv) with p-bromobenzonitrile (3s; 1 equiv) and 1-
bromo-2-ethylbenzene (3b; 1 equiv) did afford the desired
unsymmetrical terphenyl 4s in 40% isolated yield together
with only 10% of the biscoupled product 4b (Scheme 5).26
(3) Liu, J. K. Chem. Rev. 2006, 106, 2209.
(4) For selected examples, see: (a) Simoni, D.; Giannini, G.;
Roberti, M.; Rondanin, R.; Baruchello, R.; Rossi, M.;
Grisolia, G.; Invidiata, F. P.; Aiello, S.; Marino, S.;
Cavallini, S.; Siniscalchi, A.; Gebbia, N.; Crosta, L.;
Grimaudo, S.; Abbadessa, V.; Di Cristina, A.; Tolomeo, M.
J. Med. Chem. 2005, 48, 4293. (b) Roberti, R.;Pizzirani, D.;
Recanatini, M.; Simoni, D.; Grimaudo, S.; Di Cristina, A.;
Abbadessa, V.; Gebbia, N.; Tolomeo, M. J. Med. Chem.
2006, 49, 3012. (c) Ismail, M. A.; Arafa, R. K.; Brun, R.;
Wenzler, T.; Miao, Y.; Wilson, W. D.; Generaux, C.;
Bridges, A.; Hall, J. E.; Boykin, D. W. J. Med. Chem. 2006,
49, 5324. (d) Bey, E.; Marchais-Oberwinkler, S.; Negri, M.;
Kruchten, P.; Oster, A.; Klein, T.; Spadaro, A.; Werth, R.;
Frotscher, M.; Birk, B.; Hartmann, R. W. J. Med. Chem.
2009, 52, 3703. (e) Oehlrich, D.; Didier, J.-C.; Berthelot,
D. J.-C.; Gijsen, H. J. M. J. Med. Chem. 2011, 54, 669.
(5) (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(b) Miyaura, N. Top. Curr. Chem. 2002, 219, 11.
(c) Miyaura, N. In Metal-Catalyzed Cross-Coupling
Reactions; de Meijere, A.; Diederich, F., Eds.; Wiley-VCH:
Weinheim, 2004, 41–124.
(6) For leading reviews, see: (a) Molander, G. A.; Ellis, N. Acc.
Chem. Res. 2007, 40, 275. (b) Darses, S.; Genet, J.-P. Chem.
Rev. 2008, 108, 288. (c) Molander, G. A.; Canturk, B.
Angew. Chem. Int. Ed. 2009, 48, 9240.
(7) Butters, M.; Harvey, J. N.; Jover, J.; Lennox, A. J. J.; Lloyd-
Jones, G. C.; Murray, P. M. Angew. Chem. Int. Ed. 2010, 49,
5156.
(8) The Suzuki cross-coupling reactions of symmetrical
dihalobenzenes with arylboronic acids and esters have often
led to mixtures of mono- and biscoupled products, albeit
with a different selectivity according to the nature of both the
halogen employed and the boron-containing species; for a
survey, see: (a) Sinclair, D. J.; Sherburn, M. S. J. Org.
Chem. 2005, 70, 3730. (b) The double Suzuki cross-
coupling of phenyl-1,4-diboronic acid bispinacol ester with
aryl halides has also been investigated: Chaumeil, H.; Drian,
C. L.; Defoin, A. Synthesis 2002, 757.
CN
CN
PdCl2(dppf)⋅CH2Cl2
K2CO3 (3 equiv)
3b
+
2
+
THF–H2O (5:1)
50 °C, 24 h
+ 4b (10%)
Br
3s
4s (40%)
Scheme 5
In conclusion, we have shown that dipotassium phe-
nylene-1,4-bis(trifluoroborate) (2) behaves as a powerful
partner for performing palladium(0)-catalyzed one-pot
double SM cross-couplings with aryl, heteroaryl, alkenyl
and benzyl bromides to give the expected coupled prod-
ucts in moderate to good yields. For the first time, the
scope and limitations of such a methodology were also in-
vestigated with the result that the synthetic protocol set up
allowed the employment of a variety of substitution pat-
terns, including an epoxide ring. An unsymmetrically sub-
stituted p-terphenyl was also obtained starting from aryl
bromides with complementary electronic properties. Such
a straightforward methodology represents a versatile and
alternative strategy for the preparation of a variety of tri-
aryl(heteroaryl) derivatives which are of interest owing to
their promising applications as drugs and in the field of
materials science. The synthesis of novel bifunctional de-
rivatives potentially useful in chemoselective SM-type
cross-coupling reactions as well as in multistep organic
synthesis is currently being investigated.27
Synlett 2011, No. 12, 1761–1765 © Thieme Stuttgart · New York

LETTER
Synthesis of Conjugated Tri(hetero)aryl Derivatives
1765
(9) For selected examples, see: (a) Molander, G. A.; Biolatto,
B. J. Org. Chem. 2003, 68, 4302. (b) Molander, G. A.;
Petrillo, D. E.; Landzberg, N. R.; Rohanna, J. C.; Biolatto, B.
Synlett 2005, 1763. (c) Molander, G. A.; Canturk, B.;
Kennedy, L. E. J. Org. Chem. 2009, 74, 973.
(10) (a) Gueogjian, K.; Singh, F. V.; Pena, J. M.; Amaral, M. F.
Z. J.; Stefani, H. A. Synlett 2010, 427. (b) Viera, A. S.;
Cunha, R. L. O. R.; Klitzke, C. F.; Zukerman-Schpector, J.;
Stefani, H. A. Tetrahedron 2010, 66, 773.
(11) Vedejs, E.; Chapman, R. W.; Fields, S. C.; Lin, S.; Schrimpf,
M. R. J. Org. Chem. 1995, 60, 3020.
(12) Chase, P. A.; Henderson, L. D.; Piers, W. E.; Parvez, M.;
Clegg, W.; Elsegood, M. R. J. Organometallics 2006, 25,
349.
and higher temperatures proved to be less effective and
provided poor yield (15–57%) of product 4a. When Cs2CO3
was used as a base instead of K2CO3, the yield of 4a was
75%, all other conditions being identical. Comparable
results in terms of yield and reaction time were also obtained
by employing up to 6 equiv of K2CO3.
(18) Double couplings on bromoiodobenzenes, promoted by an
excess of phenylboronic acid, have often led to mixtures of
mono- and diarylated products; see: (a) Liu, L.; Zhang, Y.;
Xin, B. J. Org. Chem. 2006, 71, 3994. (b) Greenfield, A.
A.; Butera, J. A.; Caufield, C. E. Tetrahedron Lett. 2003, 44,
2729.
(19) Babudri, F.; Farinola, G. M.; Naso, F. Synlett 2009, 2740.
(20) (a) Operamolla, A.; Omar, O. H.; Babudri, F.; Farinola, G.
M.; Naso, F. J. Org. Chem. 2007, 72, 10272. (b) Gompper,
R.; Mair, H.-J.; Polborn, K. Synthesis 1997, 696.
(21) Similarly, the tetraazaterphenyl derivative 4o revealed an
absorption at lmax = 279 (DMSO) and fluorescence emission
maximum at lmax = 428 nm (see ref. 20b).
(22) The E configuration of double bonds in terphenyl 4q was
ascertained from 2D NOESY correlations.
(23) (a) Miguez, J. M. A.; Adrio, L. A.; Sousa-Pedrares, A.; Vila,
J. M.; Hii, K. K. M. J. Org. Chem. 2007, 72, 7771. (b) Gan,
X.; Jiang, W.; Wang, W.; Hu, L. Org. Lett. 2009, 11, 589.
(c) Nawaz, M.; Ibad, M. F.; Abid, O.-U.-R.; Khera, R. A.;
Villinger, A.; Langer, P. Synlett 2010, 150.
(24) The use of boron reagents for orthogonal functionalization
through Suzuki–Miyaura cross-couplings has recently been
highlighted; see: Tobisu, M.; Chatani, O. Angew. Chem. Int.
Ed. 2009, 48, 3565.
(13) (a) Spectroscopic data of 2 are reported in the Supporting
Information. The relative rapid 11B quadrupole relaxation is
most probably responsible for the missing one-bond 11B,19F
scalar coupling. Unfortunately, resolution in 11B NMR
spectrum did not improve even on employing a modified 11
B
NMR pulse sequence, as suggested: Oliveira, R. A.; Silva, R.
O.; Molander, G. A.; Menezes, P. H. Magn. Reson. Chem.
2009, 47, 873. (b) An X-ray crystallographic analysis is also
underway and the results will be reported in due course.
(14) (a) Hodgson, D. M.; Bray, C. D. In Aziridine and Epoxides
in Organic Synthesis; Yudin, A. K., Ed.; Wiley-VCH:
Weinheim, 2006, 145–184. (b) Padwa, A.; Murphree, S. S.
ARKIVOC 2006, (iii), 6. (c) Schneider, C. Synthesis 2006,
3919. (d) Capriati, V.; Florio, S.; Luisi, R.; Perna, F. M.;
Salomone, A.; Gasparrini, F. Org. Lett. 2005, 7, 4895.
(e) García-Delgado, N.; Reddy, K. S.; Solà, L.; Riera, M.;
Pericàs, M. A.; Verdaguer, X. J. Org. Chem. 2005, 70,
7426. (f) Capriati, V.; Florio, S.; Luisi, R.; Perna, F. M.;
Salomone, A. J. Org. Chem. 2006, 71, 3984. (g) Salomone,
A.; Capriati, V.; Florio, S.; Luisi, R. Org. Lett. 2008, 10,
1947. (h) Huang, K.; Wang, H.; Stepanenko, V.; De Jesús,
M.; Torruellas, C.; Correa, W.; Ortiz-Marciales, M. J. Org.
Chem. 2011, 76, 1883.
(25) Beaumard, F.; Dauban, P.; Dodd, R. H. Org. Lett. 2009, 11,
1801.
(26) In contrast to what was observed in the one-pot coupling
reaction of N-Boc-2,5-dibromopyrrole with two different
boronic acids (see ref. 25), in our case, the addition up to 3
equiv of LiCl had a detrimental effect on the yield of 4s
which, indeed, dramatically decreased to 15%. Further
investigations are currently underway to find more general
conditions for effecting unsymmetrical double SM
couplings employing salt 2 or different bifunctional
derivatives and results will be reported in due course.
(27) General Procedure for the Synthesis of Compounds
4a–s: To a suspension of dipotassium phenylene-1,4-bis-
(trifluoroborate) (2; 1.0 mmol) in THF–H2O (5.0 mL + 1.0
mL), K2CO3 (3 mmol), aryl(heteroaryl) bromide (2.1 mmol)
(note: for the synthesis of compound 4s, 1.0 mmol of both 3s
and 3b were employed instead) and PdCl2(dppf)·CH2Cl2 (5
mol%) were sequentially added under an argon atmosphere.
After the mixture was stirred at 50 °C for 24 h in a closed
reactor, the resulting solution was cooled to r.t., diluted with
brine (10 mL) and extracted with Et2O (3 × 10 mL). The
solvent was finally stripped off in vacuo and the crude
product so obtained was purified by silica gel column
chromatography (see the Supporting Information for details)
to provide the desired tri(hetero)aryl derivative.
(15) (a) Capriati, V.; Florio, S.; Luisi, R. Chem. Rev. 2008, 108,
1918. (b) Capriati, V.; Florio, S.; Salomone, A.
Oxiranyllithiums as Chiral Synthons for Asymmetric
Synthesis, Chap. 4, In Stereochemical Aspects of
Organolithium Compounds, Vol. 26; Gawley, R. E., Ed.,
In Topics in Stereochemistry, Siegel, J. S., Ed.; Verlag
Helvetica Acta: Zürich, 2010, 135-164 (c) Capriati, V.;
Florio, S.; Perna, F. M.; Salomone, A. Chem. Eur. J. 2010,
16, 9778.
(16) (a) Cattoën, X.; Pericàs, M. A. J. Org. Chem. 2007, 72,
3253. (b) Falck, J. R.; Kumar, P. S.; Reddy, Y. K.; Zou, G.;
Capdevila, J. H. Tetrahedron Lett. 2001, 42, 7211. (c) Zou,
G.; Reddy, Y. K.; Falck, J. R. Tetrahedron Lett. 2001, 42,
7213. (d) Molander, G. A.; Ribagorda, M. J. Am. Chem. Soc.
2003, 125, 11148.
(17) Different solvent mixtures (e.g., MeOH–H2O, 10:1; DMF–
H2O, 10:1; dioxane–H2O, 5:1), higher amount of H2O (e.g.,
THF–H2O, 1:1), other Pd(II) precatalysts [e.g., Pd(OAc)2]
Synlett 2011, No. 12, 1761–1765 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or
emailed to multiple sites or posted to a listserv without the copyright holder's express written permission.
However, users may print, download, or email articles for individual use.