Chelation-assisted cross-coupling of anilines through in situ activation as diazonium salts with boronic acids under ligand-, base-, and salt-free conditions

Article abstract of DOI:10.1002/chem.201300858

We describe the coupling of anilines with aryl boronic acids, under ligand-, base-, and salt-free conditions at room temperature. This new reaction proceeds through the formation of an aryl palladium alkoxo complex, which allows the transmetalation step w

Full text of DOI:10.1002/chem.201300858

FULL PAPER
DOI: 10.1002/chem.201300858
Chelation-Assisted Cross-Coupling of Anilines through In-Situ Activation as
Diazonium Salts with Boronic Acids under Ligand-, Base-, and Salt-Free
Conditions
Roxan Joncour,[a] Nicolas Susperregui,[b] Noꢀl Pinaud,[a] Karinne Miqueu,[b]
Eric Fouquet,[a] Jean-Marc Sotiropoulos,*[b] and FranÅois-Xavier Felpin*[c]
Abstract: We describe the coupling of anilines with aryl boronic acids, under
ligand-, base-, and salt-free conditions at room temperature. This new reaction
Keywords: aniline · boronic acid ·
proceeds through the formation of an aryl palladium alkoxo complex, which
cross-coupling · density functional
allows the transmetalation step with aryl boronic acids without any external base.
calculations · diazonium salt · palla-
Importantly, this sustainable procedure generates only environmentally friendly
dium
byproducts such as tBuOH, H2O, N2, and B(OH)3. The reaction mechanism has
been deeply investigated through experimental and theoretical studies.
Introduction
neutralization in an extra step. The first issue has been occa-
sionally solved for the Suzuki reaction with the in situ-prep-
aration of diazonium salts.[5,6] The second issue, also encoun-
tered with traditional electrophiles (halides or triflates), has
been partially addressed in our laboratory for the Heck re-
action with the development of a double catalytic process.[7]
Unfortunately, this efficient methodology cannot be applied
to the Suzuki–Miyaura reaction due to a distinct mechanism.
However, we felt that another approach would be attaina-
ble. Our idea grew with the recent studies on pathways for
the transmetalation step in the Suzuki–Miyaura reaction
from the groups of Jutand[8] and Hartwig.[9]
Indeed, they showed that the transmetalation step prefer-
entially occurred between a boronic acid and a palladium
hydroxo complex following the simplified catalytic cycle il-
lustrated in Scheme 1.[10] On the other hand, they found that
the rate of reaction of aryltrihydroxyborates for the trans-
metalation with arylpalladium halide complexes was several
orders of magnitude slower.
The Suzuki–Miyaura reaction is arguably one of the most
practiced methods for carbon–carbon bond formation.[1]
Whereas most studies employ aryl halides or triflates as
electrophilic partners, aryl diazonium salts have been report-
ed to be excellent surrogates for various palladium-catalyzed
reactions,[2] including Suzuki-type cross-couplings.[3,4] There-
by, these “super-electrophiles”, readily prepared from inex-
pensive anilines, compete favorably with less reactive and
more expensive aryl halides or triflates. However, two issues
still limit their use: 1) crystalline diazonium salts are consid-
ered to be hazardous compounds; 2) a stoichiometric
amount of an acidic salt (usually inorganic and originating
from the diazonium counterion) is produced and requires its
[a] R. Joncour, N. Pinaud, Prof. E. Fouquet
Universitꢀ de Bordeaux
UMR CNRS 5255, ISM
351, cours de la Libꢀration
33405 Talence Cedex (France)
[b] Dr. N. Susperregui, Dr. K. Miqueu, Dr. J.-M. Sotiropoulos
Universitꢀ de Pau et des Pays de l’Adour
UMR CNRS 5254, IPREM
2, avenue du Prꢀsident Pierre Angot
64053 Pau Cedex 9 (France)
Fax : (+33)559-407-862
E-mail: jean-marc.sotiro@univ-pau.fr
[c] Prof. F.-X. Felpin
Universitꢀ de Nantes
UFR Sciences et Techniques
UMR CNRS 6230, CEISAM
2, rue de la Houssiniꢁre, BP 92208
44322 Nantes Cedex 3 (France)
Fax : (+33)251-125-402
Scheme 1. Concurrent pathways for the Suzuki–Miyaura reaction.
Results and Discussion
E-mail: fx.felpin@univ-nantes.fr
We then realized that a palladium alkoxo complex might
also be operative following a similar mechanism. With this
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201300858.
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Table 1. Optimization studies.
Entry[a]
Variation from
Yield
[%][b]
“standard” conditions[a]
1
2
3
4
5
6
None
1a (1.2 equiv)
2a (1.2 equiv)
tBuONO (3 equiv)
Anisole (0.5 equiv) as additive
Water (1 equiv)
83
73
84
47
83
84
[a] Reaction conditions: aniline (1 mmol), boronic acid (1 mmol),
tBuONO (1.3 mmol), and [Pd(OAc)2] were mixed in MeOH at 258C and
AHCTUNGTRENNUNG
stirred for 48 h. [b] Isolated product yields.
Scheme 2. Strategy for ligand-, base-, and acid-free reactions.
aryl and even alkenyl boronic acids were reacted smoothly
with a variety of ortho-substituted anilines. Aside from a
methoxy substituent (Table 2, compounds 3a–g), nitro (com-
pounds 3h–j), bromine (compounds 3k–l), and ester (com-
pounds 3m–n) functions can act as efficient ortho-coordinat-
ing groups. From a general perspective, we believe that any
ortho-coordinating groups would be compatible for this cou-
pling. As anticipated, in the absence of the latter, palladium
intermediates are unreactive and the cross-coupled products
3o–p were isolated in low yields along with the recovered
starting materials (Table 2). The biaryls (ꢀ10–15%) arising
from the dimerization of the boronic acids are the major
side-products isolated in these transformations. In some
cases, it has been possible to slightly improve the reaction
hypothesis in mind, we imagined that Pd0 could react with
the diazonium species B, through an acid-free activation
step of anilines with tBuONO, to obtain, after nitrogen ex-
trusion, the palladium alkoxo complex C (Scheme 2).
Following the mechanistic insights reported by the groups
of Jutand and Hartwig, the complex C would be involved in
the transmetallation step with the boronic acid D via the
likely transition state E’ without assistance of a base. Lastly,
the reductive elimination would furnish the expected bi-
phenyl F and the active palladium species. In the presence
of a coordinating anion (MeOÀ), the oxidative step would
not lead to a cationic palladium species. As a consequence,
it is expected that the transmetalation would be dramatically
slowed down. Moreover, to enhance the lifetime of the pal-
ladium intermediates in the absence of any ligand, we realiz-
ed that an ortho-coordinating group would be required. If
successful, this strategy would work without any acid (re-
quired for the diazonium salt preparation) or base (required
yield by using [Pd
2ACHTUNGTERN(NUNG dba)3] (dba=dibenzylideneacetone) in-
stead of [Pd(OAc)2] (Table 2, compounds 3k and 3m–n).
AHCTUNGTRENNUNG
Indeed, the dimerization can be, at least in part, attributed
to the prior reduction of PdII to the Pd0 species.
In the search of a deeper understanding of the reaction
outcome, we studied the oxidative-addition step. We ob-
for the transmetalation step). This chelation-assisted strat-
served that when a stoichiometric amount of [PdACHTUNGTRENNUNG(OAc)2]
[11]
À
egy is related to that used for C H arylation reactions.
was added to a mixture of aniline 1a and tBuONO in
MeOH, a precipitate rapidly formed in less than 30 min.
The pale-yellow solid was carefully isolated by filtration and
kept under argon at À208C. Unfortunately, it appeared to
be quite sensitive and all attempts to make suitable crystals
for X-ray analysis failed. The solid was only soluble in
DMSO and slightly in THF, but it was unstable in these sol-
vents. Fortunately, we were able to characterize the complex
by ESI-MS analysis. A trimeric palladium species was ob-
Having laid the foundation of a conceptually new ap-
proach, we were very pleased to find that the coupling of
the 2-methoxy-5-nitroaniline 1a (1 equiv) with the 4-me-
thoxyphenylboronic acid 2a (1 equiv), in the presence of
tBuONO (1.3 equiv) and [PdACHTNUGRTENUNG(OAc)2] (2.5 mol%) in MeOH
at 258C, smoothly gave the biphenyl 3a with 83% yield
(Table 1, entry 1). The use of a slight excess of the aniline
1a or the boronic acid 2a did not improve the reaction effi-
ciency (Table 1, entries 2 and 3), and a negative effect was
observed with an excess of tBuONO (entry 4). The use of
anisole[7] as an additive did not affect the reaction outcome
(Table 1, entry 5). This result indicated the unlikely inter-
vention of cationic palladium intermediates in neutral condi-
tions. Last, the use of wet methanol still conserved the reac-
tion yield, indicating that the process is not water-sensitive
(Table 1, entry 6).
served at m/z=946.8 and assigned to structure
4
(Scheme 3). In MeOH, an exchange between acetate and
methoxy groups occurred and a second complex assigned to
structure 5 was also observed at m/z=807.8. This observa-
tion validates our mechanistic hypothesis and confirms the
À
À
occurrence of an Ar Pd OMe intermediate (compound C
in Scheme 2). In the absence of tBuONO we were able to
detect the formation of [Pd0
ACTHNUTRGNEN(UG MeOH)2CAHTUNGTREN(NGUN AcOH)2] at m/z=
With these promising preliminary results in hands, we
next focused on the reaction scope (Table 2). A variety of
291.0 [M+H+] that could be explained through the reduc-
tion of PdII into Pd0 by MeOH.
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Chelation-Assisted Cross-Coupling of Anilines
Table 2. Scope of the reaction.
FULL PAPER
1H NMR analysis of the com-
plex 4, solubilized in CDCl3
with a few drops of MeOH,[12]
showed (after 2 h of stirring)
the formation of a new complex
tentatively assigned as (2-OMe-
[13]
5-NO2Ph-Pd-OMe)n
along
3a, 83%
3c, 77%
3b, 83%
3d,70%
with the liberation of acetic
acid. From these experiments
we can conclude that a trimeric
catalyst is first formed from the
oxidative-addition step. Howev-
er, in MeOH, this complex
evolves into a new (2-OMe-5-
NO2Ph-Pd-OMe)n
which is likely the active spe-
cies. Thereby, as expected, an
alkoxy palladium complex was
formed and cationic palladium
complex,
3e, 77%
3g, 63%
3 f, 77%
3h, 73%
species were not detected.
These results were in full ac-
cordance with the observations
collected from HRMS.
3i, 70%
3j, 76%
Due to the aniline 1a being
mostly insoluble in MeOH, we
looked for another substrate,
soluble in the reaction solvent,
for in situ NMR spectroscopy
investigations. Toward this end,
we found that the dissolution of
2-nitro-4-methylaniline 1b in
MeOD led to a homogeneous
deep-yellow solution. The ini-
3k, 74%[d]
3m, 66%[d]
3o, 13%
3l, 58%
3n, 73%[d]
3p, 28%
tial formation of the expected
hydroxydiazene, formed by ad-
dition of tBuONO to aniline in
[a] Reaction conditions: aniline (1 mmol), tBuONO (1.3 mmol), boronic acid (1 mmol) and [Pd
(2.5 mol%) were mixed in MeOH (10 mL) and stirred at 258C for 48 h. [b] Yield of isolated product. [c] [Pd-
(OAc)2] (5 mol%) was used. [d] [Pd2A(dba)3] (2.5 mol%) was used.
ACHTUNGERTN(NUNG OAc)2]
MeOD, was followed by
G
CHTUNGTRENNUNG
1H NMR spectroscopy. To our
great surprise, and in contrast
to the usual textbook mechanism, hydroxydiazene 7 does
not exist in MeOD at the NMR timescale. Indeed, we in-
stead observed the formation of the diazonium alkoxyde 6
along with the remaining aniline in a 5:95 ratio after 30 min
of stirring (Scheme 4).[14] An instantaneous disappearance of
the signals attributed to the diazonium alkoxyde occurred
upon the addition of [PdACTHNUTRGNE(NUG OAc)2] and the boronic acid 2a to
the reaction mixture. This result showed that the oxidative
addition is an extremely fast step and thus is not likely to be
the rate-limiting step.
The coupling of aniline 1b with the boronic acid 2a was
also followed by 11B NMR spectroscopy at room tempera-
ture in MeOD. The spectra showed two chemical resonances
at d=30 and 17 ppm, which are attributed to the boronic
acid 2a and B(OR)3, respectively. We did not observe any
signal at upper field (dꢀ5 ppm) that should account for
borate species, confirming that, at the NMR timescale, the
boronic acid 2a is the likely active partner.
Scheme 3. Structure of palladium intermediate complexes detected by
ESI-MS spectroscopy.
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J.-M. Sotiropoulos, F.-X. Felpin et al.
the position of the ester group does not influence the stabili-
zation of the final compounds 3n and 3p, an opposite be-
havior is observed for most reaction intermediates. Indeed,
para-substituted intermediates II, III, IV, and V are, by con-
trast, strongly destabilized by 5 to 25 kcalmolÀ1. This obser-
vation correlates the experimental results and suggests that
an ortho-coordinating group is required for enhancing the
lifetime of palladium intermediates. The first transition
states (TS1), corresponding to the oxidative addition, are
late transition states with nitrogen and palladium atoms still
1
Scheme 4. Species observed by H NMR spectroscopy.
We obtained further insights into the reaction mechanism
with DFT calculations describing the elementary steps of
the catalytic cycle shown in Scheme 2. The cross-couplings
of phenylboronic acid 2b with anilines 1e and 1g, leading to
biphenyls 3n (73% yield) and 3p (28% yield), respectively,
were chosen as a case study for evaluating the importance
of the ortho-coordinating group. The calculated chemical
pathways at the B3LYP/SDD (Pd atom), 6-31G** (other
atoms) level of theory for these cross-couplings are depicted
in Figure 1. Intermediates I–VI were selected on the basis of
experimental evidences obtained from MS and NMR studies
and we only considered monomeric forms of Pd species pro-
viding that multi and mono nuclear species were likely in
equilibrium. The reaction pathways for both biphenyls (3n
and 3p) are kinetically and thermodynamically favorable.
The trajectory of the potential energy surface (PES) con-
tains three elementary steps, including: 1) the oxidative ad-
dition, 2) the transmetalation process and 3) the reductive
elimination furnishing the cross-coupled products. Although
À
À
in interaction with the phenyl ring (Cring N=1.83, Cring
Pd=2.10 ꢃ). The low activation barrier calculated for TS1
(ꢀ7 kcalmolÀ1) corroborates experimental observations and
suggests that this step is extremely fast and not rate-limiting,
regardless of the diazonium salt involved (ortho vs. para).
As previously observed for the Heck–Matsuda reaction,[15]
the nitrogen release is a crucial step of the catalytic cycle
because a strong stabilization of IIortho is observed, whereas
the pathway for IIpara is endergonic. This behavior suggests
that the loose of nitrogen is compensated by the coordina-
tion of the ester group in the ortho-position. Indeed, natural
bond orbital (NBO) calculations indicated an interaction be-
tween the ester group and the palladium atom (the sum of
these interactions is 163 kcalmolÀ1) or with antiplanar
s*PdÀO (44 kcalmolÀ1). Obviously, no such stabilization exists
in the case of the para-substituted isomer. However, the re-
action pathway toward TS2, through IIpara and IIIpara, would
Figure 1. General pathway for the reaction of para-CO2Me (dashed line) and ortho-CO2Me (solid line) anilines with phenylboronic acid.
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Chelation-Assisted Cross-Coupling of Anilines
FULL PAPER
136.1, 141.4, 161.4 ppm; IR (KBr) n˜ =1583, 1607, 2944, 3047, 3120 cmÀ1
;
be theoretically feasible on the basis of energy levels. Since
the coupling of para-substituted anilines gave low yields of
the expected biaryls along with the recovered starting mate-
rials, it could be suggested that IIpara and IIIpara quickly de-
composed and produced inactive black palladium. The
second elementary step, occurring through TS2, is kinetical-
ly discriminating because the activation barrier required for
TS2ortho is lower by 9 kcalmolÀ1 compared with TS2para. This
step can be viewed as a four-centered transition state involv-
ing the Pd center, the methoxy group, the phenyl ring, and
HRMS (ESI) calcd for C13H11NO3Na: 252.0631 [M+Na+]; found:
252.0619.
2-Methoxy-3’,4’-methylenedioxy-5-nitrobiphenyl (3c): Purification by
flash chromatography (25% EtOAc/petroleum ether) gave 3c in 77%
1
yield as a yellow solid. M.p. 166–1688C; H NMR (300 MHz, CDCl3): d=
3.93 (s, 3H), 6.01 (s, 2H), 6.89 (d, 1H, J=8.1 Hz), 6.95–7.03 (m, 3H),
8.18–8.23 ppm (m, 2H); 13C NMR (75 MHz, CDCl3): d=56.3, 101.2,
108.3, 109.9, 110.6, 123.0, 124.5, 126.1, 129.8, 131.0, 141.4, 147.7,
161.3 ppm; IR (KBr): n˜ =1577, 1610, 2897, 2941, 2970, 3060 cmÀ1; HRMS
(ESI) calcd for C14H11NO5Na 296.0529 [M+Na+]; found: 296.0534.
4’-tert-Butyl-2-methoxy-5-nitrobiphenyl (3d): Purification by flash chro-
matography (10% EtOAc/petroleum ether) gave 3d in 70% yield as a
beige solid. M.p. 147–1498C; 1H NMR (300 MHz, CDCl3): d=1.38 (s,
9H), 3.94 (s, 3H), 7.03 (d, 1H, J=9.0 Hz), 7.48 (s, 4H), 8.21–8.26 ppm
(m, 2H); 13C NMR (75 MHz, CDCl3): d=31.3, 34.6, 56.2, 110.6, 124.5,
125.3, 126.3, 129.0, 131.2, 133.1, 141.5, 151.0, 161.5 ppm; IR (KBr): n˜ =
À
the boron atom. In TS2 the Cphenyl B bond is elongated
(dBC: 1.981 ꢃ) and the phenyl ring interacts strongly with
the palladium center (dPdC: 2.217 ꢃ). Simultaneously, the
methoxy ligand, released from the metal (dPdO1: 2.037 ꢃ), is
quasi-linked to the boron atom (dBO1: 1.516 ꢃ). Again, com-
pounds IV and V, issued from TS2, are much more stable
when substituted in ortho-position by 11.5 and 6.9 kcal
molÀ1, respectively. Compounds V are structurally predis-
posed to aryl–aryl bond formation, leading to compounds
VI through the last TS3. Actually, the orthogonal arrange-
ment of the two phenyl rings places the ipso carbon atoms
face-to-face requiring, thereby, a small activation barrier for
the biaryl formation.
1586, 2864, 2900, 2962 cmÀ1
; HRMS (ESI) calcd for C17H19NO3Na:
308.1257 [M+Na+]; found: 308.1257.
4’-Fluoro-2-methoxy-5-nitrobiphenyl (3e): Purification by flash chroma-
tography (10% EtOAc/petroleum ether) gave 3e in 77% yield as a white
solid. M.p. 1448C; 1H NMR (300 MHz, CDCl3): d=3.94 (s, 3H), 7.04 (d,
1H, J=9.0 Hz), 7.13 (app t, 2H, J=8.7 Hz), 7.47–7.52 (m, 2H), 8.19–8.26
(m, 2H); IR (KBr): n˜ =1484, 1505, 1581, 2919, 2954, 2990, 3022,
3084 cmÀ1; HRMS (ESI) calcd for C13H10NO3FNa: 270.0536 [M+Na+];
found: 270.0532.
4’-Trifluoromethyl-2-methoxy-5-nitrobiphenyl (3 f): Purification by flash
chromatography (15% EtOAc/petroleum ether) gave 3 f in 77% yield as
a yellow oil. 1H NMR (300 MHz, CDCl3): d=3.95 (s, 3H), 7.06 (d, 1H,
J=9.0 Hz), 7.29 (dm, 2H, J=7.0 Hz), 7.55 (dm, 2H, J=8.9 Hz), 8.21 (d,
1H, J=2.8 Hz), 8.26 ppm (dd, 1H, J=2.8, 8.9 Hz); IR (neat): n˜ =1578,
1592, 1609, 2848, 2900, 1917, 2944, 2983, 3035, 3085, 3117 cmÀ1. HRMS
(ESI) calcd for C14H10NO4F3Na: 336.0454 [M+Na+]; found: 336.0445.
Conclusion
We have reported one of the experimentally simplest Pd-
catalyzed cross-coupling reactions. The coupling of anilines,
through in situ activation as diazonium salts, with boronic
acids proceeds under base-, acid-, and ligand-free conditions.
The process was made efficient thanks to a chelation-assist-
ed strategy. Extensive experimental and theoretical studies
support our mechanistic hypothesis and highlight the unusu-
al reactivity of aryl diazonium species in Pd-catalyzed trans-
formations. We are now working on the implementation of
this concept to other metal-catalyzed transformations.
2-Methoxy-5-nitrostilbene (3g): Purification by flash chromatography
(5% EtOAc/petroleum ether) gave 3g in 63% yield as a yellow solid.
M.p. 1118C; 1H NMR (300 MHz, CDCl3): d=3.96 (s, 3H), 6.90 (d, 1H,
J=9.0 Hz), 7.18 (d, 1H, J=16.6 Hz), 7.28–7.41 (m, 4H), 7.54 (d, 2H, J=
7.7 Hz), 8.11 (dd, 1H, J=2.9, 9.0 Hz), 8.43 ppm (d, 1H, J=2.9 Hz);
13C NMR (75 MHz, CDCl3): d=56.1, 110.3, 120.9, 121.5, 124.1, 126.7,
127.1, 128.1, 128.6, 131.5, 136.8, 141.4, 161.2 ppm; IR (KBr): n˜ =1484,
1514, 1574, 1582, 2841, 2941, 2969, 3044, 3083, 3121 cmÀ1; HRMS (ESI)
calcd for C15H13NO3Na: 278.0787 [M+Na+]; found: 278.0780.
4-Methyl-2-nitrobiphenyl (3h): Purification by flash chromatography
(5% EtOAc-petroleum ether) gave 3h in 73% yield as a yellow oil.
1H NMR (300 MHz, CDCl3): d=2.47 (s, 3H), 7.29–7.34 (m, 3H), 7.38–
7.44 (m, 4H), 7.67 ppm (s, 1H); 13C NMR (75 MHz, CDCl3): d=20.8,
124.3, 127.9, 128.0, 128.6, 131.7, 133.0, 133.4, 137.4, 138.6, 149.1 ppm; IR
(neat): n˜ =2771, 2924, 2956, 3029, 3061 cmÀ1; HRMS (ESI) calcd for
C13H11NO2Na: 236.0681 [M+Na+]; found: 236.0671.
Experimental Section
General procedure: Boronic acid (1 mmol), [Pd
ACHTUNGRTEN(NGNU OAc)2] (2 mol%) or
[Pd2A(dba)3] (2.5 mol%) and tBuONO (1.3 mmol) were added sequential-
CHTUNGTRENNUNG
4’-Methoxy-4-methyl-2-nitrobiphenyl 3i: Purification by flash chromatog-
raphy (5% EtOAc/petroleum ether) gave 3i in 70% yield as a yellow
solid. M.p. 1008C. 1H NMR (300 MHz, CDCl3): d=2.45 (s, 3H), 3.83 (s,
3H), 6.95 (d, 1H, J=8.9 Hz), 7.24 (d, 2H, J=8.9 Hz), 7.30 (d, 1H, J=
7.7 Hz), 7.39 (d, 1H, J=7.9 Hz), 7.61 ppm (s, 1H); 13C NMR (75 MHz,
CDCl3): d=20.7, 55.2, 114.1, 124.2, 129.1, 129.5, 131.6, 132.9, 132.9, 138.1,
149.1, 159.4 ppm; IR (KBr): n˜ =1496, 1516, 1534, 1613, 2839, 2834, 2968,
3054 cmÀ1; HRMS (ESI) calcd for C14H13NO3Na: 266.0787 [M+Na+];
found: 266.0793.
ly to a solution of aniline (1 mmol) in MeOH (10 mL) at 258C. The re-
sulting mixture was stirred for 48 h at 258C. After evaporation of the sol-
vents, the crude was purified by flash chromatography to give the titled
product.
2,4’-Dimethoxy-5-nitrobiphenyl (3a): Purification by flash chromatogra-
phy (20% EtOAc/petroleum ether) gave 3a in 83% yield as a yellow
solid. M.p. 1298C (lit.[16] 131–1328C); 1H NMR (300 MHz, CDCl3): d=
3.86 (s, 3H), 3.93 (s, 3H), 6.98 (d, 2H, J=9.0 Hz), 7.00 (m, 1H), 7.47 (d,
2H, J=8.9 Hz), 8.19–8.21 ppm (m, 2H); 13C NMR (75 MHz, CDCl3): d=
55.3, 56.2, 110.6, 113.7, 124.2, 126.0, 128.4, 130.5, 131.0, 141.4, 159.4,
161.4 ppm; IR (KBr): n˜ =1488, 1516, 2844, 29878, 3078 cmÀ1; HRMS
(ESI) calcd for C14H13NO4Na: 282.0736 [M+Na+]; found: 282.0741.
4’-Cyclohexyl-4-methyl-2-nitrobiphenyl (3j): Purification by flash chro-
matography (5% EtOAc/petroleum ether) gave 3j in 70% yield as a
yellow oil. 1H NMR (300 MHz, CDCl3): d=1.23–1.51 (m, 5H), 1.74–1.79
(m, 1H), 1.84–1.93 (m, 4H), 2.46 (s, 3H), 2.49–2.58 (m, 1H), 7.20–7.27
(m, 4H), 7.32 (d, 1H, J=7.7 Hz), 7.43 (dm, 1H, J=7.9 Hz), 7.62 ppm (s,
1H); 13C NMR (75 MHz, CDCl3): d=20.8, 26.1, 26.8, 34.3, 44.2, 124.2,
127.1, 127.8, 131.7, 132.9, 133.4, 134.6, 138.3, 147.9, 149.2 ppm; IR (neat):
2-Methoxy-5-nitrobiphenyl (3b): Purification by flash chromatography
(15% EtOAc/petroleum ether) gave 3b in 83% yield as a yellow solid.
M.p. 1158C; 1H NMR (300 MHz, CDCl3): d=3.93 (s, 3H), 7.04 (d, 2H,
J=9.4 Hz), 7.40–7.52 (m, 5H), 8.23–8.27 ppm (m, 2H); 13C NMR
(75 MHz, CDCl3): d=56.2, 110.7, 124.8, 126.3, 128.0, 128.3, 129.4, 131.3,
n˜ =1572, 2848, 2921, 3033, 3058 cmÀ1
;
HRMS (ESI) calcd for
C19H21NO2Na: 318.1464 [M+Na+]; found: 318.1463.
Chem. Eur. J. 2013, 00, 0 – 0
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J.-M. Sotiropoulos, F.-X. Felpin et al.
2-Bromo-4’-methoxy-5-trifluoromethylbiphenyl (3k): Purification by
flash chromatography (5% EtOAc/petroleum ether) gave 3k in 74%
yield as a yellow oil. 1H NMR (300 MHz, CDCl3): d=3.87 (s, 3H), 6.99
(dm, 2H, J=8.9 Hz), 7.36 (d, 1H, J=8.9 Hz), 7.42 (dm, 1H, J=8.5 Hz),
7.57 (d, 1H, J=1.9 Hz), 7.79 ppm (d, 1H, J=8.5 Hz); IR (neat) n˜ =1611,
147–168; c) N. Miyaura in Topics in Current Chemistry, Vol. 219
(Ed.: N. Miyaura), Springer, Berlin, 2002, p.11; d) S. Kotha, K.
Lahiri, D. Kashinath, Tetrahedron 2002, 58, 9633–9695; e) F. Bellina,
A. Carpita, R. Rossi, Synthesis 2004, 2419–2440; f) N. T. S. Phan, M.
Van Der Sluys, C. W. Jones, Adv. Synth. Catal. 2006, 348, 609–679.
[2] For recent reviews, see: a) A. Roglans, A. Pla-Quintana, M.
Moreno-MaÇas, Chem. Rev. 2006, 106, 4622–4643; b) F.-X. Felpin,
L. Nassar-Hardy, F. Le Callonnec, E. Fouquet, Tetrahedron 2011, 67,
2815–2831; c) J. G. Taylor, A. V. Moro, C. R. D. Correia, Eur. J.
Org. Chem. 2011, 2011, 1403–1428.
2838, 2909, 2936, 2959, 3004, 3040, 3068 cmÀ1
.
2-Bromo-4’-methoxybiphenyl (3l): Purification by flash chromatography
(5% EtOAc/petroleum ether) gave 3l in 58% yield as an orange oil.
1H NMR (300 MHz, CDCl3): d=3.89 (s, 3H), 7.01 (d, 2H, J=8.9 Hz),
7.18–7.23 (m, 1H), 7.36–7.42 (m, 4H), 7.70 ppm (d, 1H, J=7.7 Hz);
13C NMR (75 MHz, CDCl3): d=55.2, 113.3, 122.8, 127.3, 128.3, 130.5,
131.3, 133.0, 133.4, 142.1, 159.0 ppm; IR (neat): n˜ =1577, 1611, 2835,
[3] For a review, see: H. Bonin, E. Fouquet, F.-X. Felpin, Adv. Synth.
Catal. 2011, 353, 3063–3084.
2907, 2934, 2956, 3001, 3035, 3054 cmÀ1
.
[4] For recent examples, see: a) R. H. Taylor, F.-X. Felpin, Org. Lett.
2007, 9, 2911–2914; b) F.-X. Felpin, E. Fouquet, Adv. Synth. Catal.
2008, 350, 863–868; c) J. T. Kuethe, K. G. Childers, Adv. Synth.
Catal. 2008, 350, 1577–1586; d) F.-X. Felpin, E. Fouquet, C. Zakri,
Adv. Synth. Catal. 2009, 351, 649–655; e) H. Bonin, D. Delbrayelle,
P. Demonchaux, E. Gras, Chem. Commun. 2010, 46, 2677–2679;
f) B. Schmidt, F. Hçlter, Org. Biomol. Chem. 2011, 9, 4914–4920;
g) S. Cacchi, E. Caponetti, M. A. Casadei, A. Di Giulio, G. Fabrizi,
G. Forte, A. Goggiamani, S. Moreno, P. Paolicelli, F. Petrucci, A.
Prastaro, M. L. Saladino, Green Chem. 2012, 14, 317–320; h) X. Li,
X.-Y. Yan, H.-H. Chang, L.-C. Wang, Y. Zhang, W.-W. Chen, Y.-W.
Li, W.-L. Wei, Org. Biomol. Chem. 2012, 10, 495–497.
Methyl 3’,4’methylenedioxy-2-phenylbenzoate (3m): Purification by flash
chromatography (5% EtOAc/petroleum ether) gave 3m in 58% yield as
1
a colorless oil. H NMR (300 MHz, CDCl3): d=3.70 (s, 3H), 6.00 (s, 2H),
6.76 (dd, 1H, J=1.7, 7.9 Hz), 6.82 (d, 1H, J=1.3 Hz), 6.85 (d, 1H, J=
8.3 Hz), 7.34 (dm, 1H, J=7.5 Hz), 7.39 (dd, 1H, J=1.3, 7.5 Hz), 7.50
(app t, 1H, J=1.5, 7.5 Hz), 7.78 ppm (dm, 1H, J=7.7 Hz); 13C NMR
(75 MHz, CDCl3): d=52.0, 101.0, 108.0, 108.9, 121.7, 126.9, 129.6, 130.6,
130.9, 131.1, 135.1, 141.9, 146.9, 147.4, 169.1 ppm; IR (neat): n˜ =1573,
1728, 2895, 2951, 3001, 3064 cmÀ1; HRMS (ESI) calcd for C15H12NO4Na:
279.0627 [M+Na+]; found: 279.0639.
Methyl 2-phenylbenzoate (3n): Purification by flash chromatography
(5% EtOAc/petroleum ether) gave 3n in 73% yield as a colorless oil.
1H NMR (300 MHz, CDCl3): d=3.65 (s, 3H), 7.31–7.45 (m, 7H), 7.54
(app t, 1H, J=7.5 Hz), 7.84 ppm (d, 1H, J=7.8 Hz); 13C NMR (75 MHz,
CDCl3): d=51.9, 127.1, 127.2, 128.0, 128.2, 129.7, 130.6, 130.8, 131.2,
141.2, 142.4, 169.1 ppm; IR (neat): n˜ =1599, 1730, 2950, 2997, 3027,
3061 cmÀ1; HRMS (MALDI) calcd for C14H12O2Na: 235.0729 [M+Na+];
found: 235.0723.
[5] a) M. B. Andrus, C. Song, Org. Lett. 2001, 3, 3761–3764; b) F. Mo,
D. Qiu, Y. Jiang, Y. Zhang, J. Wang, Tetrahedron Lett. 2011, 52,
518–522.
[6] For examples of palladium-catalyzed reactions with in situ generated
aryl diazonium salts, see: a) M. B. Andrus, C. Song, J. Zhang, Org.
Lett. 2002, 4, 2079–2082; b) B. Schmidt, F. Hçlter, R. Berger, S.
Jessel, Adv. Synth. Catal. 2010, 352, 2463–2473; c) X.-F. Wu, H.
Neumann, M. Beller, Chem. Commun. 2011, 47, 7959–7961.
[7] F. Le Callonnec, E. Fouquet, F.-X. Felpin, Org. Lett. 2011, 13, 2646–
2649.
4-Phenylnitrobenzene 3o: Purification by flash chromatography (10%
EtOAc/petroleum ether) gave 3o in 13% yield as a yellow solid. M.p.
1148C [lit.[17] 112–1148C]; 1H NMR (300 MHz, CDCl3): d=7.42–7.53 (m,
3H), 7.63 (d, 2H, J=6.6 Hz), 7.74 (d, 2H, J=9.1 Hz), 8.30 ppm (d, 2H,
J=9.0 Hz); 13C NMR (75 MHz, CDCl3): d=124.1, 127.4, 127.8, 128.9,
129.1, 138.7, 147.0, 147.6 ppm; IR (KBr): n˜ =1479, 1514, 1576, 1595, 2830,
3076 cmÀ1; HRMS (ESI) calcd for C12H9NO2Na: 222.0525 [M+Na+];
found: 222.0515.
[8] a) C. Amatore, A. Jutand, G. Le Duc, Chem. Eur. J. 2011, 17, 2492–
2503; b) C. Amatore, A. Jutand, G. Le Duc, Chem. Eur. J. 2012, 18,
6616–6625.
[9] B. P. Carrow, J. F. Hartwig, J. Am. Chem. Soc. 2011, 133, 2116–2119.
[10] a) V. V. Grushin, H. Alper, Organometallics 1993, 12, 1890–1901;
b) K. Matos, J. A. Soderquist, J. Org. Chem. 1998, 63, 461–470.
[11] For selected reviews, see: a) D. Alberico, M. E. Scott, M. Lautens,
Chem. Rev. 2007, 107, 174–238; b) L.-C. Campeau, D. R. Stuart, K.
Fagnou, Aldrichimica Acta 2007, 40, 35–41; c) L. Ackermann, R.
Vicente, A. R. Kapdi, Angew. Chem. 2009, 121, 9976–10011; Angew.
Chem. Int. Ed. 2009, 48, 9792–9826; d) J. Roger, A. L. Gottumukka-
la, H. Doucet, ChemCatChem 2010, 2, 20–40.
Methyl 4-phenylbenzoate (3p): Purification by flash chromatography
(5% EtOAc/petroleum ether) gave 3p in 13% yield as a white solid.
M.p. 1188C [lit.[18] 115–1178C]; 1H NMR (300 MHz, CDCl3): d=3.95 (s,
3H), 7.40–7.47 (m, 3H), 7.62–7.68 (m, 4H), 8.12 ppm (d, 2H, J=8.7 Hz);
13C NMR (75 MHz, CDCl3): d=52.1, 127.0, 127.2, 128.1, 128.8, 128.9,
130.0, 139.9, 145.6, 166.9 ppm; IR (KBr): n˜ =1454, 1607, 1718, 2844, 2944,
2996, 3069 cmÀ1; HRMS (ESI) calcd for C14H12NO2Na: 235.0729 [M+
Na+]; found: 235.0724.
[12] The complex is insoluble in pure MeOH or CDCl3; however, it is
soluble in a mixture of these two solvents.
[13] 1H NMR (400 MHz, CDCl3): d=3.87 (s, 3H), 6.73 (d, 1H, J=
8.8 Hz), 7.48 (d, 1H, J=2.6 Hz), 7.58 ppm (dd, 1H, J=2.7, 9 Hz).
[14] 1H NMR (400 MHz, CDCl3): d=2.76 (s, 3H), 8.17 (d, 1H, J=
8.0 Hz), 8.69 (s, 1H), 8.90 ppm (d, 1H, J=8.0 Hz).
Acknowledgements
[15] N. Susperregui, K. Miqueu, J.-M. Sotiropoulos, F. Le Callonnec, E.
Fouquet, F.-X. Felpin, Chem. Eur. J. 2012, 18, 7210–7218.
[16] P. D. Leeson, D. Ellis, J. C. Emmett, V. P. Shah, G. A. Showell, A. H.
Underwood, J. Med. Chem. 1988, 31, 37–54.
[17] W.-J. Zhou, K.-H. Wang, J.-X. Wang, D.-F. Huang, Eur. J. Org.
Chem. 2010, 2010, 416–419.
We gratefully acknowledge the “Universitꢀ de Nantes”, the “Centre Na-
tional de la Recherche Scientifique (CNRS)”, the “Agence Nationale de
la Recherche” (ANR JCJC 7141) and the “Institut Universitaire de
France (IUF)” for the financial support to this project. Part of the theo-
retical work was granted access to HPC resources of IDRIS under alloca-
tion 2012 (i2012080045) made by GENCI (Grand Equipement National
de Calcul Intensif). F.-X.F is member of the “Institut Universitaire de
France (IUF)”.
[18] S.-D. Cho, H.-K. Kim, H.-s. Yim, M.-R. Kim, J.-K. Lee, J.-J. Kim, Y.-
J. Yoon, Tetrahedron 2007, 63, 1345–1352.
[1] For selected reviews, see: a) N. Miyaura, A. Suzuki, Chem. Rev.
1995, 95, 2457–2483; b) A. Suzuki, J. Organomet. Chem. 1999, 576,
Received: March 5, 2013
Published online: && &&, 2013
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Chem. Eur. J. 0000, 00, 0 – 0
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These are not the final page numbers!

Chelation-Assisted Cross-Coupling of Anilines
FULL PAPER
Cross-Coupling
R. Joncour, N. Susperregui, N. Pinaud,
K. Miqueu, E. Fouquet,
J.-M. Sotiropoulos,*
F.-X. Felpin* .................. &&&& — &&&&
Eco-couple: The cross-coupling of ani-
lines with aryl boronic acids has been
achieved under ligand-, base-, and salt-
free conditions at room temperature
(see scheme). The reaction mechanism,
investigated through experimental and
theoretical studies, proceeds through
the formation of an aryl palladium
alkoxo complex, which enables the
transmetalation step without any exter-
nal base, and gives only environmen-
tally friendly byproducts.
Chelation-Assisted Cross-Coupling of
Anilines through In-Situ Activation as
Diazonium Salts with Boronic Acids
under Ligand-, Base-, and Salt-Free
Conditions
Chem. Eur. J. 2013, 00, 0 – 0
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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These are not the final page numbers!