Transition-metal-free cross-coupling reaction of benzylic halides with arylboronic acids leading to diarylmethanes

Article abstract of DOI:10.1016/j.tetlet.2016.07.089

The cross-coupling reaction between arylboronic acids and various benzylic halides proceeded without using a transition-metal catalyst to give the corresponding diarylmethanes in moderate to good yields.

Full text of DOI:10.1016/j.tetlet.2016.07.089

Accepted Manuscript
Transition-metal-free cross-coupling reaction of benzylic halides with arylbor-
onic acids leading to diarylmethanes
Mitsuhiro Ueda, Daiki Nakakoji, Yuki Kuwahara, Kota Nishimura, Ilhyong Ryu
PII:
S0040-4039(16)30957-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.07.089
TETL 47951
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
17 June 2016
22 July 2016
28 July 2016
Please cite this article as: Ueda, M., Nakakoji, D., Kuwahara, Y., Nishimura, K., Ryu, I., Transition-metal-free cross-
coupling reaction of benzylic halides with arylboronic acids leading to diarylmethanes, Tetrahedron Letters (2016),
doi: http://dx.doi.org/10.1016/j.tetlet.2016.07.089
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1
Tetrahedron Letters
Transition-metal-free cross-coupling reaction of benzylic halides with arylboronic
acids leading to diarylmethanes
Mitsuhiro Ueda, Daiki Nakakoji, Yuki Kuwahara, Kota Nishimura, and Ilhyong Ryu
Department of Chemistry, Graduate School of Science, Osaka Prefecture University, Sakai, Osaka 599-8531, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The cross-coupling reaction between arylboronic acids and various benzylic halides proceeded
without using a transition-metal catalyst to give the corresponding diarylmethanes in moderate
to good yields.
2009 Elsevier Ltd. All rights reserved.
Available online
Transition-metal-free
Arylboronic acid
Diarylmethane
Benzylation
We recently reported the transition-metal-free Suzuki–
Miyaura coupling reaction of allylic bromides1 with arylboronic
acids, which gave the corresponding allylated products (Scheme
1, eq 1). We also reported the transition-metal-free Suzuki–
Miyaura coupling reaction of propargylic bromides2 with
arylboronic acids, which gave the corresponding propargylated
products (Scheme 1, eq 2). We thought that a similar catalyst-free
system could be extended to arylation of benzylic bromides.
Herein we would like to report the transition-metal-free cross-
coupling reaction of benzylic bromides with arylboronic acids
(eq 3).3,4,5
Scheme 1. Transition-metal-free cross-coupling reaction
Table 1. Screening of reaction conditionsa
Entry
Base
Solvent
CH2Cl2
CHBr3
Toluene
BTFc
BTF
BTF
BTF
Temp (°C)
60
Yield (%)b
1
2
3
4
5
6
7
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
CsF
32
47
38
57
41
14
14
110
110
110
110
110
110
K2CO3
KF
a Reaction conditions: 1a (1.0 equiv), 2a (1.3 equiv), base (1.5 equiv), solvent/H2O (0.4 M for 1a), bath temp. (°C), 18 h.
b Isolated yield. c Benzotrifluoride.
———
 Corresponding author. Tel.: +81-72-254-9670; fax: +81-72-254-9670; e-mail: ueda@c.s.osakafu-u.ac.jp (M. Ueda)

2
Tetrahedron Letters
Treatment
of
benzyl
bromide
(1a)
with
4-
In this reaction, water is necessary to dissolve boronic acid 2a
and benzyl alcohol was formed as by-product (21%), which was
obtained by hydrolysis of 1a. We then surveyed the effects of
solvent and reaction temperature. The reaction using CHBr3/H2O
(10/1) as the solvent at the elevated temperature such as 110 °C
methoxyphenylboronic acid (2a: 1.3 equiv) and Cs2CO3 (1.5
equiv, purchased from Wako Pure Chemical Industries, Ltd.) in a
mixed solvent of CH2Cl2/H2O (10/1) at 60 °C for 18 h gave 1-
benzyl-4-methoxybenzene (3a) in 32% yield (Table 1, entry 1).
Table 2. Transition-metal-free cross-coupling reaction of benzylic bromides 1 with arylboronic acids 2a
Entry
1
1
2
Product 3
Yield (%)b
57
2
3
4
5
6
7
55
68
49
46
42
42
8
22
9
41
57
10
11
12
29
30c
a Reaction conditions: 1 (1.0 equiv), 2 (1.3 equiv), Cs2CO3 (1.5 equiv), BTF/H2O (0.4 M for 1), 110 °C, 18 h. b Isolated yield.
c Only the (E)-isomer of 3l was obtained.

3
afforded 3a in 47% yield (entry 2). Whereas toluene/H2O (10/1)
was less effective (38%; entry 3), further improvement of the
yield was achieved using BTF(benzotrifluoride)/H2O (10/1)
(57%; entry 4). The use of CsF in BTF/H2O (10/1) as a base gave
3a in 41% yield (entry 5). However, the use of K2CO3 and KF
was far less effective (entries 6 and 7).
With the optimized reaction conditions of entry 4 in hand
(Table 1), the scope of the present metal-free Suzuki–Miyaura
coupling reaction was investigated (Table 2). 4-Methylbenzyl
bromide (1b) showed comparable reactivity with benzyl bromide
(1a) (55%; entry 2). The reaction of 2-(bromomethyl)naphthalene
(1c) with 2a gave the corresponding product 3c in 68% yield
(entry 3). 3,5-Dimethoxybenzyl bromide (1d) also reacted with
2a to afford 3d in 49% yield (entry 4).6 It is interesting to note
that bromine-containing benzyl bromides (1e and 1f) tolerated
the reaction conditions to furnish the corresponding cross-
coupling product 3e and 3g in 46% and 42% yields, respectively
without the formation of any trace amount of double arylated
products (entries 5 and 6). These are interesting, since the
palladium-catalyzed Suzuki-Miyaura coupling reaction of 1e
with 2a is known to give the biaryl product as major product.7
Indeed, when 1 mol % of Pd(OAc)2 was added to the reaction
mixture under our standard reaction conditions, the biaryl
product 4 was obtained as a major product after 5 h (Scheme 2).
p-Cyano-substituted benzyl bromide 1g gave 3g in 42 % yield
(entry 7). Electron-poor aryl boronic acid was less reactive as in
the cases of our former studies on allylation and propargylation
(entry 8). Whereas 3,4-dimethoxyphenylboronic acid (2b)
worked well for the present metal-free coupling reaction (entries
9 and 10), dimethylamino-substituted phenylboronic acid 2c gave
a poor result (entry 11). The cross-coupling reaction of trans-2-
(4-methylphenyl)vinylboronic acid (2e) with benzyl bromide (1a)
proceeded to give the benzylated E-form alkene 3l in 30% yield
(entry 12). Electron-poor aryl boronic acid, such as p-CF3-
phenylboronic acid, did not react with 1a.8 This is in contrast
with the good result by palladium-catalyzed reaction.4
Scheme 3. Transition-metal-free cross-coupling reaction of
benzylic chlorides 5 with 4-methoxyphenyl boronic acid (2a)
Scheme 4 illustrates a possible rationale for the present cross-
coupling reaction, in which we assume an ipso-attack of
arylboronic acid is involved.1a,2 As a first step, 2a would be
converted to borate anion A by H2O and Cs2CO3. A would then
react with benzyl bromide (1a) through six-membered ring
transition state B to give the cross-coupling product 3a,
accompanied by the liberation of boronic acid.9,10
Scheme 4. Possible mechanism for the formation of 3a from
2a and 1a.
In summary, we have shown that, in the presence of cesium
carbonate as a base and H2O as a co-solvent, cross-coupling
reaction of benzylic bromides and chlorides with arylboronic
acids can take place without the use of any transition-metal
catalysts. Though the yields are not so high, this protocol
provides a mild method to prepare diarylmethanes, which are
potentially useful compounds.11 Additional applications of metal-
free cross-coupling reactions are currently underway in our
Laboratory.
Scheme 2. Palladium-catalyzed Suzuki–Miyaura coupling
reaction of 1f with 2a
These catalyst-free conditions were also applicable to the
cross-coupling reaction of benzylic chlorides (Scheme 3).
Thus, the reaction of 4-methoxybenzyl chloride (5a) with 2a
gave
3m
in
47%
yield.
Similarly,
1-
(chloromethyl)naphthalene (5b) reacted with 2a to give 3n in
51% yield.
Acknowledgments
This work was supported by a Grant-in-Aid for Scientific
Research from the MEXT and the JSPS (25810024 for MU).
References and notes
1.
(a) Ueda, M.; Nishimura, K.; Kashima, R.; Ryu, I. Synlett 2012, 23,
1085-1089. Also see a contribution from the Scrivanti group: (b)
Scrivanti, A.; Beghetto, V.; Bertoldini, M.; Matteoli, U. Eur. J.
Org. Chem. 2012, 264-268.
2.
Ueda, M.; Nishimura, K.; Ryu, I. Synlett 2013, 24, 1683-1686.

4
Tetrahedron
3.
For recent reviews of palladium-catalyzed Suzuki-Miyaura coupling
12189-12195. 3f: Treu, M.; Jordis, U. Molecules 2002, 7, 18-25. 3g:
Benischke, A. D.; Knoll, I.; Rérat, A.; Gosmini, C.; Knochel, P. Chem.
Commun. 2016, 52, 3171-3174. 3h: Fan, S.; He, C.-Y.; Zhang, X.
Chem. Commun. 2010, 46, 4926-4928. 3i: Chen, C.-R.; Zhou, S.;
Biradar, D. B.; Gau, H.-M. Adv. Synth. Catal. 2010, 352, 1718-1727.
3l: Mino, T.; Kogure, T.; Abe, T.; Koizumi, T.; Fujita, T.; Sakamoto,
M. Eur. J. Org. Chem. 2013, 1501-1505. 3m: Deshmukh, M. S.;
Srivastava, A.; Das, B.; Jain, N. J. Org. Chem. 2015, 80, 10041-
10048.
reaction, see: (a) Suzuki, A. Angew. Chem. Int. Ed. 2011, 50, 6722-
6737. (b) Jana, R.; Pathak, T. P.; Sigman, M. S. Chem. Rev. 2011,
111, 1417-1492. (c) Heravi, M. M.; Hashemi, E. Tetrahedron 2012,
68, 9145-9178. (d) Johansson Seechurn, C. C. C.; Kitching, M. O.;
Colacot, T. J.; Snieckus, V. Angew. Chem. Int. Ed. 2012, 51, 5062-
5085. (e) Han, F.-S. Chem. Soc. Rev. 2013, 42, 5270-5298. (f)
Lennox, A. J. J.; Lloyd-Jones, G. C. Angew. Chem. Int. Ed. 2013,
52, 7362-7370. (g) Zafar, M. N.; Mohsin, M. A.; Danish, M.;
Nazar, M. F.; Murtaza, S. Russ. J. Coord. Chem. 2014, 40, 781-
800. (h) Maluenda, I.; Navarro, O. Molecules 2015, 20, 7528-7557.
For selected examples of transition-metal catalyzed benzylation
reactions of arylboronic acids, see: Pd; (a) Yu, J.-Y.; Kuwano, R. Org.
Lett. 2008, 10, 973-976. (b) Inés, B.; Moreno, I.; San Martin, R.;
Domínguez, E. J. Org. Chem. 2008, 73, 8448-8451. (c) Fairlamb, I. J.
S.; Sehnal, P.; Taylor, R. J. K. Synthesis 2009, 3, 508-510. (d) Alacid,
E.; Nájera, C. J. Organomet. Chem. 2009, 694, 1658-1665. (e) Ghosh,
R.; Adarsh, N. N.; Sarkar, A. J. Org. Chem. 2010, 75, 5320-5322. (f)
John, A.; Shaikh, M. M.; Butcher, R. J.; Ghosh, P. Dalton Trans.
2010, 39, 7353-7363. (g) Yu, A. J.; Li, X. D.; Peng, D. P.; Wu, Y. J.;
Chang, J. B. Appl. Organomet. Chem. 2012, 26, 301-304. (h) Zhang,
Y. Q. J. Chem. Res. 2013, 6, 375-376. (i) Guan, Z.; Li, B.; Hai, G.;
Ynag, X.; Li, T.; Tan, B. RSC Adv. 2014, 4, 36437-36443. (j) Zhao,
G.; Wang, Z.; Wang, R.; Li, J.; Zou, D.; Wu, Y. Tetrahedron Lett.
2014, 55, 5319-5322. Ni; (k) Tobisu, M.; Yasutome, A.; Kinuta, H.;
Nakamura, K.; Chatani, N. Org. Lett. 2014, 16, 5572-5575. Fe; (l)
Bedford, R. B.; Hall, M. A.; Hodges, G. R.; Huwe, M.; Wilkinson, M.
C. Chem. Commun. 2009, 6430-6432.
4.
5.
6.
Recently, the Huang group reported the metal-free cross-coupling
reaction between benzylthiolaniums and tetraphenylborates to give
diarylmethanes. see: Xu, M.-L.; Huang, W. Tetrahedron Lett. 2014,
55, 4230-4232.
Typical Procedure for a Transition-Metal-Free Suzuki–Miyaura
Cross-Coupling Reaction of Benzylic Halides with Arylboronic
Acids: A mixture of 3,5-dimethoxybenzyl bromide (1d; 0.5 mmol), 4-
methoxyphenylboronic acid (2a; 0.65 mmol, 1.3 equiv), and Cs2CO3
(0.75 mmol, 1.5 equiv) in BTF/H2O (1.65 mL, 10/1) was stirred at
110 °C for 18 h. Then, the reaction mixture was treated with aq 1 N
HCl, extracted with EtOAc and the organic layer was dried over
MgSO4. The organic layer was concentrated and the resulting residue
was purified by column chromatography on silica gel (hexane-EtOAc,
10:1) to give 1,3-dimethoxy-5-(4-methoxybenzyl)benzene (3d) as a
yellow liquid in 49% yield (63.29 mg, 0.245 mmol); 1H NMR (500
MHz, CDCl3) δ 3.75 (s, 6H), 3.80 (s, 3H), 3.86 (s, 2H), 6.32 (m, 3H),
6.82 (m, 2H), 7.11 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 41.7,
55.7(two peaks overlap), 98.3, 107.4, 107.5, 114.3, 130.3, 133.2,
144.3, 158.4, 161.2; IR(neat): 3001, 2934, 2836, 1607, 1470, 1428,
1348, 1206, 1107, 821 cm−1; HRMS (EI) m/z calcd. for C16H18O3:
258.1256, found: 258.1250.
7.
8.
Bandgar, B. P.; Bettigeri, S. V.; Phopase, J. Tetrahedron Lett. 2004,
45, 6959-6962.
Some previous work of metal-free Suzuki-Miyaura reactions was
actually catalyzed by contaminated transition metals in inorganic base
or solvent. See: Na2CO3; (a) Arvela, R. K.; Leadbeater, N. E.; Sangi,
M. S.; Williams, A.; Granados, P.; Singer, R. D. J. Org. Chem. 2005,
70, 161-168. Dimethyl carbonate; (b) Inamoto, K.; Campbell, L. D.;
Doi, T.; Koide, K. Tetrahedron Lett. 2012, 53, 3147-3148.
9.
We tested four different purity/source of Cs2CO3 [TCI, Wako, Aldrich
(99.9%), and Aldrich (99.995%)] suing the reaction of entry 6 in
Table 2. In all cases, nearly the same results were provided.
10. For pharmaceuticals having diarylmethane structures, see: (a) Juteau,
H.; Gareau, Y.; Labelle, M.; Sturino, C. F.; Sawyer, N.; Tremblay, N.;
Lamontagne, S.; Carrière, M.-C.; Denis, D.; Metters, K. M. Bioorg.
Med. Chem. 2001, 9, 1977-1984. (b) Rosowsky, A.; Chen, H.; Fu, H.;
Queener, S. F. Bioorg. Med. Chem. 2003, 11, 59-67. (c) Forsch, R.
A.; Queener, S. F.; Rosowsky, A. Bioorg. Med. Chem. 2004, 14,
1811-1815.
11. Compounds 3a, 3b, 3c, 3e, 3f, 3g, 3h, 3i, 3k, 3l, 3m, and 3n are
known in literature. 3a, 3b, 3c, 3k, 3n: Chang, S.-T.; Li, Q.; Chiang,
R.-T.; Gau, H.-M. Tetrahedron 2012, 68, 3956-3962. 3e: Brown, C.
A.; Nile, T. A.; Mahon, M. F.; Webster, R. L. Dalton Trans. 2015, 44,
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Transition-metal-free cross-coupling
reaction of benzylic halides with arylboronic
acids leading to diarylmethanes
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Mitsuhiro Ueda,* Daiki Nakakoji, Yuki Kuwahara, Kota Nishimura, and Ilhyong Ryu

5
Highlights:
Transition-metal-free cross-coupling of benzylic halides with arylboronic acids.
Ionic substitution mechanism via a six-membered ring transition state is proposed.
Arylboronic acids react with benzylic halides at ipso-position of B(OH)2.