Synthesis of biphenyl-based ligand: Application in copper-mediated chemoselective michael reaction

Article abstract of DOI:10.1080/00397911.2014.946996

A biphenyl-based ligand attached was synthesized and screened in copper-mediated Michael reaction. The catalyst system works well with carbon or sulfur nucleophiles as Michael donors and cyclohexenone or chalcones as the acceptors under mild and neutral r

Full text of DOI:10.1080/00397911.2014.946996

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Synthesis of Biphenyl Based Ligand: Application in
Copper Mediated Chemoselective Michael Reaction
M. Shyam Sundara & Ashutosh V. Bedekara
a Department of Chemistry, Faculty of Science, M. S. University of Baroda, Vadodara, India
Accepted author version posted online: 05 Sep 2014.
To cite this article: M. Shyam Sundar & Ashutosh V. Bedekar (2014): Synthesis of Biphenyl Based Ligand: Application in Copper
Mediated Chemoselective Michael Reaction, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, DOI: 10.1080/00397911.2014.946996
To link to this article: http://dx.doi.org/10.1080/00397911.2014.946996
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Synthesis of biphenyl based ligand: Application in copper mediated chemoselective
Michael reaction
M. Shyam Sundar1, Ashutosh V. Bedekar1
1Department of Chemistry, Faculty of Science M. S. University of Baroda, Vadodara,
India
Corresponding author E-mail: avbedekar@yahoo.co.in
Abstract
A biphenyl based ligand attached was synthesized and screened in copper mediated
Michael reaction. The catalyst system works well with carbon or sulfur nucleophiles as
Michael donors and cyclohexenone or chalcones as the acceptors under mild and neutral
reaction conditions in chemoselective manner.
KEYWORDS: Homogeneous catalysis, Michael reaction, Thia-Michael, Copper catalyst
INTRODUCTION
Michael reaction of active methylene compounds with , -unsaturated ketones is
one of the most powerful and well studied carbon-carbon bond forming reactions of
modern chemistry.[1] Similarly the Michael reaction with other heteroatom nucleophiles
with activated -system is extensively utilized for making carbon-heteroatom bonds.[2]
This reaction is extensively studied under various conditions such as in presence of ionic
1

liquids,[3] aqueous,[4] micellar,[5] presence of base[6] and DNA,[7] Lewis acids,[8] other
acidic reagents[9] etc. with considerable success. The Michael reaction of conjugated
systems with amines as nucleophiles, aza-Michael reaction, is quite common method to
synthesize important derivatives of -amino ketones, esters and acids. Similarly, the
reaction with sulfur nucleophile, thia-Michael reaction, is widely employed in
biosynthesis and for the synthesis of bioactive compounds[10] and for the protection of a
double bond.[11]
Many homogeneous catalyst systems are developed for promoting the Michael
reaction.[12] The homogeneous complexes of different ligands with metal salts of
vanadium,[13] copper,[14] nickel,[15] cobalt,[16] iron,[17] boron,[18] zinc,[19] ruthenium,[20]
palladium[21] etc. have been investigated for variants of Michael reaction. Some of these
catalysts works equally well with different types of nucleophiles towards reactive
conjugated substrates. The crucial aspect for a useful catalyst system is the possibility of
achieving a certain degree of selectivity in favor of one type of reaction or reactivity. For
Michael reaction the addition of amine nucleophile to
-unsaturated ketones is favored
in most of the homogeneous catalysts. The heterogeneous catalyst of Li-X-type zeolite
was found to be selective for sulfur nucleophile compared to the oxygen nucleophile for
the Michael reaction.[22] The thia-Michael reaction is also frequently studied and several
efficient catalysts are developed.[23] However, the availability of catalyst systems for
chemoselective Michael reaction is not widespread.
2

In this paper we present synthesis of a new biphenyl based bis-Schiff ligand and the
preliminary applications in copper catalyzed Michael reaction of -unsaturated
ketones. There are two literature references available for the structurally similar ligands
in the literature.[24] In one of the references its cobalt complex is explored as a catalyst for
the addition of diethyl zinc to aldehydes,[24b] while in another crystal structure of its
bromo derivative has been solved.[24c]
RESULT AND DISCUSSION:
The design of new ligands is a crucial aspect of the process of developing homogeneous
catalyst systems. The structure of new biphenyl based ligand 1 is given in Figure 1. The
present biphenyl based bis-Schiff base ligand is made with an aim to offer two
symmetrical binding cites for the complexation with metal ions and to study its catalytic
activity for important chemical transformations.
The synthesis of ligand 1 is outlined in Scheme 1. The dicarboxylic acid 2 is prepared by
oxidation of phenanthrene[25] and converted to the diol 3 by known reduction with
NaBH4-iodine.[26] We required to convert the diol 3[27] to the dibromo 4,[28] the
conditions screened are presented in supporting information. In acidic condition the
cyclization of 4 was observed,[29] while in the neutral condition the dibromo 4 was the
only product. The dibromo 4 thus obtained was converted to the diamine 6 via diazide 5,
and further converted to desired bis-Schiff base 1 in reasonably good yields.
3

The role of copper catalysts for promoting Michael reaction has been previously
established[14f] hence in the present study we chose this catalyst system. Reaction of
chalcone 7 as the -conjugated substrate, acetyl acetone as the active methylene
compound was investigated with the ligand 1 and Cu(OTf)2 as the metal source. It was
interesting to note that best result was obtained when two equivalent metal salt was
employed with respect to the bidentate ligand 1. Neither the reverse ratio nor equal ratio
of copper and ligand was effective. Absence of copper and ligand did not provide any
product under the present condition of carbon-carbon bond forming Michael reaction
(Table 1). Efforts to hasten the reaction by elevating temperature also did not see any
dramatic results. The other copper metal salts such as copper acetate and copper chloride
were ineffective under the optimized reaction conditions.
The structure of the active catalyst of the complex of ligand 1 and Cu(OTf)2 can have the
possible structure I (Figure 2). Based on our observation of best conversion, the possible
structure may be complex I formed by ratio of ligand to Cu(OTf)2 of 1:2 (entry 2, Table
1). Our initial efforts to grow crystal of the catalytic species were not successful. The
mixture of ligand and Cu(OTf)2 in 1,2-dichloroethane gave a light greenings color
powder which showed a mass peak of 1236 (TOF MS ES+) indicating to the structure I
along with four sodium ions.
Having established mild and neutral condition for Michael reaction a number of other
-unsaturated ketones were subjected to the same to test the generality (Table 2). The
reaction with other active methylene compounds with 7 under identical conditions was
4

not as effective, CH2(CN)2 (trace), CH2(COOCH3)2 (trace) and CH3COCH2COOEt (43
% Y, d.r. 80:20 by NMR).
The results of the present neutral and mild Michael reaction are encouraging and hence
were further studied from the chemoselectivity angle. It was interesting to observe
negligible conversions in oxo- and aza-Michael reaction with phenol and amines.
Reaction of cyclohexenone 17 with -naphthol did not furnish oxo-Michael product but
gave BINOL (36 % Y) by copper catalyzed oxidation reaction.[30] Similarly reaction with
amino nucleophiles as Michael donors such as piperidine, aniline, imidazole did not
furnish 1,4-addition products. On the other hand reaction with soft nucleophile such as
thiols gave the desired thia-Michael reaction products in good yields.
Reaction of cyclohexenone 17 with 2-naphthalenethiol 20 (1.5 eq.) furnished the thia-
Michael product 21 in good yield (81%) under the standard condition. The
chemoselectivity of the system was then investigated with different combinations. In the
first reaction cyclohexenone was exposed to the established conditions with piperidine
and 2-naphthalenethiol and the products were analyzed. The aza-Michael product 22 was
not detected while the thia-Michael product 21 was isolated, though in lesser yield
(Scheme 2). This observation of chemoselectivity in favor of thia-Michael over aza-
Michael is noted previously.[2a]
In the next experiment the comparison between aromatic and aliphatic thiols was
examined (Scheme 3). Reaction of the benzyl mercaptan 23 was slightly favored because
5

of more nucleophilic sulfhydryl sulfur atom and the corresponding product 24 was
formed in excess compared to the product of weaker nucleophilic aromatic thiol. This
observation is slightly different than the recently reported example for ionic liquid
mediated Michael reaction for 20 and 23 with cyclohexenone.[3d] In the study weaker
nucleophilic but stronger acidic 20 gave faster product 21 in the thia-Michael reaction.
Reaction of 17 with only aryl alkyl thiol 23 (1.5 eq.) gave product 24 in good yield (84
%), not shown in the scheme.
Reaction of 2-mercaptoethanol 25 with cyclohexene selectively gave thia-Michael
product 26 (Scheme 4), while 27 was not detected. Such observations of selectivity are in
accordance with other reported catalytic systems.[23,24j] The isolated yields of the
experiments run to test chemoselectivity were lower because only 1.0 or 1.2 equivalent
reagents were utilized to assess the selectivity and no attempts were made to optimize
conditions.
The new ligand 1 was prepared as a part of our ongoing project on atropisomeric
compounds and efforts are underway to prepare its derivatives and separate their isomers
to study the applications in asymmetric version of these reactions.
EXPERIMENTAL
Reagents were purchased from Sigma-Aldrich Chemicals Limited, SD Fine, Qualigens
Limited etc. Thin Layer Chromatography was performed on Merck 60 F254 Aluminium
coated plates. The spots were visualized under UV light or with iodine vapour. All the
6

compounds were purified by column chromatography using silica gel (60-120 mesh). All
the products were characterized by H-NMR, IR, Mass spectroscopy and by comparison
of m.p. with the reported values. 1H NMR spectra were recorded on Bruker Avance 400
Spectrometer and were run in CDCl3. Mass spectra were recorded on Thermo-Fischer
DSQ II GCMS instrument. IR spectra were recorded on a Perkin-Elmer FTIR RXI
spectrometer as KBr pallets. Melting points were recorded in Thiele’s tube using paraffin
oil and are uncorrected.
2,2’-Bis(Hydroxymethyl)Biphenyl (3)
To a one litter two neck round bottom flask, fitted with magnetic stir bar and a reflux
condenser was added sodium borohydride (7.404 g, 0.198 mol ), dry THF (200 mL),
diacid 2 (10.0 g, 0.041 mol) in one portion. The flask was cooled in an ice bath. To this a
solution of iodine (21.95 g, 0.087 mol) in dry THF (100 mL) was poured in via an
addition funnel slowly over 45 min resulting in vigorous evolution of hydrogen. After the
addition of iodine was complete the flask was heated to reflux (18 h), cooled to room
temperature and methanol (30 mL) was added cautiously until the mixture become clear.
After stirring (30 min), the solvent was removed, leaving a white paste which was
dissolved in KOH solution (20 % aq. 200 mL). The resultant solution was stirred (4 h)
and extracted with ethyl acetate (3 x 250 mL). The organic layer was dried over sodium
sulfate and concentrated in vacuum, affording a white solid (8.77 g, 99 %).
M. p. = 110 - 112 oC (Lit.[29] 110.5 - 111.5 oC)
IR (KBr):  3355, 3064, 2918, 1479, 1448, 1428, 1423, 1339, 1250, 1194, 1104, 1034,
998, 774, 755, 654 cm.-1
7

1H NMR (400 MHz, CDCl3): δ 7.51-7.49 (dd, J = 6.4 and 1.2 Hz, 2H), 7.44-7.39 (td, J =
6.0 and 1.6 Hz, 2H), 7.38-7.34 (td, J = 6.0 and 1.6 Hz, 2H), 7.18-7.16 (dd, J = 6.0 and J =
1.2 Hz, 2H), 4.35 (broad s, 4H), 3.07 (s, 2H).
Mass (EI+) m/z (%) 198 (6), 197 (40), 196 (9), 195 (10), 181 (2), 180 (2), 179 (11), 168
(14), 167 (100), 165 (1).
2,2’-Bis(Bromomethyl)Biphenyl (4):
To an oven dried two neck round bottom flask triphenyl phoshine (25.76 g, 0.098 mol)
and acetonitrile (100 mL) was added and cooled in an ice bath. To this stirred mixture
bromine (5.29 mL, 0.103 mol) was slowly added (30 min). After addition, the yellow
slurry was formed to which the diol 3 (10.0 g, 0.047 mol) was added in one portion the
yellow slurry changed to a clear solution, after 10 min again the yellow slurry was
formed. The whole reaction mixture was stirred (15 h) at room temperature. Then solvent
was removed at reduced pressure and the resulting product was wash with water (2 250
mL) and extracted with ethyl acetate (2 250 mL). The organic layer were dried over
sodium sulfate and concentrated in vacuum. The crude product was purified by column
chromatography on silica gel using petroleum ether as eluent to give 2,2 –
bis(bromomethyl)biphenyl 4 (13.98 g, 88%) as colorless prisms.
M. p. = 86-88 oC (Lit.[31] 87-89 oC)
IR (KBr): υ 3064, 3025, 1972, 1558, 1479, 1434, 1272, 1219, 1158, 1135, 1006, 953,
805, 772, 606, 537cm.-1
8

1H NMR (400 MHz, CDCl3): δ 7.59-7.56 (dd, J = 7.6 and 1.6 Hz), 7.47-7.43 (td, J = 7.6
and 1.6 Hz, 2H), 7.42-7.38 (td, J = 7.6 and 1.6 Hz, 2H), 7.31-7.28 (dd, J = 7.6 and 1.6
Hz, 2H), 4.39-4.36 (d, J = 10 Hz, 2H), 4.23-4.21 (d, J = 10 Hz, 2H).
Mass (EI+) m/z (%) 348 (20), 346 (36), 344 (48), 342 (23), 314 (20), 312 (60), 311 (12),
310 (100), 310 (10), 308 (79), 306 (22), 279 (19), 274 (76), 272 (51), 241 (24), 239 (34),
236 (18), 61 (12), 57 (9).
2,2’-Bis(Azidomethyl)Biphenyl (5).
A solution of dibromo (4) (7.0 g, 0.177 mol), sodium azide (3.35 g, 0.044 mol) in
acetonitrile (30 mL) was refluxed for 24 h. The mixture was cooled to room temperature
and solvent was removed at high vacuum, the crude product was quenched with water.
The aqueous layer was extracted with ethyl acetate (3 250 mL) and then dried with
anhydrous sodium sulfate. The organic solvent was evaporated under reduced pressure to
give a pale yellow liquid as crude product, which was purified by column
chromatography on silica gel using petroleum ether as eluent to give diazide 5 (5.35 g,
98%) as a colorless oil.
Colorless oil.[32]
IR (Neat):  3063, 3023, 2941, 2877, 2097, 1598, 1477, 1446, 1344, 1256, 1193, 1007,
886, 759 cm.-1
1H NMR (400 MHz, CDCl3): δ 7.52-7.41 (m, 6H), 7.26-7.24 (m, 2H), 4.18-4.14 (d, J =
13.6 Hz, 2H), 4.11-4.08 (d, J = 13.6 Hz, 2H).
9

Mass (EI+) m/z (%) 207 (7), 195 (10), 194 (12), 193 (20), 192 (17), 181 (15), 180 (100),
179 (20), 178 (15), 167 (11), 166 (18), 165 (36), 164 (8), 153 (12), 52 (38), 151 (17), 77
(9), 76 (8), 63 (8), 51 (7).
2,2'-{(1E,1'E)-(([1,1'-Biphenyl]-
2,2'diylbis(Methylene))Bis(Azanylylidene))Bis(Methanylylid- Ene)}Diphenol (1):
A solution of diazide 5 (2.0 g, 0.007 mol) in ethanol (20 mL) was hydrogenated (H2
balloon) in presence of palladium/carbon (10 % Pd, 0.2 g) for 15 h with stirring at room
temperature. After the reaction was complete (tlc), the catalyst was removed by filtration
through Celite and wash with ethanol (2 X 5 mL). The filtered solution was concentrated
to its half volume on rotary evaporator.
To this salicylaldehyde (2.02 mL, 0.018 mol) was added and the mixture stirred at room
temperature. After about 1h, slowly yellow slurry was formed and the reaction was
continue (15 h). The yellow precipitates were filtered through sintered funnel and wash
with cold ethanol (2 x 5 mL), further purified by recrystallization from methanol to get
yellow crystals of 1 (2.08 g, 65%).
Mp. = 128-130 C.
IR (KBr): 3649, 3060, 3017, 2884, 1670, 1636, 1582, 1500, 1472, 1462, 1441, 1375,
1333, 1279, 1210, 1159, 1119, 1058, 1030, 995, 959, 943, 895, 876, 847, 757, 722, 655
cm.-1
10

1H NMR (400 MHz, CDCl3) : δ 13.33 (s, 2H), 7.78 (s, 2H), 7.44-7.36 (m, 6H), 7.31-7.26
(m, 2H), 7.24-7.22 (d, J = 6.8 Hz, 2H), 7.06-7.04 (dd, J = 7.6 and 1.2 Hz, 2H), 6.95-6.93
(d, J = 8.4 Hz, 2H), 6.85-6.82 (m, 2H), 4.59-4.56 (d, J = 14.0 Hz, 2H), 4.36-4.33 (d, J =
14.0 Hz, 2H).
13C NMR (100 MHz, CDCl3): 165.76, 160.95, 139.79, 135.87, 132.30, 131.48, 129.88,
128.99, 128.18, 127.43, 118.67, 118.58, 116.89, 61.61.
Mass (EI+) m/z (%) 301 (4), 300 (21), 299 (92), 298 (6), 286 (3), 180 (16), 179 (90), 178
(100), 177 (7), 175 (7), 166 (9), 165 (30), 152 (5), 134 (3), 122 (6), 121 (35), 119 (4), 106
(10), 77 (5).
Anal. Calcd. for C28H24N2O2: C, 79.98; H, 5.75; N, 6.66. Found: C, 79.68; H, 5.67; N,
6.77.
4-Acetyl-1,3-Diphenylhexane-1,5-Dione (8) [Table 2, Entry 1]:
In an oven dried round bottom flask (10 mL capacity) placed
copper(II)trifluomethanesulfonate (17 mg, 0.048 mmol, 10.0 mol %) and the Ligand 1
(11 mg, 0.026 mmol, 5.5 mol%) in 1,2–dichloroethane (2 mL) stirred (15 min). to this
mixture the appropriate chalcone (0.10 g, 0.48 mmol, 1.0 eq.), acety acetone (0.07 g
,0.72 mmol, 1.5 eq.) was added and resulting mixture was stirred at room temperature (6
d). After the completion of reaction (as monitored by TLC) the material was loaded on
silica gel column for chromatographic separation using light petroleum ether:ethyl acetate
(100:0 to 70:30) as eluent to obtain a white solid (8) (0.10 g, 67%).
M. p. = 144-146 oC (Lit.[8g] 146-147 oC)
11

IR (KBr):  3085, 3060, 3028, 2938, 2916, 1693, 1595, 1496, 1449, 1411, 1262, 1242,
1209, 1187, 1154, 1074, 1004, 982, 948, 919, 746, 700, 688 cm.-1
1H NMR (400 MHz, CDCl3): δ 7.84-7.81 (m, 2H), 7.55-7.50 (m, 1H), 7.43-7.39 (m, 2H),
7.26-7.21 (m, 4H), 7.19-7.17 (m, 1H), 4.34-4.31 (d, J = 11.2 Hz, 1H), 4.26-4.19 (m, 1H),
3.36-3.29 (dd, J = 16.4 and 9.2 Hz, 1H), 3.22-3.17 (dd, J = 16.4 and 4 Hz, 1H), 2.29 (s,
3H), 1.89 (s, 3H).
Mass (EI+) m/z (%) 266 (4), 264 (47), 248 (5), 247 (27), 246 (13), 209 (5), 208 (5), 147
(5), 146 (11), 130 (6), 119 (6), 114 (5), 106 (5), 104 (100), 102 (8), 90 (4), 78 (4), 76
(43), 68 (5).
For detail procedure and characterization for other examples, see supporting Information.
CONCLUSION
The new ligand 1 is easy to make and is effective in copper catalyzed Michael reaction.
Further the homogeneous catalysts system is capable of assisting Michael reaction in
chemoselective manner for the useful carbon-carbon and carbon-sulfur bond forming
Michael reaction.
SUPPORTING INFORMATION
Full experimental procedures and analytical data of all the catalytic applications.
Supplemental data for this article can be accessed on the publisher’s website.
ACKNOWLEDGMENTS
12

Financial support for this work by Council of Scientific and Industrial Research (CSIR),
New Delhi [No. 01(2386)/10/EMR-II] is gratefully acknowledged. We also thank Prof.
N.D. Kulkarni and Prof. B.V. Kamath for their support and constant encouragement.
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17

Table 1 Optimization of reaction parameters for Michael reaction.
No Ratioa
Conditions Isolated yield/%
Acetyl acetone (eq.) Cu(OTf)2 Ligand 1 (mol %)
(mol %)
10
1
2
3
4
5
6
7
8
9
1.0
1.5
1.5
1.5
1.5
1.5
1.5
2.0
1.5
5.5
5.5
10
10
0
r.t., 6 d
r.t., 6 d
r.t., 6 d
r.t., 6 d
r.t., 6 d
r.t., 6 d
35
10
67.6
trace
trace
NRb
trace
10
5.5
0
10
0
10
5.5
5.5
5.5
5.5
75 oC, 30 h 21
10
r.t., 6 d
r.t., 6 d
r.t., 6 d
37
10c
10d
trace
trace
10 1.5
aFor PhCOCH=CHPh 7 (1.0 eq.), 1,2-dichloroethane; bNo reaction. cWith Cu(OAc)2,
dWith CuCl2
18

Table 2 Examples of Michael reaction with the present catalysts system.a
No
1
Product
Yieldb (%)
67
-Unsaturated ketone
O
CH(COCH3)2
O
C6H5
C6H5
8
7
O
CH(COCH3)2
O
2
3
54
89
4BrC6H4
4BrC6H4
10
9
O
Ph
O
S
C6H5
C6H5
7
11
4
O
65
O
CH(COCH3)2
C6H5
C6H5
12
13
Cl
Cl
5
6
40
81
O
O
Ph
C6H5
S
C6H5
14
7
O
CH(COCH3)2
Ph
O
Ph
Ph
Ph
16
15
19

O
O
O
O
7
8
82
CH(COCH3)2
17
17
18
19
83c
CH(COCH3)COOEt
aWith acetyl acetone (1.5 eq.), 1,2-dichoroethane, Cu(OTf)2 (10.0 mol %), 1 (5.5 mol %),
r.t., 6 d; bIsolated, cd.r. = 50:50.
20

Scheme 1 Synthesis of ligand 1. Reaction conditions: a. NaBH4, I2, THF, reflux, 18 h,
99%; b. PPh3, Br2, MeCN, r.t., 15 h, 88%; c. NaN3, MeCN, reflux, 24 h, 98%. d. H2, Pd-
C (10%), EtOH, 1atm., r.t., 15 h; e. salicylaldehyde, EtOH, r.t., 15 h, 65% from 5.
21

Scheme 2 Selective thia-Michael reaction of 17.
22

Scheme 3 Selectivity towards R-SH compared to Ar-SH.
23

Scheme 4 Selectivity between thiol and alcohol.
24

Figure 1 The new biphenyl based ligand for the present study.
25

Figure 2 Possible compositions of complex of ligand 1 and Cu(OTf)2.
26