Ligand-free palladium catalyzed Ullmann biaryl synthesis: 'Household' reagents and mild reaction conditions

Article abstract of DOI:10.1039/c8gc03862g

A palladium catalysed Ullmann biaryl synthesis has been developed using hydrazine hydrate as the reducing reagent at room temperature. The combination of Pd(OAc)₂ and hydrazine hydrate works smoothly for the coupling of both electron-rich and electron-deficient aryl iodides, as well as hetero-aryl iodides, leading to a wide range of biaryls in good to excellent yields. The reaction requires only 1 mol% Pd(OAc)₂ and the in situ generated palladium naoparticles are found to be active catalysts.

Full text of DOI:10.1039/c8gc03862g

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Ligand-free palladium catalyzed ullmann biaryl synthesis:
‘household’ reagents and mild reaction conditions
Xinchi Gong,a Jie Wu,a Yunge Meng,a Yulan Zhang,a Long-Wu Yeb and Chunyin Zhu*ab
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A
palladium catalysed Ullmann biaryl synthesis has been hydroquinone.9 Li and co-workers realized the homocoupling
developed using hydrazine hydrate as the reducing reagent under of aryl halides for the synthesis of symmetrical biaryls either in
room temperature. The combination of Pd(OAc)2 and hydrazine aqueous acetone or in water by using zinc as the reducing
hydrate works smoothly for the coupling of both electron-rich reagent.10 Another advance in this area is the development of
and electron-deficient aryl iodides, as well as hetero-aryl iodides, various Pd complexes/nanoparticles11,12 that can catalyze the
leading to a wide range of biaryls in good to excellent yields. The couplings of aryl halides, however, still requiring elevated
reaction requires only 1 mol% Pd(OAc)2 and the in-situ generated temperature. Also the cost and availability of those specific Pd
palladium naoparticles is found to be active catalysis.
complexes/nanoparticles may further limit their application in
practical synthesis. In comparison, reports on the practical
coupling reaction for biaryl synthesis employing cheap and
readily available catalysts/reagents as well as mild reaction
conditions, have to date remained scarce. In connection with
our interest in hydrazine chemistry13, we discovered that
hydrazine hydrate can serve as the reducing reagent in ligand-
free Pd(OAc)2 catalyzed coupling of aryl halides under room
temperature with N2 instead of inorganic salts as the by-
product, permitting a mild and practical biary synthesis using
Biaryls are core structures that can be found in
pharmaceuticals, agrochemicals1, natural products2, organic
functional materials3, and ligands4. For decades, the coupling
of two aromatic units has evolved to be one of the most
important methods for the biaryl synthesis.5,6 While the past
century has witnessed significant advances in transition metal-
catalyzed cross-couplings between aryl halides and
organometallic reagents (e.g. Suzuki, Stille, Negishi and Hiyama
coupling reactions), Ullmann biary synthesis7 is still recognized
as a straightforward method for the synthesis of numerous
symmetrical and unsymmetrical biaryls from aryl halides
without the need for preformation of organometallic species.8
However, this reaction usually requires stoichiometric input of
readily available reagents and catalysts (scheme 1).
a) Transition-metal catalyzed C-X/C-M cross-couplings
M
X
cat. [T.M.]
Ar2
Ar1
Ar2
Ar1
X = I, Br, Cl, OTs, OTf, et al.
M = B(OR)2, SnR3, ZnX, SiR3, MgX et al.
o
Cu(0) or Cu(I) salts and relatively harsh conditions (> 200 C),
which somewhat limits its practical application in organic
synthesis. As a consequence, the search for milder variations
has become a major research interest in this field. Palladium
has been found to catalyze the couplings of aryl halides in the
presence of reducing reagents such as hydroquinone, alcohol,
amines, triphenylarsine, formate salt, zinc, and indium. For
example, Rawal and co-workers developed a convenient
procedure for both inter- and intramolecular homocoupling of
aryl halides using catalytic palladium in the presence of
b) Conventional Ullmann biaryl synthesis
Cu(0) or Cu(I) salts
(1 - 5 equiv.)
X
X
Ar2
Ar1
Ar2
Ar1
high temperature
c) Pd-catalyzed Ullmann-type biaryl synthesis
cat. [Pd]
reductant
X
X
Ar2
Ar1
waste
Ar1
Ar2
high temperature
d) This work
Pd(OAc)2
N2H4·H2O
X
X
a. School of Chemistry and Chemical Engineering, Jiangsu University, Zhenjiang
212013, PR China. E-mail: zhucycn@gmail.com
Ar2
Ar1
N -
2
Ar2
Ar1
Room temperature
b. State Key Laboratory of Physical Chemistry of Solid Surfaces, Xiamen University,
Xiamen 361005, P.R. China.
Scheme 1. Different synthetic methods of biaryls
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
Initially, the coupling product was isolated with 86% yield
from a 2-hour reaction of 1-chloro-4-iodobenzene in DMSO in
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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the presence of Pd(OAc)2 (20 mol%) and hydrazine hydrate (2
Journal Name
After establishing suitable conditions, the scoVpieew oArftichleoOmnlione-
DOI: 10.1039/C8GC03862G
equiv.) under room temperature (Table 1, entry 1). The same coupling of various aryl halides was explored (Table 2). Initially,
coupling product can also be generated using DMF as the aryl iodides with various aromatic/hetero aromatic rings were
solvent, however, with lower reaction rate and yield (Table 1, investigated (2a−2k), and most of the para-substituted aryl
entry 2). Surprisingly this reaction was totally inhibited under iodides were found to undergo the desired transformation
room temperature in other solvents, such as acetone, ethyl affording yields greater than 80% (2b, 2e-i, and 2k), while
acetate, THF, ethanol, dichloromethane and acetonitrile (Table meta-substituted substrate also showed comparable activity
1, entries 3-8). To lower the catalyst loading, reactions with 10 leading to desired biaryl product in good yield (2c). But when
mol%, 5 mol%, 2.5 mol% of Pd(OAc)2 were carried out steric pressure was applied at the ortho position, the reactivity
individually (Table 1, entries 9-11), and it was found that the decreased so dramatically that no desired coupling product
reaction went much slower with less Pd(OAc)2 as the one with was isolated under current conditions (2d). This observation
2.5 mol% Pd(OAc)2 hardly made any progress over a 48-hour indicates that the reaction is very susceptible to steric
period. Then a mixture of DMF and DMSO (v/v, 3:1) was tested hindrance. The electronic nature of the substrates was shown
as the solvent, and improved reactivity was observed as shown to have little influence on the reaction efficiency, and aryl
in entries 12-13 compared to entries 10-11. Interestingly, the iodides with electron-donating or electron-withdrawing
addition of a hard base like K3PO4, could significantly enhance substituents on the aromatic ring could be converted to
the reactivity, as 2.5 mol% Pd(OAc)2 was able to consume all corresponding biaryls in good to excellent yields (2b, 2h vs 2i,
the starting materials in 6 hours, leading to the desired biaryl 2k). Notably hetero aryl iodide like 2-iodopyridine also worked
product with 86% yield (Table 1, entry 14) and 1 mol% smoothly under current conditions affording an excellent yield
Pd(OAc)2 could accomplish the reaction in 10 hours with 82% of 89%. Finally, aryl bromides and chlorides were evaluated
yield (Table 1, entry 15). Finally, by using 4 equivalents of under current conditions, but none of them showed enough
hydrazine hydrate, 1 equivalent of K3PO4 and 1 mol% Pd(OAc)2, activity to give isolable product, indicating that oxidative
the reaction went smoothly to a full conversion in 10 hours, addition of C-X to Pd maybe the rate-determining step for this
resulting in the desired biaryl with 87% yield (Table 1, entry 16). transformation. To demonstrate the synthetic utilities of this
Notably, unlike most Pd-catalyzed reactions, this reaction strategy, we also conducted a gram-scale reaction of 1i, which
proceeds soomthly under air without any protection, thus provided 2i in 89% yield.
simplifying the operation.
a
Table
2
.
Substrate scope of homo-coupling of aryl iodides
a
Table 1. Effect of Reaction Parameters on coupling reaction
Pd(OAc)2 (1 mol %)
N2H4·H2O (4 equiv.)
(Het)Ar
(Het)Ar
1
I
(Het)Ar
Pd(OAc)2 (x mol %)
N2H4·H2O (y equiv.)
RT, K3PO4 (1 equiv.)
DMF - DMSO
2
Cl
Cl
Cl
I
CH3
Room temperature
CH3
H3C
entry
1
solvent
DMSO
x
20
20
20
20
20
20
20
20
10
5
y
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
4
additive
time
2 h
yieldb/%
--
--
--
--
--
--
--
--
--
--
--
--
--
86
67
0
H3C
CH3
2
DMF
12 h
8 h
CH3
2d
, 0%
2c
, 74%
2b
, 82%
2a
, 85%
3
Acetone
AcOEt
4
8 h
0
F
Br
Cl
5
THF
8 h
0
6
C2H5OH
CH2Cl2
8 h
0
F
Br
N
Cl
2g
, 86%
2f
, 87%
2e
, 78%
7
8 h
0
8
CH3CN
17 h
18 h
48 h
48 h
10h
72 h
6 h
0
CF3
CN
O
9
DMSO
85
63
<5
84
76
86
82
87
N
F3C
10
11
12
13
14
15
16
DMSO
NC
O
b
2k
, 82%
2j
2h
2i
, 89%
, 81%
, 90% (89% )
DMSO
2.5
5
a1.0 mmol of 1, 2.2 mg Pd(OAc), 4.0 mmol of hydrazine hydrate, 1.0 mmol of
K3PO4, 0.75 mL DMF + 0.25 mL DMSO, room temperature, isolated yield. b1.0
gram of 1i was used.
DMF:DMSOc
DMF:DMSOc
DMF:DMSOc
DMF:DMSOc
DMF:DMSOc
2.5
2.5
1
In the reaction of 1-iodo-2-methylbenzene 1d, although no
coupling product 2d was isolated, we observed the formation
of toluene which is the simple reducing product from 1-iodo-2-
methylbenzene. To investigate the steric effect, we carried on
to test more substrates including sterically hindered aryl
iodides and more complicated aryl iodides. As shown in Table
3, without any exception, all the ortho-substituted aryl iodides
d
K3PO4
d
K3PO4
10 h
d
1
K3PO4
8 h
a1.0 mmol of 1-chloro-4-iodobenzene in solvent (1.0 mL) at room temperature;
bisolated yield; cv/v, 3:1; d1.0 equiv. of K3PO4
2 | J. Name., 2012, 00, 1-3
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(1l-o) were reduced to simple aromatic compounds in good iodobenzene was used (entry 14). To seek other possible ways
View Article Online
DOI: 10.1039/C8GC03862G
yields under the standard conditions. The same reduction was to improve the selectivity, some ligands and additives were
observed in the reaction of the complicated substrate 1p tested. As shown in Table 5, phosphine ligands including PPh3,
which was designed to undergo an intramolecular coupling dppp and dppe were found to inhibit the reaction, as it only
originally. However, substrate 1q that is structurally similar to gave a conversion less than 10% in the presence of PPh3 while
substrate 1p remained intact under the standard conditions. being totally shut down in the presence of dppp or dppe
The same results were found with 2-iodothiophene 1r and 1- (entries 1-3). 2,2-bipyridine and TBAC were also employed as
iodonaphthalene 1s, as neither coupling nor reducing product ligand/additive in this reaction, but none of them was able to
were isolated.
improve the selectivity significantly (entries 4-5).
a
a
Table
3
.
The reaction of sterically hindered and complicated aryl iodides
Table 4. Evaluation of cross-coupling
standard conditions
substrate
product
substrate
I
product
Ar1 Ar1
Ar1 Ar2
Ar2 Ar2
Ar1I
Ar2I
5
4
3
OH
OH
Ph
entry
Ar1
Ph
Ar2
ratio (3:4:5)
yieldb/%
Ph
O
O
I
I
2p', 58%
1
2
4-OMe-Ph
4-OMe-Ph
4-OMe-Ph
4-OMe-Ph
4-OMe-Ph
4-OMe-Ph
4-CN-Ph
25：31：44
25：30：45
34：21：45
22：38：40
25：33：44
29：56：15
20：50：30
20：46：34
22：48：30
27：33：40
--：67：33
--：68：32
--：71：29
--：78：22
81
77
75
83
84
90
92
83
89
85
89
87
87
86
1l
2l', 68%
1p
Bn
4-Me-Ph
3-Me-Ph
4-Br-Ph
2-Py
CH2OH
I
N
I
CH2OH
--
I
3
1m
2m', 78%
1q
4
S
NH2
I
NH2
5
I
--
--
1r
6
4-F-Ph
1n
2n', 79%
I
H
H
N
7
4-OMe-Ph
4-F-Ph
N
O
O
I
8
4-CN-Ph
2o', 83%
1s
1o
9
4-CF3-Ph
4-Cl-Ph
4-F-Ph
4-CN-Ph
a1.0 mmol of 1, 2.2 mg Pd(OAc), 4.0 mmol of hydrazine hydrate, 1.0 mmol of
K3PO4, 0.75 mL DMF + 0.25 mL DMSO, room temperature, isolated yield.
10
11c
12d
13e
14f
4-CN-Ph
Next, the cross-coupling was evaluated by subjecting two
different aryl iodides (1:1 mol) to the standard conditions. As
shown in Table 4, different combination of two aryl iodides
showed diverse selectivity. Major homo-coupling products
were observed with aryl iodide bearing strong electron-
donating group (e.g. –OMe) in the reaction with an aryl iodide
bearing weak electron-donating groups (entries 1-4). The
reaction of 1-iodo-4-methoxybenzene with hetero aryl iodide
(2-iodopyridine) was also found to prefer homo-coupling
(entry 5). Interestingly, the reactions involving aryl iodides
with strong electron-withdrawing groups (e.g. –CN, -F, -CF3)
tended to give more cross-coupling products (entries 6-9),
except for the reaction between 4-iodobenzonitrile and 1-
chloro-4-iodobenzene (entry 10). The highest cross-coupling
selectivity was obtained in the reaction of 1-iodo-4-
methoxybenzene with 1-fluoro-4-iodobenzene, from which
three biaryl products were isolated with total 90% yield and
56% of the them was unsymmetrical biaryl product (entry 6).
This cross-coupling selectivity can be improved by using one of
the two substrates in excess amount (entries 11-14). The
reaction of 2.0 equivalents of 1-fluoro-4-iodobenzene with 1.0
equivalent of 1-iodo-4-methoxybenzene led to a ratio of 67:33
for unsymmetrical/symmetrical biaryl (entry 11). Further study
revealed that higher loading of 1-fluoro-4-iodobenzene can
enhance the selectivity of cross-coupling and the ratio can be
increased to 78:22 when 5.0 equivalents of 1-fluoro-4-
4-OMe-Ph
4-OMe-Ph
4-OMe-Ph
4-OMe-Ph
4-F-Ph
4-F-Ph
4-F-Ph
a1.0 mmol of Ar1I, 1.0 mmol of Ar2I, 4.4 mg Pd(OAc), 8.0 mmol of hydrazine
hydrate, 2.0 mmol of K3PO4, 1.5 mL DMF + 0.5 mL DMSO, room temperature.
bisolated yield. 2.0 mmol of Ar1I, 1.0 mmol of Ar2I. d3.0 mmol of Ar1I, 1.0 mmol
c
of Ar2I. e4.0 mmol of Ar1I, 1.0 mmol of Ar2I. f5.0 mmol of Ar1I, 1.0 mmol of Ar2I
Table 5. Effect of ligands/additives on cross-coupling selectivitya
standard conditions
Ar1 Ar1
Ar1 Ar2
Ar2 Ar2
Ar1I
Ar2I
Ar1 = 4-F-Ph
Ar2 = 4-OMe-Ph
5
4
3
entry ligand/additive
ratio (3:4:5)
--
--
--
--：72：28
--：76：24
yield/%b
<10
0
0
82
88
c
1
2
3
4
5
PPh3
dpppd
dpped
bpyd
TBACe
aStandard conditions: 5.0 mmol of 1-fluoro-4-iodobenzene, 1.0 mmol of 1-iodo-
4-methoxybenzene, 4.4 mg Pd(OAc), 8.0 mmol of hydrazine hydrate; 2.0 mmol of
K3PO4, 1.5 mL DMF + 0.5 mL DMSO, room temperature; bisolated yield; c10 mol%;
d5 mol%; c20 mol%; dppp = 1,3-Bis(diphenylphosphino)propane; dppe = 1,2-
Bis(diphenylphosphino)ethane; bpy
Tetrabutylammonium chloride
=
2,2
′
-bipyridine; TBAC
=
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For insight into the reaction mechanism, especially the high
activity of palladium catalyst, it is noticed that some fine dark
grey particles precipitated out during the reaction. This
precipitate was found to be able to promote the coupling
reaction, when being re-subjected to aryl iodides. So we
wonder if the real catalytic species was some type of palladium
nanoparticles (PdNPs)14 and pre-formation of PdNPs was then
carried out by treating Pd(OAc)2 with excess hydrazine hydrate
in the mixture of DMSO and DMF (1:3). The resulted
precipitate was filtrated and washed to give a dark grey
powder, from which PdNPs with dimensions of 50–100 nm
were observed upon SEM measurement (Figure 1). Moreover,
this pre-formed PdNPs, replacing Pd(OAc)2, demonstrated
excellent catalytic activity in the homo-coupling of 4-
iodobenzonitrile under standard conditions (Scheme 2).
Notably PdNPs can be recovered in good yields and its catalytic
activity maintained after 3 cycles (table of Scheme 2).
Pd(OAc)2
N2H4·H2O
View Article Online
DOI: 10.1039/C8GC03862G
Ar Ar
2
ArI 
1
Pd0

PdNPs
O.A.
R.E.
II
ArPdIIAr
7

ArPd I
N2H4·H2O
PdI2
6
T.M.
O.A. = oxidative addition; R.E. = reductive elimination
T.M. = transmetallation
8
Scheme 3. Proposed mechanistic pathway.
Conclusions
N2H4·H2O
Pd(OAc)2
PdNPs
In conclusion, we have developed a palladium catalysed
Ullmann biaryl synthesis using hydrazine hydrate as the
reducing reagent. This reaction avoids the need for metal
reductants which is neither cost-effective nor environmentally
benign. Instead, hydrazine hydrate that is readily available and
cheap, serves a good partnership with Pd(OAc)2 in promoting
the coupling reaction of aryl iodides under room temperature.
The reaction works smoothly for both electron-rich and
electron-deficient aryl iodides, as well as hetero-aryl iodides,
leading to a wide range of biaryls in good to excellent yields.
Preliminary mechanistic studies suggested active catalytic
species for this transformation is palladium nanoparticles that
can be easily prepared by treating Pd(OAc)2 with hydrazine
hydrate. Taken together with its operational simplicity, readily
available reagents, broad substrates scope, and amenability to
gram-scale synthesis, this green reaction will find practical
application for the synthesis of biaryl compounds.
71% yield
DMSO : DMF (1:3), RT
Figure 1. (up) Preparation of PdNPs. (down) SEM image of PdNPs.
PdNPs (1 mol %)
NC
CN
NC
I
standard conditions
2i
Acknowledgments
cycle 2i
PdNPs recovered
We acknowledge the Qing Lan Project of Jiangsu Province and
Jiangsu University Foundation (No. 13JDG059) for finance
support. We thank Dr. Peng Wang from Shanghai Institute of
Organic Chemistry (SIOC) for helpful discussion on palladium
nanoparticles.
1.
2.
3.
87%
77%
74%
75%
81%
74%
Scheme 2. PdNPs catalysed homo-coupling of 4-iodobenzonitrile.
On the basis of these experimental observations, a plausible
mechanism is proposed (Scheme 3). The reaction is initiated by Notes and references
the reduction of Pd(OAc)2 to Pd0 in the presence hydrazine
1
O. Baudoin, M. Cesario, D. Gue´nard and F. Gue´ritte, J. Org.
hydrate. Herein, the active Pd0 species is found to be in the
form of nanoparticles, which accounts for its high activity
under room temperature. Then the oxidative addition of aryl
iodide to Pd0 results in the formation of PdII complex 6. The
transmetallation between two molecules of PdII complex 6
leads to intermediate 7, along with PdI2 which could also be
reduced to Pd0 by hydrazine hydrate. Final reductive
elimination of intermediate 7 affords the desired coupling
product, as well as the Pd0 species which can re-enter the
catalytic cycle.
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Green Chemistry
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View Article Online
DOI: 10.1039/C8GC03862G
Ligand-free palladium catalyzed ullmann biaryl synthesis:
‘household’ reagents and mild reaction conditions
Xinchi Gong,a Jie Wu,a Yunge Meng,a Yulan Zhang,a Long-Wu Yeb and Chunyin Zhu*ab
aSchool of Chemistry and Chemical Engineering, Jiangsu University, Zhenjiang 212013, PR China.
E-mail: zhucycn@gmail.com
bState Key Laboratory of Physical Chemistry of Solid Surfaces, Xiamen University, Xiamen 361005,
P.R. China
Pd(OAc)2
N2H4·H2O
I
I
Ar2
Ar1
N -
2
Ar2
Ar1
Room temperature
N2H4·H2O replacing metal reductants: .Mild reaction conditions
.Convenient operation
.Less inorganic waste