Nickel-catalyzed one-pot synthesis of biaryls from phenols and arylboronic acids via C-O activation using TCT reagent

Article abstract of DOI:10.1016/j.jorganchem.2015.01.009

In this study, the direct Nickel-catalyzed Suzuki-Miyaura coupling reaction of phenols and arylboronic acids via C-O bond activation using 2,4,6-trichloro-1,3,5-triazine (TCT) is described. Initially, phenols were reacted with TCT to give the corresponding 2,4,6-triaryloxy-1,3,5-triazine (TAT) products. Subsequently, arylboronic acid, base and Ni-catalyst were added to the generated aryl C-O electrophile to obtain the final biaryl product. This study represents a simple and direct method for the synthesis of biaryls from phenolic compounds using sub-stoichiometric amounts of TCT as a cheap and readily available C-O activating reagent.

Full text of DOI:10.1016/j.jorganchem.2015.01.009

Accepted Manuscript
Nickel-catalyzed one-pot synthesis of biaryls from phenols and arylboronic acids via
C-O activation using TCT reagent
Nasser Iranpoor, Farhad Panahi, Fereshteh Jamedi
PII:
S0022-328X(15)00023-6
10.1016/j.jorganchem.2015.01.009
JOM 18874
DOI:
Reference:
To appear in: Journal of Organometallic Chemistry
Received Date: 6 October 2014
Revised Date: 3 January 2015
Accepted Date: 12 January 2015
Please cite this article as: N. Iranpoor, F. Panahi, F. Jamedi, Nickel-catalyzed one-pot synthesis
of biaryls from phenols and arylboronic acids via C-O activation using TCT reagent, Journal of
Organometallic Chemistry (2015), doi: 10.1016/j.jorganchem.2015.01.009.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Nickel-catalyzed one-pot synthesis of biaryls from phenols
and arylboronic acids via C-O activation using TCT reagent
a
a
a
Nasser Iranpoor,* Farhad Panahi and Fereshteh Jamedi
a
Department of Chemistry, College of Sciences, Shiraz University, Shiraz, 71454, Iran. Email:
iranpoor@susc.ac.ir
O
N
O
O
Ar
Ar
N
N
B(OH)2
Ar
Ni(PCy ) Cl
2
3
2
2)
Ar
+
K PO
3
4
OH
Cl
N
Cl
Ar
Ar
1)
N
N
Ar
+
Cl
TCT
NaH
dioxane
1
10 o
C
20 entries
70-85 %

ACCEPTED MANUSCRIPT
Nickel-catalyzed one-pot synthesis of biaryls from phenols and
arylboronic acids via C-O activation using TCT reagent
a
a
a
Nasser Iranpoor,* Farhad Panahi , and Fereshteh Jamedi
a
Department of Chemistry, College of Sciences, Shiraz University, Shiraz, 71454, Iran.
Email: iranpoor@susc.ac.ir
Abstract
In this study, the direct Nickel-catalyzed Suzuki-Miyaura coupling reaction of phenols and
arylboronic acids via C-O bond activation using 2,4,6-trichloro-1,3,5-triazine (TCT) is described.
Initially, phenols were reacted with TCT to give the corresponding 2,4,6-triaryloxy-1,3,5-triazine
(TAT) products. Subsequently, arylboronic acid, base and Ni-catalyst were added to the
generated aryl C-O electrophile to obtain the final biaryl product. This study represents a simple
and direct method for the synthesis of biaryls from phenolic compounds using sub-stoichiometric
amounts of TCT as a cheap and readily available C-O activating reagent.
Keywords: Suzuki-Miyaura reaction, Biaryl, Phenol, 2,4,6-Trichloro-1,3,5-triazine, Nickel
Introduction
Biaryls have an imperative structural motif, which exist extensively in pharmaceutical,
advanced materials and natural compounds with a wide range of chemical, biological and
physical applications [1]. Transition metal-catalyzed Suzuki−Miyaura reactions have been
known as a potent and essential method for the synthesis of this class of compounds [2]. At the
1

ACCEPTED MANUSCRIPT
present, the Suzuki–Miyaura coupling has been well developed and is currently one of the
efficient methodologies for the synthesis of biaryls in both laboratory and industry [3].
In the recent years, remarkable progress has also been developed to use phenolic compounds in
the cross-coupling reactions instead of aryl halides due to the higher diversity, abundance, and
availability of these materials [4]. The most used aryl C-O electrophiles are ethers,[5]
carboxylates,[6] carbamates,[7] carbonate,[8,7c] phosphoramides,[9] phosphonium salts,[10]
phosphates,[11] pivalates,[6b] sulfamates,[12,7c] tosylates,[13] mesylates[14,12b] and heteroaryl
ethers [15].
In the most cases, phenolic compounds were first converted to the corresponding aryl C-O
electrophiles and then used in metal-catalyzed reaction. Recently, the in situ activation of
phenols has emerged as an attractive approach for Ni-catalyzed cross-coupling reactions
(Scheme 1) [16].
Scheme 1
Scheme 1. Activation of phenolic compounds for the in situ generation of aryl C-O electrophiles
to use in metal-catalyzed C-C bond formation reactions
The in situ phenol activation strategy provides important advantages over previous methods
including, single step operation, efficiency, economy, and environmental impact [16].
Considering the aforementioned points, we decided to use an efficient reagent which can easily
react with phenols to convert them into an active aryl C-O electrophile for participation in metal-
catalyzed coupling reactions.
2

ACCEPTED MANUSCRIPT
In our previous studies, we reported that 2,4,6-trichloro-1,3,5-triazine (TCT) is an efficient
C-O activating reagent and by the use of this reagent, phenolic compounds were converted
directly to their corresponding amines, arenes, and symmetrical biphenyls [17]. In continuation
of this study, we would like to introduce an efficient method for direct Ni-catalyzed Suzuki-
Miyaura coupling of phenols using TCT regent. In the course of our study, we found that Li et
al. has used 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT, B) for the activation of phenolic
compounds in the synthesis of biaryls (Scheme 2) [15].
Scheme 2
Scheme 2. The use of heteroaryl ethers (C) for synthesis of biaryls starting from TCT in a three-
step process
As shown in Scheme 2, TCT reagent is the starting material for activation of phenolic
compounds, but this method is a three step process. First, TCT was converted to CDMT and then
reacted with phenol in order to generate aryl C-O electrophile (C). Finally, C reacts with aryl
boronic acid to give biaryl. On the other hand, activation of one equivalent of phenol is achieved
by one equivalent of TCT. Herein, we disclose a direct Ni-catalyzed Suzuki–Miyaura coupling
of phenols and arylboronic acids via C–O activation using TCT reagent. In this method,
activation of phenols using TCT is a one-pot process and one equivalent of TCT is used for
activation of three equivalents of phenol, avoiding pre-activation steps and using sub-
stoichiometric amounts of TCT.
Results and Discussion
The applied conditions for the synthesis of 2,4,6-tris(p-aryloxy)-1,3,5-triazine (TAT) are based
on our previous method [17]. The in situ generated TAT was used in the cross-coupling with
3

ACCEPTED MANUSCRIPT
arylboronic acids for the synthesis of biaryls. To survey the possibility of direct Suzuki–Miyaura
coupling reaction via C-O bond activation using TCT reagent, p-cresol (1a) and phenylboronic
acid (2a) was selected as model substrates for optimization study. The obtained results are
summarized in Table 1.
Table 1
Table 1. Optimization of the conditions for the coupling of p-cresol and phenylboronic acid
a
using TCT as a C-O activating agent
The reaction of p-cresol and phenylboronic acid in 1,4-dioxane using NiCl .5H O as catalyst
2
2
and K PO as a base resulted no product (Table 1, entry 1). The reactivity of Ni(PPh ) Cl as
3
4
3 2
2
catalyst having a monodentate ligand was evaluated and only 40% of the product was obtained
3 2 2
(Table 1, entry 2). The yield was enhanced to 85% when Ni(PCy ) Cl was used as catalyst
(
Table 1, entry 3). Catalysts having bidentate ligands such as NiCl (dppe), NiCl (dppp), and
2
2
NiCl (dppf) were also tested, but no superiority was observed (Table 1, entries 4-6) [18].
2
Among the used bases and solvents, K PO was found as the most suitable base [19] and 1,4-
3
4
dioxane as the preferred solvent (Table 1, entries 7-12). Also, 7.5 mol% of Ni(PCy ) Cl , 4
3
2
2
3 4
equiv. of K PO and 3 equiv. of phenylboronic were found to be the optimum amounts of the
catalyst, base and coupling partner respectively (Table 1, entries 13-17).
Consequently, we selected the optimum conditions for the preparation of other biaryl compounds
starting from commercially accessible phenols and arylboronic acids (Scheme 3).
Scheme 3
4

ACCEPTED MANUSCRIPT
Scheme 3. Cross-coupling of different phenolic derivatives with arylboronic acids. Reaction
conditions: Phenol (1 mmol), boronic acid (3 mmol), K PO (4 mmol), 1,4-dioxane (5 mL),
3
4
under argon gas and reaction time = 24h. All yields are isolated products.
As shown in Scheme 3, various phenols and boronic acids were surveyed. Both electron-rich (3a
&
3b) and electron-poor phenols (3c & 3d) furnished excellent yields of the corresponding
products. Isovanilline as a naturally occurring phenol with two functional groups (OMe and
CHO) was also used as a phenolic partner and compound 3e was obtained in 82% yield. 4-
Fluorophenol was used as substrate and 4-fluoro-1,1'-biphenyl compound (3f) was obtained in
8
4% yield, demonstrating that carbon-fluorine bond is robust under our optimized conditions
[3c]. Due to the interaction of heteroatoms in heteroaryl compounds with metal catalysts and the
low reported yields in many catalytic systems,[20] we decided to synthesize compounds 3g-l
from phenolic substrates in order to show the merit and applicability of our synthetic approach in
synthesis of this category of compounds. Since, naphthalene structural units are widely used in
designing of the advanced material for application in organic electronic devices,[21] we also
synthesized compounds 3m-o from naphthols in good yields. The functional group compatibility
of the reaction was highlighted by the synthesis of compound 3p as a xanthene product (Scheme
4
) [22].
Scheme 4
Scheme 4. Synthesis of a xanthene-based biaryl. Reaction conditions: phenolic compound (1
mmol), thiophen-2-ylboronic acid (3 mmol), K PO (4 mmol), 1,4-dioxane (5 mL), under argon
3
4
gas, reaction time = 24h. Yields are isolated products.
5

ACCEPTED MANUSCRIPT
The structural diversity of this process was further established using estrone leading to the
formation of the steroid derivative 3r (Scheme 5).
Scheme 5
Scheme 5. Synthesis of a steroid derivative from estrone and phenyl boronic acid. Reaction
3 4
conditions: phenolic compound (1 mmol), phenyl boronic acid (3 mmol), K PO (4 mmol), 1,4-
dioxane (5 mL), under argon gas, reaction time = 24h. Yields are isolated product.
We also proposed a plausible mechanism for this reaction as shown in Scheme 6. Some
experiments were conducted to obtain a deeper insight into the reaction mechanism (Scheme 7).
In an experiment, under the optimized conditions, 4a was converted to 3a, demonstrating that the
generated TAT during the reaction process acts as aryl C-O electrophile (Scheme 7). When
1
,3,5-tris(p-tolyloxy)benzene (5a) was used instead of 2,4,6-tris(p-tolyloxy)-1,3,5-triazine (4a)
no product was obtained (Scheme 7). This experiment clarifies that the ortho nitrogen atom in
the structure of TCT has important role in the activation of C-O bond. Accordingly, it seems that
Ni catalyst coordinates first with the ortho nitrogen atom of TAT and this action facilities the
oxidative addition of Ni to C-O bond (steps I-III). After transmetalation (step IV), and reductive
elimination (step V), the desired product is obtained (Scheme 2). The catalytic reaction cycle is
essentially similar to the general Ni-catalyzed cross-coupling mechanism for aryl halides and
boronic acids [23].
Scheme 6
Scheme 6. The proposed mechanism for direct Ni-catalyzed cross-coupling of phenols with
arylboronic acids using TCT reagent
6

ACCEPTED MANUSCRIPT
Scheme 7
Scheme 7. An experiment to show the role of ortho nitrogen atom in the structure of TCT in
activation of C-O bond. Reaction conditions: 4a or 5a (0.34 mmol), phenylboronic acid (3
mmol), K PO (4 mmol), 1,4-dioxane (5 mL), under argon gas, reaction time = 24h and isolated
3
4
yield.
Conclusions
In conclusion, we have exposed the direct Nickel-catalyzed cross-coupling reaction of phenol
derivatives with arylboronic acids mediated by TCT reagent. The protocol carried out efficiently
with a variety of substrates to give the corresponding products in high yields. This study suggests
that TCT as a cheap, readily available and efficient reagent could find valuable synthetic
applications for other coupling reactions in the future.
Experimental Section
General Experimental Details
Chemicals were purchased from Fluka and Aldrich chemical companies and used without further
purification. The known products were characterized by comparison of their spectral and
1
13
physical data with those reported in the literature. H (250 MHz) and C NMR (62.9 MHz)
spectra were recorded on a Bruker Advance spectrometer in CDCl3 solutions with
tetramethylsilane (TMS) as the internal standard. FT-IR spectroscopy (Shimadzu FT-IR 8300
spectrophotometer) was employed for characterization of the products. Melting points were
determined in open capillary tubes in a Barnstead electro-thermal 9100 BZ circulating oil
melting point apparatus. The reaction monitoring was accomplished by TLC on silica gel
7

ACCEPTED MANUSCRIPT
PolyGram SILG/UV254 plates. Column chromatography was carried out on columns of silica
gel 60 (70-230 mesh).
General procedure for direct Ni-catalyzed cross-coupling of phenols and arylboronic acids
mediated by TCT reagent
Into a conical three-necked flask (50 mL), a mixture of phenol (1 mmol), and NaH (1.5 mmol)
were stirred in dry 1,4-dioxane (10 mL) for 1h at room temperature. Then 0.37 mmol of TCT
was added to the reaction media and let stirring continue for another hour. Afterward the reaction
mixture was stirred at 110 °C for 10h. Then arylboronic acid (3 mmol), Ni(PCy ) Cl (7.5
3
2
2
mol%), and K PO (4.0 mmol) was added to the reaction mixture under argon gas. The mixture
3
4
was stirred for another 24h. After completion of the reaction confirmed by TLC the reaction
mixture was cooled down to room temperature and 50 mL of CH Cl and 50 mL of water were
2
2
added. After the extraction of dichloromethane from water, the organic extract was dried over
Na SO . The products were purified by column chromatography (hexane/ethyl acetate) to obtain
2
4
the desired purity.
Acknowledgements
The financial supports of research councils of Shiraz University and the grant from Iran National
Elite Foundation are gratefully acknowledged.
Electronic Supplementary Information (ESI) available: Experimental procedures, spectral
1
13
data and copies of H, C NMR for all synthesized compounds.
References and notes
[1] (a) P. Lloyd-Williams, E. Giralt, Chem. Soc. Rev. 30 (2001) 145-157;
8

ACCEPTED MANUSCRIPT
(
(
(
[
(
(
b) L. Pu, Chem. Rev. 98 (1998) 2405-2494;
c) A. Khalafi-Nezhad, F. Panahi, J. Organomet. Chem. 717 (2012) 141-146;
d) O. A. Akrawi, M. Hussain, P. Langer, Tetrahedron Lett. 52 (2011) 1093-1095.
2] (a) T. Welton Chem. Rev. 99 (1999) 2071-2083;
b) A. F. Littke, G. C. Fu, Angew. Chem. Int. Ed. 41 (2002) 4176-4211;
c) N. Iranpoor, H. Firouzabadi, A. Safavi, S. Motevalli, M. M. Doroodmand, Appl.
Organometal. Chem. 26 (2012) 417-422;
(
d) H. Firouzabadi, N. Iranpoor, M. Gholinejad, J. Organomet. Chem. 695 (2010) 2093-2097;
e) A. Safavi, N. Maleki, N. Iranpoor, H. Firouzabadi, A. R. Banazadeh, R. Azadi, F. Sedaghati,
(
Chem. Commun. (2008) 6155-6157;
(
[
(
(
(
f) J. Yamaguchi, K. Muto, K. Itami, Eur. J. Org. Chem. (2013) 19-30.
3] (a) F. Schneider, A. Stolle, B. Ondruschka, H. Hopf, Org. Process Res. Dev. 13 (2009) 44-48;
b) R. Martin, S. L. Buchwald, Acc. Chem. Res. 41 (2008) 1461-1473;
c) M. Tobisu, T. Xu, T. Shimasaki, N. Chatani, J. Am. Chem. Soc. 133 (2011) 19505-19511;
d) V. Pandarus, D. Desplantier-Giscard, G. Gingras, F. Béland, R. Ciriminna, M. Pagliaro, Org.
Process Res. Dev. 17 (2013) 1492-1497;
(e) C. Valente, S. Calimsiz, K. H. Hoi, D. Mallik, M. Sayah, M. G. Organ, Angew. Chem. Int.
Ed. 51 (2012) 3314-3332;
9

ACCEPTED MANUSCRIPT
(
(
(
(
[
f) V. Polshettiwar, A. Decottignes, C. Len, A. Fihri, ChemSusChem 3 (2010) 502-522;
g) H. Bonin, E. Fouquet, F.-X. Felpin, Adv. Synth. Catal. 353 (2011) 3063-3084;
h) E. J.-G. Anctil, V. Snieckus, J. Organomet. Chem. 653 (2002) 150-160;
i) H. Groger, J. Prakt. Chem. 342 (2000) 334-339.
4] (a) B. M. Rosen, K. W. Quasdorf, D. A. Wilson, N. Zhang, A. Resmerita, N. K. Garg, V.
Percec, Chem. Rev. 111 (2011) 1346-1416;
(
(
[
[
b) D.-G. Yu, B.-J. Li, Z.-J. Shi, Acc. Chem. Res. 43 (2010) 1486-1495;
c) T. Mesganaw, N. K. Garg, Org. Process Res. Dev. 17 (2013) 29-39.
5] M. Tobisu, T. Shimasaki, N. Chatani, Angew. Chem. Int. Ed. 47 (2008) 4866-4869.
6] (a) B.-T. Guan, Y. Wang, B.-J. Li, D.-G. Yu, Z.-J. Shi, J. Am. Chem. Soc. 130 (2008) 14468-
1
4470;
(b) K. W. Quasdorf, X. Tian, N. K. Garg, J. Am. Chem. Soc. 130 (2008) 14422-14423.
[7] (a) K. W. Quasdorf, A. Antoft-Finch, P. Liu, A. L. Silberstein, A. Komaromi, T. Blackburn,
S. D. Ramgren, K. N. Houk, V. Snieckus, N. K. Garg, J. Am. Chem. Soc. 133 (2011) 6352-6363;
(b) M. Baghbanzadeh, C. Pilger, C. O. Kappe, J. Org. Chem. 76 (2011) 1507-1510;
(c) K. W. Quasdorf, M. Riener, K. V. Petrova, N. K. Garg, J. Am. Chem. Soc. 131 (2009)
1
7748-17749.
[8] (a) P. Leowanawat, N. Zhang, V. Percec, J. Org. Chem. 77 (2012) 1018-1025;
1
0

ACCEPTED MANUSCRIPT
(
[
[
[
b) R. Kuwano, R. Shimizu, Chem. Lett. 40 (2011) 913-915.
9] Y. -L. Zhao, Y. Li, Y. Li, L.-X. Gao, F.-S. Han, Chem. Eur. J. 16 (2010) 4991-4994.
10] S.-M. Li, J. Huang, G.-J. Chen, F.-S. Han, Chem. Commun. 47 (2011) 12840-12842.
11] H. Chen, Z. Huang, X. Hu, G. Tang, P. Xu, Y. Zhao, C. -H. Cheng, J. Org. Chem. 76 (2011)
2
338-2344.
[12] (a) G. –J. Chen, F. –S. Han, Eur. J. Org. Chem. (2012) 3575-3579;
(b) N. Zhang, D. J. Hoffman, N. Gutsche, J. Gupta, V. Percec, J. Org. Chem. 77 (2012) 5956-
5
964.
[13] (a) C.-H. Xing, J.-R. Lee, Z.-Y. Tang, J. R. Zheng, Q. S. Hu, Adv. Synth. Catal. 353 (2011)
2
051-2059;
(
[
[
[
b) H. Gao, Y. Li, Y.-G. Zhou, F.-S. Han, Y.-J. Lin, Adv. Synth. Catal. 353 (2011) 309-314.
14] V. Percec, J.-Y. Bae, D. H. Hill, J. Org. Chem. 60 (1995) 1060-1065.
15] X.–J. Li, J.–L. Zhang, Y. Geng, Z. Jin, J. Org. Chem. 78 (2013) 5078-5084.
16] (a) D. -G. Yu, B. -J. Li, S. -F. Zheng, B. -T. Guan, B. -Q. Wang, Z. -J. Shi, Angew. Chem.
Int. Ed. 49 (2010) 4566-4570;
(b) F.-A. Kang, Z. Sui, W. V. Murray, Eur. J. Org. Chem. (2009) 461-479;
(c) G. –J. Chen, J. Huang, L. –X. Gao, F. –S. Han, Chem. Eur. J. 17 (2011) 4038-4042;
(d) F.-A. Kang, Z. Sui, W. V. Murray, J. Am. Chem. Soc. 130 (2008) 11300-11302;
1
1

ACCEPTED MANUSCRIPT
(e) C. Shi, C. C. Aldrich, Org. Lett. 12 (2010) 2286-2289;
(f) F.-A. Kang, J. C. Lanter, C. Cai, Z. Sui, W. V. Murray, Chem. Commun. 46 (2010) 1347-
1
349;
(
(
(
(
(
(
g) V. P. Mehta, S. G. Modha, E. V. Van der Eycken, J. Org. Chem. 75 (2010) 976-979;
h) K. W. Quasdorf, X. Tian, N. K. Garg, J. Am. Chem. Soc. 130 (2008) 14422-14423;
i) A. Sharma, D. Vachhani, E. Van der Eycken, Org. Lett. 14 (2012) 1854-1857;
j) D.–G. Yu, Z.–J. Shi, Angew. Chem., Int. Ed., 50 (2011) 7097-7100;
k) Y. –L. Zhao, G. –J. Wub, F.–S. Han, Chem. Commun., 48 (2012) 5868-5870;
l) L. Chen, H. Lang, L. Fang, M. Zhu, J. Liu, J. Yu, L. Wang, Eur. J. Org. Chem. (2014) 4953-
4
957.
[17] a) N. Iranpoor, F. Panahi, Adv. Synth. Catal. 356 (2014) 3067. b) N. Iranpoor, F. Panahi,
Org. Lett. 2014, DOI: 10.1021/ol503560e.
[
18] a) NiCl (dppf) was prepared from NiCl ·6H O and bisphosphine ligand (dppf) according to
2 2 2
a literature procedure: A.W. Rudie, D. W. Lichtenberg, M. L. Katcher, A. Davison, Inorg. Chem.
7 (1978) 2859. b) The NiCl (dppp) complexe was synthesized from NiCl ·6H O and the
1
2
2
2
corresponding bisphosphine ligand according to a literature procedure: G. R. Van Hecke, W. D.
Horrocks, Inorg. Chem. 5 (1966) 1968. c) NiCl (PCy ) was prepared from NiCl ·6H O and
2
3 2
2
2
PCy ligand according to a literature procedure: T. Saito, H. Munakata, H. Imoto, Inorg. Synth.
3
1
7 (1977) 84.
[19] L. Liu, S. Zhang, H. Chen, Y. Lv, J. Zhu, Y. Zhao, Chem. Asian J. 8 (2013) 2592-2595.
1
2

ACCEPTED MANUSCRIPT
[
[
[
20] X. Chen, L. Zhou, Y. Li, T. Xie, S. Zhou, J. Org. Chem., 79 (2014) 230-239.
21] Y. Zou, D. D. Young, A. Cruz-Montanez, A. Deiters, Org. Lett. 10 (2008) 4661-4664.
22] K. Niknam, F. Panahi, D. Saberi, M. Mohagheghnejad, J. Heterocyclic Chem., 47 (2010)
2
92-300.
[23] F.-S. Han, Chem. Soc. Rev., 42 (2013) 5270-5298.
1
3

ACCEPTED MANUSCRIPT
Table 1. Optimization of the reaction conditions for the synthesis of biaryl from p-cresol and arylboronic
a
acids using TCT as a C-O activator reagent
b
Entry
Ni-catalyst (mol%)
Solvent (T/°C)
Base
Yield (%)
1
2
3
4
5
6
7
8
9
NiCl (10)
1,4-dioxane (110)
1,4-dioxane (110)
1,4-dioxane (110)
1,4-dioxane (110)
1,4-dioxane (110)
1,4-dioxane (110)
toluene (110)
K PO4
0
2
3
Ni(PPh
3
)
2
Cl
2
(5)
K
3
PO
4
40
85
60
82
85
75
75
60
68
65
0
Ni(PCy ) Cl (5)
K PO4
3
3
2
2
Ni(dppe)Cl (5)
K PO4
3
2
Ni(dppp)Cl (5)
K PO4
3
2
Ni(dppf)Cl (5)
K PO4
3
2
Ni(PCy
3
)
2
Cl
2
(5)
K
3
PO
4
Ni(PCy ) Cl (5)
xylene (110)
K PO4
3
3
2
2
Ni(PCy
3
)
2
Cl
2
(5)
THF (80)
3 4
K PO
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
Ni(PCy ) Cl (5)
1,4-dioxane (110)
1,4-dioxane (110)
1,4-dioxane (110)
1,4-dioxane (110)
1,4-dioxane (110)
1,4-dioxane (110)
1,4-dioxane (110)
1,4-dioxane (110)
K CO3
2
3
2
2
Ni(PCy
3
)
2
Cl
2
(5)
KOt-Bu
Ni(PCy ) Cl (5)
-
3
2
2
Ni(PCy
3
)
2
Cl
2
(2.5)
K
3
PO
4
53
86
87
Ni(PCy ) Cl (7.5)
K PO4
3
3
2
2
Ni(PCy ) Cl (10)
K PO4
3
3
2
2
c
Ni(PCy ) Cl (7.5)
K PO4
3
84
3
2
2
d
1
Ni(PCy ) Cl (7.5)
K PO4
3
76
3
2
2
a
b
Reaction conditions: 1a (1 mmol), 2a (3 mmol), base (4 mmol), solvent (5 mL), time = 24h. Isolated
c
d
yield. 3 mmol of base was used. 2 mmol of phenylboronic acid was used.

ACCEPTED MANUSCRIPT
G X
[Ni]
Ar OH
Ar
O
G
C-C bond formation
In situ
then
Aryl C-O electrophile
N
O
R
O
S
G =
P N
N
,
Mg ,
2
,
CH3
O

ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
1
. TCT (0.37 mmol), NaH (1.5 mmol)
o
1,4-dioxane, 110 C, 12h, Ar
1
Ar1 Ar2
a-r
Ar OH
2
. Ni(PCy ) Cl (7.5 mol%)
3 2 2
1
mmol
2
3
Ar B(OH) (3 mmol),
2
o
K PO (4 mmol), 110 C, 24h
3
4
H C
NC
3
O N
2
O CH3
b: 84%
3d: 82%
3a: 87%
3c: 86%
3
OHC
F
N
N
O CH3
e: 82%
3f: 84%
3g: 80%
3h: 82%
3
CH3
H C
3
S
S
N
O
O
3i: 77%
3j: 81%
3k: 80%
N
S
3l: 78%
3m: 82%
3n: 83%
3o: 82%
H C
CH3
H C
CF3
H C
3
3
3
3p: 81%
3q: 83%
3r: 80%

ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Cl
N
N
Ar1 OH
Ar1
O
Ar1
O
O
Cl
N
Cl
N
N
N
N
N
O
N
OH
0
[
Ni ]
O
Ar1
(I)
(VII)
O
N
O
O
N
O
Ar2
N
N
N
N
[Ni0]
0
[
Ni ]
O
O
(VI)
(II)
Ar2
O
NiII]
O
N
O
[
N
N
N
N
0
[
Ni ]
O
N
O
O
O
N
O
(V)
B(OH)3
O
N
O
N
N
0
[
Ni ]
N
N
(III)
Ar2 B(OH)2
O
[
NiII]
O
(IV)

ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
►
►
►
Nickel-catalyzed cross-coupling reactions of phenol derivatives with arylboronic acids
In situ activation of phenols using TCT for utilization in C-C coupling reactions
TCT as a cheap, readily available reagent for C-O bond activation of phenolic
compounds
Direct synthesis of biaryls from phenols using TCT as C-O bond activator
►

ACCEPTED MANUSCRIPT
Nickel-catalyzed one-pot synthesis of biaryls from phenols
and arylboronic acids via C-O activation using TCT reagent
Nasser Iranpoor,* Farhad Panahi, and Fereshteh Jamedi
Department of Chemistry, College of Sciences, Shiraz University, Shiraz, 71454, Iran
Email: iranpoor@chem.susc.ac.ir
Outline
1
1
3
1
1
. Experimental procedures
.2. Procedure for the synthesis of 9-(4-hydroxyphenyl)-3,3,6,6-tetramethyl-
,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione (1p)
.3. Synthesis of 2,4,6-tris(p-tolyloxy)-1,3,5-triazine (4a)
.4. Synthesis of 1,3,5-tris(p-tolyloxy)benzene (5a)
2
3
. Spectral data for synthesized compounds
1
13
. Copies of H, C NMR for all synthesized compounds
S1

ACCEPTED MANUSCRIPT
1
1
. Experimental procedures
.2. Procedure for the synthesis of 9-(4-hydroxyphenyl)-3,3,6,6-tetramethyl-
1
3
,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione (1p)
OH
To a solution of 4-hydroxybenzaldehyde (1 mmol), 5,5-
dimethyl-1,3-cyclohexane-dione (2 mmol) and aryl amine (1
mmol) in ethanol (2 mL) in ethanol (2 mL) in a round-bottom
flask, SBSSA (0.03 g) was added. The mixture was heated
under reflux conditions and the reaction was monitored by
TLC. After completion of the reaction, the mixture was filtered
O
O
O
1
p
and the remaining was washed with warm ethanol in order to separate catalyst. Then,
water (20 mL) was added to the filtrate and was allowed to stand at room temperature
for 1 h. During this time, crystals of the pure product were formed, which were
collected by filtration and dried. For further purification, the product recrystalized
1
from hot ethanol (85%, 0.31g). H NMR (250 MHz, CDCl ): δ (ppm) = 0.97 (s, 6H),
3
1
7
2
1
.08 (s, 6H), 2.09-2.26 (m, 4H), 2.45 (s, 4H), 4.65 (s, 1H), 6.51 (d, J = 7.4 Hz, 2H),
1
3
.04 (d, J = 7.4 Hz, 2H), 7.17 (s, 1H). C NMR (62.5 MHz, CDCl ): δ (ppm) = 27.4,
3
9.3, 30.9, 32.4, 41.0, 50.7, 115.4, 116.0, 129.3, 135.5, 154.8, 162.6, 197.3.
.3. Synthesis of 2,4,6-tris(p-tolyloxy)-1,3,5-triazine (4a)
Into a canonical flask (50 mL), a mixture of p-
O
N
O
cresol (3.1 mmol), and NaH (5 mmol) were
stirred in dry 1,4-dioxane (10 mL) for 1h at
room temperature. Then 1 mmol of TCT was
added to the reaction media and let stirring
N
N
H
3
C
CH
3
O
4a
H C
3
continue for another hour. Afterward the raction mixture was stirred at 110 °C for
0h. After completion of the reaction, as indicated by TLC, the mixture was cooled
down to room temperature and the solvent was removed under vacum. Then, 50 mL
of CHCl and 100 mL of water was added to the crude prduct and CHCl was
extracted from water. The organic extract was dried over Na SO . The product was
1
3
3
2
4
1
purified by recrystalization in CHCl to affored pure product. H NMR (250 MHz,
3
1
) K. Niknam, F. Panahi, D. Saberi, and M. Mohagheghnejad, J. Heterocyclic Chem., 2010, 47, 292
S2

ACCEPTED MANUSCRIPT
1
3
3
CDCl ): δ (ppm) = 2.35 (s, 9H), 7.05 (d, J = 8.1 Hz, 6H), 7.16 (d, J = 8.0 Hz, 6H). C
NMR (62.5 MHz, CDCl ): 21.0, 121.0, 130.2, 135.1, 149.9, 174.6. Anal. Calcd. for
3
C H N O : C, 72.17; H, 5.30; N, 10.52. Found: C, 72.02; H, 5.21; N, 10.41.
2
4
21
3
3
2
1
.4. Synthesis of 1,3,5-tris(p-tolyloxy)benzene (5a)
Into a 100-mL, three-necked, round-bottom
flask equipped with a magnetic stirrer, a reflux
condenser, a Dean-Stark trap and a nitrogen
inlet, 1,3,5-tribromobenzene (0.40 g, 1.27
mmol), p-cresol (0.46g, 4.25 mmol), sodium
O
O
H C
CH3
3
O
5
a
H C
3
carbonate (0.5 g, 4.72 mol), and copper(I) iodide (0.04g) were placed. Dimethyl
acetamide (DMAc) (5mL) and Toluene (1 mL) were then carefully poured in the
flask. The mixture was then heated to 160 °C. The water generated during the reaction
was removed by toluene azeotropic distillation for 4-5 h. After completion of
dehydration, the mixture was further stirred under reflux for 90h and poured into
distilled water containing 1 mL of conc. hydrochloric acid. The precipitate that
formed was collected by filtration and air-dried. For further purification, the product
1
was purified by column chromatography to afford product as yellow solid: H NMR
(
250 MHz, DMSO-d ): δ (ppm) = 2.32 (s, 9H), 6.25 (s, 3H), 7.03 (d, J = 7.9 Hz, 6H),
6
1
3
7
.13 (d, J = 8.1 Hz, 6H). C NMR (62.5 MHz, DMSO-d
6
): 19.9, 101.8, 118.9, 129.1,
1
30.4, 154.8, 158.9. Anal. Calcd. for C H O : C, 81.79; H, 6.10. Found: C, 81.68;
2
7
24
3
H, 6.01.
2
. Spectral data for synthesized compounds
3
2
.1. 4-Methyl-1,1'-biphenyl (3a)
1
H NMR (250 MHz, CDCl ): δ (ppm) = 2.53 (s, 3H), 7.37-7.47 (m, 2H), 7.51-7.57 (m,
3
1
3
5
1
H), 7.62-7.74 (m, 2H). C NMR (62.5 MHz, CDCl
29.4, 130.1, 131.4, 132.1, 138.1.
3
): 21.6, 127.4, 127.5, 127.8, 128.8,
2
3
) I. Y. Jeon, L. –S. Tan and J. –B. Baek, Polymer Preprints 2008, 49, 89.
) D. Zim, V. R. Lando, J. Dupont, A. L. Monteiro, Org. Lett. 2001, 3, 3049.
S3

ACCEPTED MANUSCRIPT
4
2
.2. 2-Methoxy-1,1'-biphenyl (3b)
1
H NMR (250 MHz, CDCl ): δ (ppm) = 3. 79 (s, 3H), 6.98-7.05 (m, 2H), 7.29-7.42 (m,
3
1
3
5
1
H), 7.54 (d, J = 8.1 Hz, 2H). C NMR (62.5 MHz, CDCl ): δ (ppm) = 55.6, 111.5,
3
21.1, 127.0, 128.1, 128.9, 129.6, 131.2, 138.9, 157.0.
5
2
.3. 4-Nitro-1,1'-biphenyl (3c)
1
H NMR (250 MHz, CDCl
3
): δ (ppm) = 7.45-7.76 (m, 7H), (d, J = 8.9 Hz, 2H), 8.31 (d, J
1
3
=
9.0 Hz, 2H). C NMR (62.5 MHz, CDCl ): δ (ppm) = 124.9, 127.6, 127.9, 128.9,
3
1
29.5, 129.7, 141.1, 147.8.
6
2
.4. [1,1'-Biphenyl]-4-carbonitrile (3d)
1
13
H NMR (250 MHz, CDCl ): δ (ppm) = 7.41-7.48 (m, 3H), 7.58-76 (m, 6H). C NMR
3
(62.5 MHz, CDCl
3
): δ (ppm) = 110.8, 118.6, 127.3, 127.5, 128.7, 128.9, 129.3, 129.5,
1
29.9, 130.5, 132.1, 139.8, 146.2.
4
2
.5. 2-Methoxy-[1,1'-biphenyl]-4-carbaldehyde (3e)
1
H NMR (250 MHz, CDCl
3
): δ (ppm) = 3.93 (s, 3H), 7.28-7.45 (m, 5H), 7.52-7.60 (m,
1
3
3
1
H), 10.05 (s, 1H). C NMR (62.5 MHz, CDCl ): δ (ppm) = 55.8, 109.6, 125.3, 127.4,
3
12 2
27.5, 128.3, 128.4, 129.4, 131.6, 136.5, 137.2, 157.1, 191.9. Anal. Calcd. for C14H O :
C, 79.23; H, 5.70. Found: C, 79.19; H, 5.61.
7
2
.6. 4-Fluoro-1,1'-biphenyl (3f)
1
H NMR (250 MHz, CDCl
3
): δ (ppm) = 7.13 (t, J = 9.0 Hz, 2H), 7.34-7.44 (m, 3H) 7.53-
1
3
7
1
.58 (m, 4H). C NMR (62.5 MHz, CDCl ): 115.3, 127.4, 127.5, 128.8, 137.1, 139.9,
3
9
61.1, 163.7. Anal. Calcd. for C12H F: C, 83.70; H, 5.27 Found: C, 83.62; H, 5.19.
8
2
.7. 2-Phenylpyridine (3g)
1
H NMR (250 MHz, CDCl ): δ (ppm) = 7.23 (d, J = 9.0 Hz, 1H) 7.43-7.99 (m, 7H), 8.71
3
1
3
(
s, 1H). C NMR (62.5 MHz, CDCl
3
): 120.3, 122.4, 126.3, 127.7, 137.0, 139.5, 149.3,
1
8
57.1. Anal. Calcd. for C H N: C, 85.13; H, 5.85; N, 9.03 Found: C, 85.02; H, 5.78; N,
1
1
9
.96.
4
5
2
6
7
8
) N. Kataoka, Q. Shelby, J. P. Stambuli, J. F. Hartwig, J. Org. Chem. 2002, 67, 5553.
) Iranpoor, N.; Firouzabadi, H.; Safavi, A.; Motevalli, S.; Doroodmand, M. M. Appl. Organometal. Chem.
012, 26, 417.
) Li, X. –J.; Zhang, J. –L.; Geng, Y.; Jin, Z. J. Org. Chem. 2013, 78, 5078.
) J.-H. Li, W.-J. Liu, Y.-X. Xie, J. Org. Chem., 2005, 70, 5409.
) N. Kudo, M. Perseghini, G. C. Fu, Angew. Chem., Int. Ed. 2006, 45, 1282.
S4

ACCEPTED MANUSCRIPT
6
2
.8. 3-Phenylpyridine (3h)
1
H NMR (250 MHz, CDCl ): δ (ppm) = 7.32-7.58 (m, 6H), 7.86-7.88 (m, 1H), 8.59 (d, J
3
1
3
=
4Hz, 1H), 8.86 (s, 1H). C NMR (62.5 MHz, CDCl ): δ (ppm) = 123.4, 127.1, 128.3,
3
1
9
9
29.1, 134.5, 136.7, 137.8, 149.3, 149.4. Anal. Calcd. for C11H N: C, 85.13; H, 5.85; N,
.03 Found: C, 85.00; H, 5.76; N, 8.97.
9
2
.9. 4-(4-Methoxyphenyl)pyridine (3i)
1
H NMR (250 MHz, CDCl ): δ (ppm) = 3.87 (s, 3H), 7.00 (d, J = 8.3 Hz, 2H), 7.50 (d, J
3
1
3
=
5.4 Hz, 2H), 7.62 (d, J = 8.3 Hz, 2H), 8.62 (d, J = 5.4 Hz, 2H). C NMR (62.5 MHz,
CDCl ): δ (ppm) = 55.4, 114.5, 121.2, 128.0, 130.4, 147.8, 150.1, 150.7, 160.8. Anal.
Calcd. for C H NO: C, 77.81; H, 5.99; N, 7.56 Found: C, 77.75; H, 5.91; N, 7.49.
3
1
2
11
1
0
2
.10. 2-(4-Methoxyphenyl)thiophene (3j)
1
H NMR (250 MHz, CDCl ): δ (ppm) = 3.83 (s, 3H), 6.91 (d, J = 5.2 Hz, 2H), 6.97-7.06
3
1
3
(
m, 1H), 7.20-7.26 (m, 2H), 7.53 (d, J = 4.7 Hz, 2H). C NMR (62.5 MHz, CDCl ): δ
3
(ppm) = 55.4, 114.1, 122.0, 123.8, 127.2, 127.4, 127.8, 143.9, 159.1. Anal. Calcd. for
C H OS: C, 69.44; H, 5.30 Found: C, 69.38; H, 5.22.
11
10
2
.11. 2-([1,1'-biphenyl]-4-yl)thiophene (3k)
1
13
H NMR (250 MHz, CDCl ): δ (ppm) = 7.32-7.49 (m, 7H), 7.54-7.59 (m, 5H). C NMR
3
(
62.5 MHz, CDCl ): δ (ppm) = 127.5, 127.8, 128.0, 128.3, 128.8, 129.6, 133.1, 141.3,
3
1
42.4, 150.1. Anal. Calcd. for C16
H12S: C, 81.32; H, 5.12 Found: C, 81.25; H, 5.06.
8
2
.12. 3-(Thiophen-2-yl)quinoline (3l)
1
H NMR (250 MHz, CDCl
3
): δ (ppm) = 7.17-7.26 (m, 1H), 7.40-7.56 (m, 4H), 7.81-8.08
1
3
(
m, 3H), 9.2 (s, 1H). C NMR (62.5 MHz, CDCl ): δ (ppm) = 123.9, 125.4, 127.0,
3
1
27.4, 127.5, 128.3, 128.7, 128.8, 131.2, 139.9, 146.8, 148.2. Anal. Calcd. for C H NS:
1
3
9
C, 73.90; H, 4.29; N, 6.63 Found: C, 73.81; H, 4.20; N, 6.54.
1
1
2
.13. 1-Phenylnaphthalene (3m)
1
13
H NMR (250 MHz, CDCl
3
): δ (ppm) = 7.24-7.52 (m, 5H), 7.82-7.99 (m, 7H). C NMR
(
62.5 MHz, CDCl ): δ (ppm) = 125.0, 125.9, 126.0, 126.2, 126.8, 128.4, 128.6, 129.2,
3
1
9
31.2, 133.5, 137.3, 140.6, 141.7. Anal. Calcd. for C H : C, 94.08; H, 5.92 Found: C,
16
12
4.01; H, 5.85.
9
1
1
) O. Kobayashi, D. Uraguchi, T. Yamakawa, Org. Lett. 2009, 11, 2679.
0) X. Chen, L. Zhou, Y. Li, T. Xie, S. Zhou, J. Org. Chem. 2014, 79, 230.
1) D. –G. Yu and Z. –J. Shi, Angew. Chem. Int. Ed. 2011, 50, 7097.
S5

ACCEPTED MANUSCRIPT
9
2
.14. 2-Phenylnaphthalene (3n)
1
H NMR (250 MHz, CDCl ): δ (ppm) = 7.36 (d, J = 9.7 Hz, 2H), 7.41-7.49 (m, 3H),
3
1
3
7
.68-7.79 (m, 2H), 7.87-7.90 (m, 4H), 8.02 (s, 1H). C NMR (62.5 MHz, CDCl ): δ
3
(ppm) = 125.8, 125.9, 126.9, 127.0, 127.1, 128.7, 132.2, 132.9, 133.9, 134.2, 138.6,
1
41.3. Anal. Calcd. for C H : C, 94.08; H, 5.92 Found: C, 93.98; H, 5.83.
16 12
8
2
.15. 2-(Naphthalen-1-yl)thiophene (3o)
1
H NMR (250 MHz, CDCl ): δ (ppm) = 7.19-7.32 (m, 4H), 7.44-7.58 (m, 3H), 7.84-7.97
3
1
3
(
m, 2H), 8.22-8.25 (m, 1H). C NMR (62.5 MHz, CDCl ): δ (ppm) = 125.1, 125.2,
3
1
1
25.3, 125.8, 126.7, 126.8, 127.2, 127.4, 127.5, 128.6, 128.7, 129.3, 131.5, 132.0, 133.25,
41.1. Anal. Calcd. for C H S: C, 94.08; H, 5.92 Found: C, 94.01; H, 5.87.
1
4
10
1
2
2
.16. 4,4'-Dimethyl-1,1'-biphenyl (3p)
1
13
H NMR (250 MHz, CDCl /TMS): δ (ppm) = 2.06 (s, 6H), 7.18-7.30 (m, 8H). CNMR
3
(
62.5 MHz, CDCl /TMS): δ (ppm) = 19.8, 126.5, 127.0, 129.3, 129.8, 136.7, 141.6. Anal.
3
Calcd. for C14
H14: C, 92.26; H, 7.74 Found: C, 92.18; H, 7.65.
2
.17. 4-Methyl-4'-(trifluoromethyl)-1,1'-biphenyl (3q)
1
H NMR (250 MHz, CDCl
3
/TMS): δ (ppm) = 2.40 (s, 3H), 7.27 (d, J = 9.2 Hz, 2H), 7.48
1
3
(
d, J = 6.5 Hz, 2H), 7.70 (s, 4H). CNMR (62.5 MHz, CDCl /TMS): δ (ppm) = 21.1,
3
1
20.2, 120.2, 123.0, 125.6, 127.1, 128.6 (q, 31.5 Hz), 129.6, 136.8, 138.0, 144.6. Anal.
Calcd. for C14 : C, 71.18; H, 4.69. Found: C, 71.04; H, 4.58.
.18. 1-(p-Tolyl)naphthalene (3r)
11 3
H F
2
1
H NMR (250 MHz, CDCl
3
/TMS): δ (ppm) = 2.46 (s, 3H), 2.29-2.53 (m, 8H), 7.84-7.93
1
3
(
m, 3H). CNMR (62.5 MHz, CDCl /TMS): δ (ppm) = 21.2, 125.3, 125.7, 125.9, 126.1,
3
1
26.8, 127.3, 128.2, 129.0, 129.9, 131.7, 133.7, 136.9, 137.8, 140.2. Anal. Calcd. for
14: C, 93.54; H, 6.46. Found: C, 93.48; H, 6.38.
.19. 3,3,6,6-Tetramethyl-9-(4-(thiophen-2-yl)phenyl)-3,4,5,6,7,9-hexahydro-1H-
17
C H
2
xanthene-1,8(2H)-dione (3s)
1
H NMR (250 MHz, CDCl ): δ (ppm) = 0.98 (s, 6H), 1.10 (s, 6H), 2.12-2.28 (m, 4H),
3
2
7
.47 (s, 4H), 4.70 (s, 1H), 7.14-7.18 (m, 2H), 7.25-7.29 (m, 1H), 7.41-7.44 (m, 2H), 7.65-
1
3
3
.79 (m, 2H). C NMR (62.5 MHz, CDCl ): δ (ppm) = 27.1, 29.6, 32.2, 32.7, 41.6, 50.3,
1
2) Toummini, D.; Ouazzani, F.; Taillefer, M. Org. Lett. 2013, 15, 4690-4693.
S6