Palladium-catalyzed unsymmetrical aryl couplings in sequence leading to o-teraryls: Dramatic olefin effect on selectivity

Article abstract of DOI:10.1039/c000526f

Selectively substituted o-teraryls are obtained by palladium/norbornene- catalyzed reaction of aryl iodides, aryl bromides and aryl boronic acids in ordered sequence; high selectivity is attained thanks to the addition of diethyl maleate acting as palladi

Full text of DOI:10.1039/c000526f

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Palladium-catalyzed unsymmetrical aryl couplings in sequence leading to
o-teraryls: dramatic olefin effect on selectivityw
Elena Motti, Nicola Della Ca’, Sara Deledda, Emanuela Fava, Francesca Panciroli and
Marta Catellani*
Received 11th January 2010, Accepted 13th April 2010
First published as an Advance Article on the web 11th May 2010
DOI: 10.1039/c000526f
Selectively substituted o-teraryls are obtained by palladium/
norbornene-catalyzed reaction of aryl iodides, aryl bromides and
aryl boronic acids in ordered sequence; high selectivity is attained
thanks to the addition of diethyl maleate acting as palladium ligand.
Olefins are known to remarkably influence transition-metal-
catalyzed processes.1 In particular, oxidative addition,1a,f
reductive elimination1k and coupling1a steps have been
reported to be quite sensitive to their influence. Controlling
a sequence of several organometallic steps by olefin addition
should be regarded as a very simple and effective way to arrive
at complex molecules selectively. To this aim we have
addressed the synthesis of o-teraryl derivatives, which belong
to an important class of aromatic compounds exhibiting unique
properties useful in the field of advanced materials and in
medicinal chemistry.2 In particular, ortho-teraryls are interesting
for molecular dynamics properties2b and biological activity.2c
We have developed a one-pot reaction involving sequential
cross-coupling of iodoarenes, containing ortho-electron-
donating substituents, with bromoarenes bearing electron-
withdrawing groups, followed by aryl coupling with arylboronic
acids (Scheme 1; R1 = electron-donating, R2 = electron-
withdrawing group). Owing to the directing action of the
palladium/norbornene dual catalyst,3 the aryl halides couple
Scheme
2
Palladium/norbornene-catalyzed aryl–aryl coupling
followed by Heck reaction.
ortho to the original C–I bond, which in its turn couples with
aryl boronic acids in the final step, leading to o-teraryls.
The selectivity in the expected cross-coupling product 3 turns
out to be low, however. Thus, the reaction of o-iodotoluene
(1; R1 = Me), methyl o-bromobenzoate (2; R2 = CO2Me) in
1 : 1 molar ratio with phenylboronic acid under the conditions of
Scheme 1 led to a mixture of three products 3, 54 and 64 (R1 =
Me, R2 = CO2Me) in 0.6 : 1 : 1 molar ratio. The lack of selectivity
is in sharp contrast with the analogous reaction with olefins
previously reported by us (Scheme 2),3e which is highly selective.
We reasoned that the origin of this disappointing behavior
had to be found in the absence of an appropriate olefin.
The latter worked as a reagent in the reaction depicted in
Scheme 2 but could also act as ligand. We were pleased to find
that the addition of an olefin, containing electron-withdrawing
substituents and not involved as reagent, increased the selectivity
in compound 3 dramatically (Scheme 1).
We thus decided to explore the behavior of a series of activated
olefins in the reaction of Scheme 1. They were found to be effective
in the order: diethyl or dimethyl maleate Z diethyl fumarate >
methyl cinnamate c methyl crotonate. Table 1 reports the results
obtained with ortho-substituted aryl iodides and bromides in the
presence and in the absence (in parentheses) of diethyl maleate,
which turned out to be the olefin of choice.
As shown in Table 1, entries 1–9, the non selective reaction
leading to products 3–6 (yields reported in parentheses) can be
converted into a selective one in the presence of diethyl
maleate in 1.6 : 1 molar ratio to the aryl halides.5 Aryl iodides
containing an ortho alkyl substituent such as the methyl and
i-propyl ones (entries 1, 4) or additional methyl groups in meta
and para positions (entries 2 and 3) lead to satisfactory results
when caused to react with methyl o-bromobenzoate and
phenylboronic acid in the presence of diethyl maleate. The
added electron-poor olefin dramatically reduces, if not
completely prevents, the formation of teraryls 5 and 6 resulting
from homo-coupling of the corresponding iodides and
bromides.4 A similar behavior is observed with 1-iodonaphthalene
and methyl o-bromobenzoate (entry 5) as well as with
Scheme
1 Palladium/norbornene-catalyzed aryl–aryl coupling
followed by Suzuki reaction.
Dipartimento di Chimica Organica e Industriale and CIRCC,
`
Universita di Parma, V. le G. P. Usberti, 17/A, 43124 Parma, Italy.
E-mail: marta.catellani@unipr.it; Fax: +39 0521 905472;
Tel: +39 0521 905415
w Electronic supplementary information (ESI) available: General
procedure and characterization data of new compounds. See DOI:
10.1039/c000526f
ꢀc
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Table 1 Reaction of ortho-substituted aryl iodides (1) and bromides (2) with phenylboronic acida
Entry
R1 in 1
R2 in 2
3 Yield (%)b,c
4 Yield (%)b,c
5 Yield (%)b,c
6 Yield (%)b,c
1
2
3
4
5
6
7
8
Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
Me + 4-CO2Me
NHCOCF3
NO2
87 (30)
68 (30)
82 (24)
84 (46)
86 (65)
78 (55)
83 (50)
78 (40)
61 (5)
—
—
—
—
—
—
—
7 (45)
3 (55)
3 (89)
—
3 (50)
3 (44)
5 (48)
— (30)
7 (25)
2 (37)
—
6 (50)
6 (53)
4 (53)
4 (40)
5 (22)
5 (43)
—
Me + 3-Me
Me + 4-Me
i-Pr
Naphthyl
Me
Me
Me
Me
Me
CF3
2 (2)
5 (9)
9
10
11
SO2Me
CF3
CO2Me
10 (34)
30 (—)
—
— (38)
—
3 (10)
—
67 (83)
a
Reactions were carried out with Pd(OAc)2 (0.022 mmol), norbornene (0.55 mmol), diethyl maleate, if used (1.76 mmol), K2CO3 (4.40 mmol), the
aryl iodide (1.10 mmol), the aryl bromide (1.10 mmol) and phenylboronic acid (1.32 mmol) in DMF (20 mL) under nitrogen at 105 1C for
24 h. Isolated yield; GC yield for values below 10%. In parentheses: yield in the absence of diethyl maleate.
b
c
o-iodotoluene and o-bromotrifluoroacetanilide as bromide
partner (entry 7). o-Iodotoluene in combination with
methyl p-bromobenzoate behaves analogously, provided that a
further substituent is present ortho to Br as in methyl
4-bromo-3-methylbenzoate (entry 6). The positive effect of
the olefin is also at work in the reaction of o-iodotoluene
and o-bromonitrobenzene (entry 8) to depress the formation,
in this case, of teraryl 4. With the same ortho substituted aryl
iodide and o-bromo(methylsulfonyl)benzene (entry 9) the use
of the olefin is needed to control the formation of teraryls 4, 5
and 6. Exceptions are offered by the reaction of o-iodotoluene
with o-trifluoromethylbromobenzene and phenylboronic acid
(entry 10) and o-trifluoromethyliodobenzene with methyl
o-bromobenzoate and phenylboronic acid (entry 11). These
cases will be considered later.
aryl units, coming from the iodo- and bromo-arene, respectively.
The catalytic cycle proceeds with norbornene deinsertion,
likely caused by steric effects, to form the biarylpalladium
intermediate 11.9,10 Reaction of intermediate 11 with aryl-
boronic acid gives compound 3. Formation of the symmetrical
teraryl 5, in which both rings come from the initial aryl iodide,
is due to preferential reaction of the latter with palladium(0)
and also with palladacycle 9. The catalytic cycle can be
initiated as well by aryl bromide, more activated than the aryl
iodides, thus leading to the corresponding palladacycle of type
9, and then can proceed by reaction either of the aryl bromide
or of the aryl iodide. In the former case the symmetrical teraryl
6 is obtained, while in the latter the unsymmetrical product 4 is
formed.
As previously reported,3a,b,9 an ortho-substituent in the aryl
Formation of compound 3 can be explained according to
our previously reported finding3a,b (Scheme 3). Oxidative addition
of palladium(0) to the aryl iodide followed by stereoselective
norbornene insertion leads to the cis, exo arylnorbornylpalladium
iodide 8.6 This species readily undergoes ring closure through
sp2 C–H bond activation,7 to give palladacycle 9,8 which
selectively reacts with the aryl bromide to afford the inter-
mediate 10, thus allowing the cross-coupling of two different
iodide 1 is needed to cause selective aryl–aryl coupling in the
reaction step from palladacycle
9 to intermediate 10
(Scheme 3). By contrast, the electron-withdrawing substituent
in aryl bromide 2 is not needed in the ortho position. We thus
carried out the reaction of an ortho-substituted aryl iodide,
such as o-iodotoluene, with aryl bromides bearing electron-
withdrawing substituents in the meta or para position
(Table 2). Results are collected separately in Table 2 because
in these cases maleic ester addition mainly affects selectivation
of 14 in respect to products other than teraryls.12
o-Iodotoluene and 1-iodonaphthalene give good yields with
variously meta- and para-substituted bromobenzenes as well
as with p-bromopyridine. Substituted and unsubstituted aryl
boronic acids behave similarly.
Addition of the maleic ester to the reaction mixture thus
leads to satisfactory selectivity. As anticipated, exceptions are
offered by some substituents such as the o-CF3 in aryl iodides
and bromides. In the former case (Table 1, entry 11) the
substituent strongly favors the initial reaction of the aryl
iodide with palladium(0) but inhibits the subsequent reaction
of the aryl iodide itself with palladium(II),13 so that addition of
the maleic ester is no longer necessary. In the latter case
(Table 1, entry 10) the o-CF3 is again unable to cause the aryl
bromide to react with the palladium(II) complex but reacts
with palladium(0) faster than o-iodotoluene, which instead can
react with palladium(II). As a result compound 4 (entry 10) is
formed. Addition of the maleic ester depresses the reaction of
the aryl bromide with palladium(0) in favor of terphenyl 5.
Scheme 3 Proposed reaction pathway for the formation of teraryl 3
through aryl–aryl coupling and Suzuki reaction. L = solvent, diethyl
maleate, coordinating substrates.
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Table 2 Reaction of ortho-substituted aryl iodides with aryl bromides
bearing electron-withdrawing groups, followed by coupling with aryl
boronic acidsa
Notes and references
1 (a) J. B. Johnson and T. Rovis, Angew. Chem., Int. Ed., 2007, 46, 2,
and references therein; (b) C. Defieber, H. Grutzmacher and
¨
E. M. Carreira, Angew. Chem., Int. Ed., 2008, 47, 4482;
(c) A. Devasagayaraj, T. Stiidemann and P. Knochel, Angew. Chem.,
Int. Ed. Engl., 1996, 34, 2723; (d) A. E. Jensen and P. Knochel, J. Org.
Chem., 2002, 67, 79; (e) C. Amatore, E. Carre, A. Jutand and
´
Y. Medjour, Organometallics, 2002, 21, 4540; (f) A. Jutand, Pure
Appl. Chem., 2004, 76, 565; (g) J. W. Sprengers, M. de Greef,
M. A. Duin and C. J. Elsevier, Eur. J. Inorg. Chem., 2003, 3811;
(h) B. Crociani, S. Antonaroli, A. Marini, U. Matteoli and
A. Scrivanti, Dalton Trans., 2006, 2698; (i) Y. Mace
J. S. Fairlamb and A. Jutand, Organometallics, 2006, 25, 1795; (j) I. S.
´
, A. R. Kapdi, I.
Entry
R1
R2
X
R3
14 Yield (%)b,c
J. Fairlamb, Org. Biomol. Chem., 2008, 6, 3645; (k) M. Pe
´
rez-
rez-
Rodrıguez, A. A. C. Braga, M. Garcia-Melchor, M. H. Pe
´
´
´
1
2
3
4
5
6
7
8
Me
Me
Me
Me
Me
Me
Me
Naphthyl
Naphthyl
Naphthyl
Naphthyl
4-CO2Me
3-CF3
4-CF3
3-NO2
4-NO2
4-CN
H
4-CO2Me
H
H
CH
CH
CH
CH
CH
CH
N
CH
N
N
H
H
H
H
H
H
H
H
84 (61)
85 (60)
89 (66)
78d (10)
90 (7)
77 (70)
70 (61)
94 (85)
88 (75)
84 (73)
95 (80)
Temprano, J. A. Casares, G. Ujaque, A. R. de Lera, R. Alvarez,
F. Maseras and P. Espinet, J. Am. Chem. Soc., 2009, 131, 3650.
2 (a) L. A. Adrio, J. M. Antelo Mıguez and K. K. Hii, Org. Prep.
´
Proced. Int., 2009, 41, 331, and references therein; (b) V. M. Syutkin
and S. Yu. Grebenkin, J. Chem. Phys., 2009, 131, 024502; (c) F. Barth,
S. Martinez and M. Rinaldi-Carmona, US Pat., 7 390 924, 2008.
3 (a) M. Catellani, E. Motti and N. Della Ca’, Acc. Chem. Res., 2008,
41, 1512; (b) M. Catellani, Top. Organomet. Chem., 2005, 14, 21;
(c) J. Tsuji, Palladium Reagents and Catalysts—New Perspectives for
the 21st Century, John Wiley & Sons, Chichester, 2004, p. 409;
(d) D. Alberico, M. E. Scott and M. Lautens, Chem. Rev., 2007,
107, 174; (e) F. Faccini, E. Motti and M. Catellani, J. Am. Chem.
Soc., 2004, 126, 78; (f) for related chemistry using norbornene see: 1d;
B. Mariampillai, J. Alliot, M. Li and M. Lautens, J. Am. Chem. Soc.,
2007, 129, 15372; Y.-B. Zhao, B. Mariampillai, D. A. Candito,
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4 E. Motti, A. Mignozzi and M. Catellani, J. Mol. Catal. A: Chem.,
2003, 204–205, 115.
9
10
11
H
4-Me
4-F
H
N
a
Reactions were carried out with Pd(OAc)2 (0.022 mmol), norbornene
(0.55 mmol), diethyl maleate, if used (1.76 mmol), K2CO3 (4.40 mmol),
the aryl iodide (1.10 mmol), the aryl bromide (1.10 mmol) and the aryl
boronic acid (1.32 mmol) in DMF (20 mL) under nitrogen at 105 1C
b
c
for 24 h. Isolated yield. In parentheses: yield in the absence of
d
diethyl maleate. Yield increased to 90% in 90 h.
The reason for the maleic ester effect shown in Tables 1 and
2 should be found in the ability of this olefin to coordinate
palladium species and to stabilize palladium(0). The latter is
known to intervene in the oxidative addition and in the
reductive elimination steps, the former being depressed1a,f
and the latter accelerated.1k
5 Yield and selectivity decrease using a higher or lower amount of
diethyl maleate. The latter was recovered together with ca. 20% of
the corresponding E isomer (fumarate).
6 (a) H. Horino, M. Arai and N. Inoue, Tetrahedron Lett., 1974, 15,
647; (b) C.-S. Li, C.-H. Cheng, F.-L. Liao and S.-L. Wang,
J. Chem. Soc., Chem. Commun., 1991, 710; (c) M. Portnoy,
Y. Ben-David, I. Rousso and D. Milstein, Organometallics, 1994,
13, 3465; (d) M. Catellani, C. Mealli, E. Motti, P. Paoli, E. Perez-
Carreno and P. S. Pregosin, J. Am. Chem. Soc., 2002, 124, 4336.
7 (a) G. Dyker, Angew. Chem., Int. Ed., 1999, 38, 1698; (b) F. Kakiuchi
and N. Chatani, Adv. Synth. Catal., 2003, 345, 1077; (c) A. R. Dick
and M. S. Sanford, Tetrahedron, 2006, 62, 2439.
8 (a) I. P. Beletskaya and A. V. Cheprakov, J. Organomet. Chem.,
2004, 689, 4055; (b) M. Catellani and G. P. Chiusoli, J. Organomet.
Chem., 1992, 425, 151; (c) M. Catellani and G. P. Chiusoli,
J. Organomet. Chem., 1988, 346, C27; (d) C.-H. Liu, C.-S. Li and
C.-H. Cheng, Organometallics, 1994, 13, 18.
9 M. Catellani and E. Motti, New J. Chem., 1998, 22, 759;
M. Catellani, E. Motti and S. Ghelli, Chem. Commun., 2000, 2003.
10 Norbornene thus acts as catalyst. However, to favor its insertion
into the arylpalladium bond of complex 7, norbornene must be
present in sufficient concentration to counteract the Suzuki
coupling11 at this stage. The best results were achieved using half
the stoichiometric amount of norbornene.
To account for our results the maleic ester effect should
lower the reactivity of aryl bromide in respect to that of the
aryl iodide. In view of the extreme complexity of a kinetic
analysis of the sequences involved, however, we refrain from
putting forward speculations, limiting ourselves to the
synthetic results, which offer a valuable tool to the experi-
menter. The methodology indeed offers a valid alternative to
other coupling reactions,2a,11e in particular to the two-step
Suzuki reaction of bifunctional arenes with aryl boronic acids,
inasmuch as these products are obtained in one-pot from
simple and readily available building blocks.
Some of the obtained teraryls (compounds 3 and 14) display
interesting properties in that the presence of ortho substituents
prevents rotation of the aryl rings as evidenced by NMR
spectroscopy.4 For example, the ortho and meta carbons of
the unsubstituted phenyl ring of compound 3 (R1 = i-Pr,
R2 = CO2Me) resonate at four distinct chemical shifts.
In conclusion we have worked out a catalytic sequential
coupling methodology which leads to good selectivity thanks
to the addition of maleic ester to the reaction mixture as ligand
for palladium. As a matter of fact it has become possible to
obtain teraryl derivatives in a one-pot reaction starting from
simple aryl iodides and bromides used in equimolar amounts.
Financial support by MIUR and the University of Parma is
gratefully acknowledged.
11 (a) A. Suzuki, Pure Appl. Chem., 1994, 66, 213; (b) A. Suzuki, Chem.
Commun., 2005, 4759; (c) J. Hassan, M. Sevignon, C. Gozzi, E. Schulz
´
and M. Lemaire, Chem. Rev., 2002, 102, 1359; (d) M. Catellani,
E. Motti and M. Minari, Chem. Commun., 2000, 157;
(e) J. M. Antelo Mıguez, L. A. Adrio, A. Sousa-Pedrares, J. M. Vila
´
and K. K. Hii, J. Org. Chem., 2007, 72, 7771.
12 By-products formation strongly depends on substituents. For example,
in the absence of diethyl maleate p-bromonitrobenzene (Table 2, entry
5) gives an 80% yield of 4-nitrobiphenyl while the meta isomer leads to
the formation of only ca. 20% of the corresponding biphenyl together
with other by-products containing norbornene.
13 As we previously observed,3b,e the presence of the o-CF3 in both
iodobenzene and bromobenzene inhibits the reaction of these aryl
halides with palladacycles of type 9 (Scheme 3). This suggests a strong
interference of the o-CF3 group with the palladium(II) species.
ꢀc
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 4291–4293 | 4293