A 2-((4-Arylpiperazin-1-yl)methyl)phenol ligated Pd(II) complex: An efficient, versatile catalyst for Suzuki-Miyaura cross-coupling reactions

Article abstract of DOI:10.1039/c5nj03450g

N,N,O-Tridentate palladium(ii) complexes [Pd(OAc){R-C₄H₈N₂(CH₂Ar)}] (R = Ph, Ar = 4-tBu-C₆H₃-OH (4a)) and [2,4-di-tBu-C₆H₂-OH, R = benzyl (4b)] 4a and 4b have been synthesized from the corresponding 2-((4-arylpiperazin-1-yl)methyl)phenol ligands 3a and 3b in quantitative yields. The synthesized ligands and their palladium(ii) complexes were characterized by NMR, IR and HRMS analyses. Complex 4a has been used as an efficient catalyst for the Suzuki cross-coupling reaction of 5-iodovanillin and 5-bromosalicylaldehyde with various arylboronic acids in low catalytic amounts (0.01-0.05 mol% of 4a). Moreover, this catalytic system is even applicable for Suzuki coupling reactions of deactivated aryl bromides and aryl chlorides, affording the cross-coupling products in good to excellent yields with a broad substrate scope.

Full text of DOI:10.1039/c5nj03450g

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A 2-((4-Arylpiperazin-1-yl)methyl)phenol ligated
Pd(II) complex: an efficient, versatile catalyst for
Suzuki–Miyaura cross-coupling reactions†
Cite this:DOI: 10.1039/c5nj03450g
a
b
Srinivas Keesara* and Saiprathima Parvathaneni
4 8 2 2 6 3
N,N,O-Tridentate palladium(II) complexes [Pd(OAc){R-C H N (CH Ar)}] (R = Ph, Ar = 4-tBu-C H –OH
(
4a)) and [2,4-di-tBu-C –OH, R = benzyl (4b)] 4a and 4b have been synthesized from the corres-
6 2
H
ponding 2-((4-arylpiperazin-1-yl)methyl)phenol ligands 3a and 3b in quantitative yields. The synthesized
ligands and their palladium(II) complexes were characterized by NMR, IR and HRMS analyses. Complex
4a has been used as an efficient catalyst for the Suzuki cross-coupling reaction of 5-iodovanillin and
Received (in Montpellier, France)
4th December 2015,
Accepted 4th July 2016
5
-bromosalicylaldehyde with various arylboronic acids in low catalytic amounts (0.01–0.05 mol% of 4a).
Moreover, this catalytic system is even applicable for Suzuki coupling reactions of deactivated aryl
bromides and aryl chlorides, affording the cross-coupling products in good to excellent yields with a
broad substrate scope.
DOI: 10.1039/c5nj03450g
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The Suzuki–Miyaura cross-coupling reaction brings enormous
ease for synthesis of acid, hydroxyl, amine and aldehyde functional
Introduction
1
0
Design and development of simple, economical, suitable organo- group containing biphenyl derivatives. The Suzuki coupling
metallic catalysts that can maintain environmentally benign products of 5-iodovanillin derivatives have great importance in
conditions have become an important goal for C–C cross- food materials, pesticides, plant cell walls and key structural
1
11
coupling reactions in organic synthesis. The Suzuki–Miyaura elements in natural products. Nantenine is an alkaloid which
cross-coupling reaction of aryl halides with arylboronic acids contains 5-arylvanillin as a basic scaffold and it acts as an
1
2
is one of the most popular palladium catalyzed C–C bond- antagonist at the 5-HT2A serotonin receptor. 6-Arylmethyl-5-
2
forming reactions. This reaction has vast importance in the hydroxy-7-phenyl-chromone derivatives that inhibit the replication
total synthesis of various natural products, pharmaceuticals, of HCV (chronic hepatitis C virus) activities are also synthesized
3
13
polymers and agrochemicals. Its synthetic attractiveness is due from 5-arylvanilline units (Fig. 1). The direct preparation of
to the coupling capability of sterically demanding substrates 5-arylvanillin is particularly attractive in the context of biaryl
and the enormous extent of different functional groups under synthesis, and a few 5-arylvanillin compounds have been synthe-
4
mild experimental conditions. There is a great demand to sized and published previously by using magnesium and indium
incorporate non-toxic reagents to make this process industrially reagents with high catalyst loading (4 mol% of palladium) along
5
14
viable for scale-up production. Thus there is a great demand in with expensive phosphine ligands at elevated temperatures.
the market for the development of new palladium catalysts with
6
high turnover number, reaction rate, yields and selectivity.
Development of air and moisture-stable Pd-catalysts for C–C
cross-coupling reactions still remains as an important challenge
7
to be solved. In particular, C–C cross-coupling reactions catalyzed
by phosphine-free Pd complexes have great value due to their low
8
cost and ease of handling. Many nitrogen ligands coordinated
with palladium(II) complexes have been reported for different C–C
9
cross-coupling reactions.
a
School of Chemistry, University of Hyderabad, Hyderabad-500046, India.
E-mail: drsrinivaskeesara@yahoo.com
b
Catalysis Division, CSIR-Indian Institute of Chemical Technology (IICT), India
†
Electronic supplementary information (ESI) available. See DOI: 10.1039/c5nj03450g
Fig. 1 Structures of bioactive compounds.
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Recently, B. Schmidt and coworkers reported a Pd/C catalyzed N,N,O tridentate ligands 3a–b were further treated with Pd(OAc) in
1
5
Suzuki coupling of 5-iodovanillin. Similarly 5-bromosalicyl- dichloromethane to give the desired palladium(II) complexes 4a–b
aldehyde coupled products were found to be useful intermediates in high yields. These complexes are soluble in polar and nonpolar
in organic syntheses and the pharmaceutical industry with high solvents. We observed the solubility of these complexes to be
16,17
biological activities.
Bioactive molecules like sHA 14-1 and normal in hexane, but high in chloroform, dichloromethane,
CXL017 were prepared from 5-arylsalicylaldehyde, which were acetonitrile and N,N-dimethylformamide. The air and moisture
proved to be promising candidates for the treatment of cancer stable Pd(II) complexes were characterized by NMR, mass and IR
18
with multiple drug resistance (Fig. 1). The Suzuki cross-coupling spectroscopy. All the ligands and their palladium(II) complexes
reaction of 5-bromosalicylaldehyde with arylboronic acid under were in good conformity with the results of NMR.
19
different reaction conditions was unsuccessful.
The phenolic OH proton signals of the ligands 3a–b dis-
As part of our ongoing research, we report herein the synthesis appeared in their corresponding Pd(II) complexes, which con-
and characterization of 2-((4-arylpiperazin-1-yl)methyl)phenol firms the coordination of the metal ion with the oxygen atom by
ligated palladium(II) complexes, as well as the investigation of deprotonation. This results in the loss of one acyl group as
2
their catalytic activity in the Suzuki cross-coupling reaction. To acetic acid from Pd(OAc) . The NMR spectra of these complexes
date very few reports have been published in the literature on showed one set of methyl proton signals in the range d 1.29–1.98.
piperazine moiety containing ligands to accelerate Pd-catalyzed Further, the positive-mode spectra of High Resolution Mass
Suzuki–Miyaura coupling reactions. M. S. Balakrishna and Spectrometry (HRMS) also confirm the formation of Pd(II) com-
co-workers have documented piperazine based palladium cata- plexes 4a and 4b.
2
0
lysts for Heck and Suzuki cross-coupling reactions. Z. G. Zhou’s
To evaluate the catalytic activity of the palladium(II) com-
group has reported the Suzuki reaction of aryl halides and homo- plexes (4a–b), the Suzuki–Miyaura cross-coupling reaction of
coupling of arylboronic acids with piperazine ligands using aryl halides with arylboronic acids was studied. 5-Iodovanillin
2
1
Pd(II) salts.
5a and phenylboronic acid 6a were chosen to establish a model
All the methods reported for biphenyl synthesis from reaction for the optimization of the reaction conditions. The
5
-iodovanillin and 5-bromosalicylaldehyde employed high amounts preliminary results are shown in Table 1. We screened different
of catalyst (4–5 mol%) and expensive phosphine ligands. Therefore, bases for the coupling reaction of 5a with 6a in a 1 : 1 ratio of
it is crucial to develop simple and efficient Pd catalytic systems for water and methanol system. We observed that the reaction
the Suzuki cross-coupling reaction. In this regard we describe our proceeded well with high yields of the desired coupling product
results on the optimization and scope of cross-coupling reactions of 7a with inorganic (K CO , LiOHꢀH O and K PO ) as well as
2
3
2
3
4
5
-iodovanillin, 5-bromosalicylaldehyde, deactivated aryl bromides organic (DABCO and Et N) bases (entries 1–3 and 5, 6). This
3
and aryl chlorides with different arylboronic acids, catalyzed by coupling reaction afforded high conversion with the majority of
Pd(II) complex 4a.
screened bases with only variation in the reaction time. In the
O, 7a was observed in high yield within 5 h,
case of LiOHꢀH
whereas K CO
2
2
3
requires 8 h for product formation. Gratifyingly,
Results and discussion
20
The piperazine ligands 3a–b were prepared as shown in Scheme 1.
a
Table 1 Optimization reaction of 5-iodovanillin with phenylboronic acid
This involves the reaction between N-arylpiperazine, aqueous HCHO
and phenol derivatives in methanol under reflux conditions to
afford ligands 3a–b in almost quantitative yields. The resulting
b
Entry
Base
CO
Solvent
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
K
2
3
H
H
H
H
H
H
H
H
H
2
2
2
2
2
2
2
2
2
O + MeOH
O + MeOH
O + MeOH
O + MeOH
O + MeOH
O + MeOH
O + MeOH
O + MeOH
O
8
5
97
99
96
20
96
95
LiOHꢀH
2
O
K PO
3 4
12
24
20
24
24
24
20
24
24
24
24
NaOAcꢀ3H
2
O
DABCO
Et N
3
c
–
Nr
d
LiOHꢀH
LiOHꢀH
LiOHꢀH
LiOHꢀH
LiOHꢀH
LiOHꢀH
2
O
2
O
2
O
2
O
2
O
2
O
r5
60
85
10
11
12
13
MeOH
CH CN
c
3
Nr
Toluene
DMF
20
10
a
Reaction conditions: 5-iodovanillin (1 mmol), phenylboronic acid
O + MeOH
Scheme 1 Synthesis of ligands 3a–b and their palladium(II) complexes 1 : 1, 2 mL) at room temperature. Isolated yield. Nr = no reaction.
(
1.2 mmol), base (2 mmol), catalyst 4a 0.01 mol%, solvent (H
2
b
c
d
4
a–b.
Without catalyst 4a.
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excellent product formation was observed with K
3
PO
4
in a Table 2 Coupling reactions of 5-iodovanillin with a various arylboronic
prolonged reaction time of 12 h. Low product formation was
a
acids
observed with NaOAcꢀ3H O base even under long-standing
2
conditions (entry 4). Moreover, strong base LiOHꢀH O is more
2
suitable for the coupling of 5a with arylboronic acids than other
bases (K
2
CO
3
, K
3
PO
4
, DABCO, Et
3
N and NaOAcꢀ3H
2
O). Without
a base no reaction was observed (entry 7). As expected poor
b
yields of 7a (r5%) were observed under catalyst-free conditions Entry Ar
Product
Time (h) Yield (%) Ref.
(
entry 8). Next, we studied the solvent effect on the above
coupling reaction with LiOHꢀH
2
O as base. In contrast to the
c
1
2
3
4
5
6
7
8
6
6
8
8
6
8
6
3
99, 94
—
—
—
—
—
—
—
—
aqueous methanol system, independent reactions of water and
methanol solvents gave 7a in low yields (entries 9 & 10). No or
poor yield of 7a was observed in the case of acetonitrile, toluene and
DMF (entries 11–13). It clearly showed that the solvent plays a key
role in the cross-coupling reaction. Thus from all the screenings,
97
96
the best results were observed with the LiOHꢀH
system using 0.01 mol% of catalyst 4a at room temperature
entry 2).
With the appropriate solvent and base in hand, next we
2 2
O–H O/MeOH
(
97
studied the scope of Pd(II) complex 4a for the Suzuki–Miyaura
cross-coupling reaction of 5-iodovanillin 5a with a variety of
phenylboronic acids 6a–j. The results are summarised in Table 2.
A range of arylboronic acids were converted to the corresponding
coupled products 7a–h with 5a in excellent yields at room
temperature (entries 1–8). However, arylboronic acids bearing
electron-withdrawing or electron-donating groups showed a
trivial effect on the coupling reaction. Next, we observed the
substituent effect of arylboronic acids showing the variation of
reaction time for their cross-coupling reactions. Phenylboronic
acid 6a, 4-methylbenzeneboronic acid 6b, 4-fluorobenzene-
boronic acid 6e and 2-naphthylboronic acids 6g took 6 h for
conversion into their corresponding products 7a, 7b, 7e and 7g
96
94
95
97
9
1
24
24
24
85
80
—
—
—
(entries 1, 2, 5 and 7). Whereas 4-OMe, 4-CN and 4-OAc sub-
stituted arylboronic acids 6c, 6d and 6f require 8 h of reaction
time for successful couplings (entries 3, 4 and 6). However,
when 3-chlorobenzeneboronic acid 6h was used as the sub-
strate for 5a coupling, the reaction completed within 3 h with
0
1
9
7% yield (entry 8). We also used sterically hindered aryl-
boronic acids to obtain ortho-Me and OMe groups substituted
-arylvanillins 7i and 7j in good yields, 85% and 80%, respec-
tively (entries 9 and 10). Next, we observed 84% and no yield of
a for 5-bromovanillin 5b and 5-chlorovanillin 5c as partners in
Suzuki cross-coupling reactions (entry 11).
d
e
1
84 , Nr
5
a
Reaction conditions: 5-iodovanillin (1.0 mmol), arylboronic acid
O (1 mmol), H O + MeOH
2 mL, 1 : 1) at room temperature. Isolated yield. Carried out with
(
(
1.2 mmol), catalyst 4a 0.01 mol%, LiOHꢀH
2
2
7
b
c
d
0
.01 mol% of catalyst 4b. Reaction with 5-bromovanillin and catalyst
e
Further we extended the above-optimized reaction conditions 0.05 mol% of 4a at 60 1C. Reaction with 5-chlorovanillin and catalyst
to the Suzuki–Miyaura cross-coupling reaction of 5-bromosalicyl-
0
.05 mol% of 4a at 100 1C. Nr = no reaction.
aldehyde 5d with different arylboronic acids (Table 3). We
observed low yield for the 5d coupling reaction with 6a at room 4-cyano 6d, 4-fluoro 6e and 4-chloro 6k moieties and electron-
temperature by using 0.01 mol% of catalyst 4a. Here we donating group 4-methoxy substituted arylboronic acids 6c
required high temperature and catalyst loading for efficient reacted well with 5d, resulting in 5-aryl substituted salicylalde-
cross-coupling of substrates to complete the reaction. When the hydes (8c–e and 8b) in excellent yields (entries 2–5). However,
concentration of catalyst 4a was increased from 0.01 mol% to the reaction of 3-chlorobenzeneboronic acid 6h with 5d pre-
0
.05 mol%, the yield of the corresponding coupling product 8a ferred K PO base over LiOHꢀH O for efficient coupling (entry 6).
3
4
2
increased from 40% to 86% at 60 1C (entry 1). In comparison When sterically hindered 2-methylphenylboronic acid 6i and
with the reported 5-phenylsalicylaldehyde synthesis, the pre- 2-methoxyphenylboronic acid 6j were used as substrates,
sent catalyst amount (0.05 mol%) was very low. A variety of coupling products 8h and 8i were formed with moderate yields
1
9
arylboronic acids bearing electron-withdrawing groups such as in 30 h of reaction time (entries 8 and 9). No coupling product
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Table 3 Coupling reactions of 5-bromosalicylaldehyde with various variety of arylboronic acids using 3 mol% of 4a, 2 mmol
a
arylboronic acids
LiOHꢀH
2
O, and 2 mL of DMF at 100 1C for 24 h. We observed
good yields of the desired products 9n–q for electron-deficient aryl
chlorides such as 1-chloro-4-nitrobenzene 5k, 4-chloroacetophenone
5l and 4-chlorobenzophenone 5m (entries 1–4). In the case of
chlorobenzene 5n and 4-chlorotoluene 5o as reaction partners,
low to moderate yields of the coupled products 9r, 9a and 9b were
obtained only after 30 h (entries 5–8). However, we observed less
than 10% of homo-coupling products of arylboronic acids for the
Suzuki cross-coupling of aryl chlorides.
b
Entry Ar
1
Product
Time (h) Yield (%) Ref.
c
15
15
15
15
15
12
15
86, 40
94
16
2
3
4
5
6
7
18a
—
Table 4 Coupling reactions of arylboronic acids with a variety of aryl
a
bromides
92
90
16
88
16
b
Entry
1
Aryl halide
R
Product
Yield (%)
Ref.
d
86
—
H
96
2b
88
79
18b
2
3
4
5
6
7
8
H
F
94
92
94
86
90
82
86
2b
22a
22e
2b
8
9
30
30
24
—
Cl
H
F
74
18a
16
d
e
1
0
84 , Nr
22a
22e
2b
a
Reaction conditions: 5-bromosalicylaldehyde (1.0 mmol), arylboronic
O (2 mmol), H O (2 mL)
at 60 1C. Isolated yield. Reaction with 0.01 mol% catalyst 4a at room
(2 mmol) used as base. Reaction with 5-chloro-
salicylaldehyde and 1 mol% of 4a at 100 1C. Nr = no reaction.
acid (1.2 mmol), catalyst 4a 0.05 mol%, LiOHꢀH
2
2
b
c
d
e
temperature.
K PO
3 4
Cl
H
was noticed for 5-chlorosalicylaldehyde 5e as a partner in the
Suzuki cross-coupling reaction (entry 10).
On the other hand, we examined the efficiency of this
catalyst 4a for the Suzuki reaction of deactivated aryl bromides
9
F
90
82
22a
22d
5f–j with different arylboronic acids (6a, 6e and 6h) under the
above-optimized reaction conditions at 50 1C. The cross- 10
coupling reactions of deactivated aryl bromides were carried
out well, and obtained good yields for all the corresponding
biaryl products 9a–m. This reaction proceeded smoothly with
the electron-rich aryl bromides bearing 4-Me and OMe groups
at para-, meta- and ortho-positions (entries 1–10). However, we 12
observed good yields for the most challenging substrate 4-SMe
group containing aryl bromide 5j when employed as a coupling
partner with different arylboronic acids for a prolonged reac-
tion time of 15–24 h (entries 11–13).
Cl
c
1
1
H
F
92
8a
c
90
22c
—
c
1
3
Cl
88
a
Reaction conditions: aryl halide (1 mmol), arylboronic acid (1.2 mmol),
O (2 mmol), H O + MeOH (2 mL, 1 : 1) at
To understand the efficiency of our complex 4a, we extended
the Suzuki cross-coupling reaction of aryl chlorides with a 50 1C for 15 h. Isolated yield. Reaction time: 24 h.
catalyst 4a 0.01 mol%, LiOHꢀH
2
2
b
c
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Table 5 Coupling reactions of arylboronic acids with a variety of aryl aryl bromides with different arylboronic acids proceeded well
a
chlorides
using low catalyst loadings (0.01 mol%). This catalytic system is
even applicable for challenging ArCl couplings. An excellent
functional group tolerance with high yields in aqueous systems
makes this method more economically viable in terms of green
perspectives.
b
Entry Aryl halide
1
R
Product
Yield (%) Ref.
Experimental section
General procedure for the synthesis of ligands 3a–b
H
80
81
76
80
64
62
56
60
2b
1c
In a 100 mL round bottom flask piperazine (10 mmol), 40%
aqueous formaldehyde solution (2.1 mL, 30 mmol) and methanol
2
3
4
5
6
7
Me
H
(
50 mL) were added and refluxed for 2 h. This reaction mixture
was allowed to cool to room temperature. Phenol derivatives
2a or 2b) (20 mmol) were directly added to the reaction mixture
(
2b
22b
2b
2b
2b
2b
and again refluxed for 12 h. Then the reaction mixture was
allowed to stand at room temperature for cooling and the
resulting solid (90–95% yield) was filtered off and dried under
vacuum.
OMe
H
c
c
c
c
General procedure for the preparation of Pd(II) complexes 4a–b
To a flask containing ligand (3a or 3b) (0.5 mmol) and Pd(OAc)
0.5 mmol), 30 mL of CH Cl was added at room temperature
2
H
(
2
2
and stirred for 12 h. The reaction mixture was washed with water
to remove AcOH generated in the reaction mixture. The solvent
was removed under reduced pressure and the resulting brown
solid was dried under high vacuum to obtain the pure Pd(II) com-
plexes (4a or 4b) in 94–96% yield.
Me
OMe
8
1
Pd(II) complex 4a. Brown solid, m.p.: 180 1C. H NMR (400 MHz,
a
Reaction conditions: aryl chloride (1 mmol), arylboronic acid CDCl
3
, TMS) d 7.36 (t, J = 8.84 Hz, 2H), 7.15 (d, J = 8.58 Hz, 1H),
.03–6.94 (m, 4H), 6.78 (d, J = 8.58 Hz, 1H), 3.94 (d, J = 10.10 Hz,
H), 3.74 (s, 2H), 3.57 (d, J = 12.88 Hz, 2H), 3.42 (t, J = 11.11 Hz, 2H),
(1.2 mmol), catalyst 4a 3 mol%, LiOHꢀH
2
O (2 mmol), DMF (2 mL) at
00 1C for 24 h. Isolated yield. Reaction time: 30 h.
7
2
3
b
c
1
13
.05 (d, J = 12.88 Hz, 2H), 1.29 (m, 12H); C NMR (100 MHz, CDCl
3
)
d 162.8, 150.4, 138.5, 129.2, 127.0, 126.5, 123.8, 119.9, 118.5, 115.5,
The catalytic efficiency of complex 4a exhibits several advan-
5
5.3, 52.8, 43.6, 33.7, 31.5, 29.6; FTIR (KBr): n~ = 2955, 1722,
tages, observed from the above results (Tables 1–5). (1) The low
catalyst loading is sufficient for efficient coupling of iodo- and
bromoaryl compounds (0.01–0.05 mol%). (2) The operation of
this reaction is very simple without the use of any susceptible
reagents. (3) Hydroxy- and aldehyde-substituted aryl halide
coupling reactions proceeded well under aqueous systems with
the air stable catalyst 4a. (4) The main feature of this process was
the efficient synthesis of 5-arylvanillin from a particular solvent
system and all the inorganic bases. (5) Lastly, the developed
complex 4a is even applicable for non-activated chloro coupling
reactions.
ꢁ
1
+
1573 cm ; HRMS: calcd for C H N OPd (M–OAc) = 429.1158,
21 27 2
found: 429.1080.
1
Pd(II) complex 4b. Brown solid, m.p.: 176 1C. H NMR (400
MHz, CDCl , TMS) d 7.38 (m, 6H), 6.84 (s, 1H), 4.22 (s, 2H), 4.14
s, 2H), 3.57–3.12 (m, 4H), 2.61–2.25 (m, 4H), 1.98 (s, 3H), 1.44
3
(
(
1
3
s, 9H), 1.31 (s, 9H); C NMR (100 MHz, CDCl
3
) d 178.9, 163.5,
40.5, 136.9, 131.4, 130.3, 128.9, 128.6, 126.2, 125.6, 125.0, 62.3,
1.8, 59.7, 54.9, 54.8, 35.2, 33.9, 31.6, 30.8, 29.5, 23.6; FTIR
1
6
ꢁ1
(
(
KBr): n~ = 2954, 1718, 1573 cm ; HRMS: calcd for C H N OPd
26 37 2
M–OAc) = 499.1941, found: 499.1935.
+
General procedure for the Suzuki–Miyaura cross-coupling
reaction of 5-iodovanillin
Conclusion
In conclusion, we have developed a new N,N,O-tridentate derived A mixture of 5-iodovanillin (1.0 mmol), arylboronic acid (1.2 mmol),
palladium(II) complex for the Suzuki reaction of 5-iodovanillin, LiOHꢀH O (2.0 mmol) and Pd complex 4a (0.01 mol% in 0.1 mL
2
5-bromosalicylaldehyde and deactivated aryl bromides in an DMF) in a 1 : 1 ratio of water and methanol system (2 mL) was
aqueous system. We obtained a variety of 5-arylvanillin and stirred at room temperature for 6 h. After confirmation of
-arylsalicylaldehyde derivatives in excellent yields. These biaryl completion of the reaction by TLC, the reaction mixture was
units can serve as key structural elements in different pharma- extracted with ethyl acetate and dried over MgSO . The solvent
ceutical intermediates. Coupling reactions of various deactivated was removed under reduced pressure and the residue was
5
4
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purified by column chromatography on silica gel using ethyl
acetate/hexane as the eluent to afford the desired products.
3 -Chloro-6-hydroxy-5-methoxybiphenyl-3-carbaldehyde 7h
1
(entry 8, Table 2). White solid, m.p.: 136 1C. H NMR (400 MHz,
6
-Hydroxy-5-methoxybiphenyl-3-carbaldehyde 7a (entry 1, CDCl , TMS) 9.58 (s, 1H), 7.98 (s, 1H), 7.62 (s, 1H), 7.51–7.47 (m,
3
1
Table 2). White solid, m.p.: 130 1C. H NMR (400 MHz, CDCl , 2H), 7.41 (s, 1H), 7.35–7.34 (m, 1H), 6.85 (s, 1H), 3.98 (s, 3H);
TMS) 9.73 (s, 1H), 7.51 (s, 2H), 7.39–7.25 (m, 5H), 6.61 (s, 1H),
.84 (s, 3H); C NMR (100 MHz, CDCl
47.5, 136.3, 129.1, 128.7, 128.4, 127.8, 127.6, 107.4, 56.4; HRMS: exact mass calculated for C14
HRMS: exact mass calculated for C14
found m/z = 229.0856.
3
1
3
C NMR (100 MHz, CDCl ) 190.9, 162.7, 148.8, 147.5, 138.1,
3
1
3
3
1
3
) 191.1, 159.1, 148.8, 134.1, 129.6, 129.1, 128.2, 127.7, 127.2, 126.2, 107.9, 56.4;
+
H12ClO
3
[M + H]
=
+
H
O
13 3
[M + H] = 229.0865, 263.0475, found m/z = 263.0443.
0
0
6-Hydroxy-5-methoxy-2 -methyl-[1,1 -biphenyl]-3-carbaldehyde
0
0
1
6-Hydroxy-5-methoxy-4 -methyl-[1,1 -biphenyl]-3-carbaldehyde 7i (entry 9, Table 2). White solid, m.p.: 130 1C. H NMR (400 MHz,
1
7
b (entry 2, Table 2). White solid, m.p.: 148 1C. H NMR (400 MHz, CDCl , TMS) 9.75 (s, 1H), 7.73 (s, 1H), 7.37 (s, 1H), 7.25–7.22 (m,
3
CDCl , TMS) 9.73 (s, 1H), 7.41–7.39 (m, 3H), 7.28 (s, 1H), 7.16 (d, 3H), 7.15–7.13 (m, 1H), 6.36 (s, 1H), 3.92 (s, 3H), 2.12 (s, 3H);
3
13
13
J = 7.83 Hz, 2H), 6.51 (s, 1H), 3.84 (s, 3H), 2.29 (s, 3H); C NMR
C NMR (100 MHz, CDCl ) 190.9, 148.6, 147.1, 136.7, 135.8,
3
(
1
C
100 MHz, CDCl ) 191.1, 148.6, 147.3, 137.4, 133.2, 129.0, 128.8, 130.0, 129.8, 129.1, 129.0, 128.1, 128.0, 125.7, 107.4, 56.2, 19.8;
3
+
15 3
28.5, 127.5, 107.1, 56.2, 21.1; HRMS: exact mass calculated for HRMS: exact mass calculated for C15H O [M + H] = 243.1021,
+
15
H
4
O
15 3
[M + H] = 243.1021, found m/z = 243.0989.
found m/z = 243.1021.
0
0
0
-Methoxy-6-hydroxy-5-methoxybiphenyl-3-carbaldehyde 7c
entry 3, Table 2). Light yellow solid, m.p.: 130 1C. H NMR (entry 10, Table 2). Light yellow solid, m.p.: 138 1C. H NMR
6-Hydroxy-2 ,5-dimethoxy-[1,1 -biphenyl]-3-carbaldehyde 7j
1
1
(
(
400 MHz, CDCl , TMS) 9.78 (s, 1H), 7.50 (d, J = 9.09 Hz, 2H), (400 MHz, CDCl , TMS) 9.73 (s, 1H), 7.34 (m, 2H), 7.30 (t, J =
3
3
7
3
1
1
.41 (m, 1H), 7.31 (s, 1H), 6.92 (d, J = 9.09 Hz, 2H), 6.43 (s, 1H), 8.33 Hz, 1H), 7.24 (d, J = 7.57 Hz, 1H), 6.99–6.92 (m, 2H), 6.49 (s,
1
3
13
.91 (s, 3H), 3.77 (s, 3H); C NMR (100 MHz, CDCl ) 191.1, 1H), 3.87 (s, 3H), 3.72 (s, 3H); C NMR (100 MHz, CDCl ) 190.9,
3
3
59.2, 148.6, 147.4, 130.2, 129.2, 128.6, 128.4, 127.3, 113.9, 156.4, 149.1, 147.6, 131.4, 130.2, 129.7, 129.5, 128.9, 125.1 (d),
07.1, 56.4, 55.3; HRMS: exact mass calculated for C15 120.8, 111.2, 107.5, 56.1, 55.6; HRMS: exact mass calculated for
15 4
H O
+
+
[M + H] = 259.0970, found m/z = 259.0949.
15 15 4
C H O [M + H] = 259.0970, found m/z = 259.0974.
0
4
-Cyano-6-hydroxy-5-methoxybiphenyl-3-carbaldehyde 7d
1
General procedure for the Suzuki–Miyaura cross-coupling
reaction of 5-bromosalicylaldehyde
(
entry 4, Table 2). Light yellow solid, m.p.: 160 1C. H NMR
(400 MHz, CDCl , TMS) 9.79 (s, 1H), 7.66 (m, 4H), 7.42 (d, J =
3
1
3
19.95 Hz, 2H), 6.78 (s, 1H), 3.93 (s, 3H); C NMR (100 MHz, A mixture of 5-bromosalicylaldehyde 5d (1.0 mmol), arylboronic
CDCl ) 190.7, 148.8, 147.6, 141.5, 132.1, 129.8, 129.4, 127.7, acid (1.2 mmol), LiOHꢀH O (2.0 mmol) and Pd complex 4a
3
2
1
C
18.8, 111.2, 108.6, 56.5; HRMS: exact mass calculated for (0.05 mol% in 0.1 mL DMF) in a 1 : 1 ratio of water and methanol
+
15
H
12NO
3
[M + H] = 254.0817, found m/z = 254.0802.
system (2 mL) was stirred at 60 1C for 24 h. To the cooled solution
0
4
4
-Fluoro-6-hydroxy-5-methoxybiphenyl-3-carbaldehyde 7e water was added, extracted with ethyl acetate and dried over MgSO .
1
(
(
2
entry 5, Table 2). White solid, m.p.: 112 1C. H NMR The solvent was removed under reduced pressure and the residue
400 MHz, CDCl , TMS) 9.76 (s, 1H), 7.50 (s, 2H), 7.38 (d, J = was purified by column chromatography on silica gel using ethyl
6.77 Hz, 2H), 7.04 (s, 2H), 6.53 (s, 1H), 3.90 (s, 3H); F NMR acetate/hexane as the eluent to give the desired products.
3
1
9
1
3
0 0 0
(
376.46 MHz, CDCl ) d: n~ ꢁ114.31 (s, 1 F); C NMR (100 MHz,
3 -Formyl-4 -hydroxy-[1,1 -biphenyl]-4-carbonitrile 8c (entry 3,
3
1
CDCl ) 190.9, 163.5 (d, J = 248.09 Hz), 148.5, 147.3, 132.1, 130.7 Table 3). White solid, m.p.: 149 1C. H NMR (400 MHz, CDCl ,
3
3
(
5
d, J = 8.05 Hz), 129.1, 128.2, 126.5, 115.4 (d, J = 21.95 Hz), 107.4, TMS) d 11.11 (s, 1H), 10.01 (s, 1H), 7.81–7.67 (m, 6H), 7.14 (d, J =
+
13
6.3; HRMS: exact mass calculated for C14
H12FO
3
3
[M + H] = 8.58 Hz, 1H); C NMR (100 MHz, CDCl ) d 196.3, 161.8, 143.6,
2
47.0770, found m/z = 247.0776.
135.4, 134.0, 132.7, 132.0, 131.0, 127.8, 127.0, 120.7, 118.5, 110.8;
0
0
+
4
-Acetyl-6-hydroxy-5-methoxy-[1,1 -biphenyl]-3-carbaldehyde HRMS: exact mass calculated for C14H10NO [M + H] = 223.0633,
2
1
7
f (entry 6, Table 2). Orange solid, m.p.: 120 1C. H NMR found m/z = 223.0797.
(
400 MHz, CDCl , TMS) 9.85 (s, 1H), 8.02 (m, 2H), 7.73 (m,
5-(-3-Chlorophenyl)salicylaldehyde 8f (entry 6, Table 3).
3
1
2
H), 7.52–7.33 (m, 2H), 7.04 (s, 1H), 3.97 (s, 3H), 2.62 (s, 3H); Light yellow solid, m.p.: 70 1C. H NMR (400 MHz, CDCl3,
1
3
C NMR (100 MHz, CDCl ) 198.0, 190.9, 149.0, 147.6, 147.3, TMS) d 10.95 (s, 1H), 9.89 (s, 1H), 7.65 (m, 2H), 7.45 (m, 1H),
3
1
3
1
3
36.1, 135.9, 129.3, 128.3, 128.1, 126.3, 108.7, 56.4, 26.6; HRMS: 7.35–7.23 (m, 3H), 7.01 (m, 1H); C NMR (75 MHz, CDCl )
+
exact mass calculated for C16
m/z = 271.0960.
H
15
O
4
[M + H] = 271.0970, found d 196.4, 161.4, 141.1, 135.5, 134.9, 131.8, 130.2, 127.4, 126.7,
124.7, 120.7, 118.3, 113.7; HRMS: exact mass calculated for
+
4
-Hydroxy-3-methoxy-5-(naphthalen-2-yl)benzaldehyde 7g
C
13
H10ClO
2
[M + H] = 233.0369, found m/z = 233.0370.
1
0
0
(entry 7, Table 2). White solid, m.p.: 164 1C. H NMR (400 MHz,
4-Hydroxy-2 -methyl-[1,1 -biphenyl]-3-carbaldehyde 8h (entry 8,
1
CDCl , TMS) 9.76 (s, 1H), 7.96 (s, 1H), 7.80–7.75 (m, 3H), 7.65 (m, Table 3). Brown liquid. H NMR (400 MHz, CDCl , TMS) d 10.93
3
3
1
H), 7.49 (s, 1H), 7.39–7.37 (m, 2H), 7.31 (s, 1H), 6.30 (s, 1H), 3.85 (s, 1H), 9.83 (s, 1H), 7.42 (s, 2H), 7.19–7.12 (m, 4H), 6.98 (d, J =
13
13
(s, 3H); C NMR (100 MHz, CDCl ) 191.1, 148.9, 147.5, 133.8, 8.84 Hz, 1H), 2.19 (s, 3H); C NMR (75 MHz, CDCl ) d 196.5,
3
3
1
1
C
33.3, 132.7, 129.3, 128.8, 128.2, 128.1, 127.8, 127.6 (d), 127.0, 160.5, 139.9, 137.9, 135.3, 133.8, 133.7, 130.4, 129.6, 127.6, 126.0,
26.3, 126.2, 107.9, 56.4; HRMS: exact mass calculated for 120.2, 117.3, 20.3; HRMS: exact mass calculated for C14
H O
13 2
+
+
18
H
15
O
3
[M + H] = 279.1021, found m/z = 279.1023.
[M + H] = 213.0916, found m/z = 213.0910.
New J. Chem.
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Paper
General procedure for the Suzuki–Miyaura cross-coupling
reaction of aryl bromides
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1.2 mmol), LiOHꢀH
Pd complex 4a in freshly prepared DMF solution (0.01 mol% in
.1 mL DMF) was stirred at 50 1C for the desired reaction time.
2 2
O (2.0 mmol), H O + MeOH (1 : 1, 2 mL), and
0
8
2
448–8451; (c) L. Liu, Y. Dong and N. Tang, Green Chem.,
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corresponding coupling products.
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0
5 A. M. Rouhi, Chem. Eng. News Archive, 2004, 82, 49–58.
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1
Table 4). Light yellow solid, m.p.: 48 1C. H NMR (400 MHz,
CDCl , TMS) 7.54 (s, 1H), 7.49–7.42 (m, 3H), 7.36–7.28 (m, 4H),
3
13
2
.51 (s, 3H); C NMR (100 MHz, CDCl ) 142.3, 138.5, 136.4, 134.7,
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30.0, 127.4, 127.1, 126.9, 126.8, 124.9, 15.7; HRMS: exact mass
+
431–440.
calculated for C H ClS [M] = 234.0270, found m/z = 234.0261.
13 11
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4
1.2 mmol), LiOHꢀH
2
O (2.0 mmol), DMF (2 mL), and Pd complex
a (3 mol%) was stirred at 100 1C for the desired reaction time.
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Acknowledgements
KS thanks the University Grants Commission (UGC), New Delhi,
for Dr D. S. Kothari postdoctoral research fellowship. SP thanks
the CSIR, New Delhi, for a Senior Research Associateship. Special
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New J. Chem.
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