W. Chen et al. / Tetrahedron Letters 52 (2011) 1677–1679
1679
Most importantly however, when inexpensive Ni(acac)2 was
Acknowledgments
used as a catalyst, optimum results were obtained (Table 1, entries
15–19). After 10 min of microwave heating at 180 °C using only
1 mol % of the catalyst and 1 equiv of K2CO3, 93% conversion to
the diarylmethane was obtained, providing a 77% isolated yield
of diphenylmethanol after purification by flash chromatography
(Table 1, entry 16). Reducing the reaction temperature to 170 °C
or 150 °C led to somewhat reduced conversions (Table 1, entries
17 and 18).
In addition, a control experiment employing a reaction vessel
made out of strongly microwave absorbing silicon carbide (SiC)
using the same microwave instrument demonstrated that the
improvements in reaction rate are the result of a purely thermal ef-
fect (Table 1, entry 19).12
With optimized reaction conditions in hand, the scope and lim-
itations of this novel high-speed arylation protocol were examined
employing a variety of aromatic and aliphatic aldehydes as well as
different arylboronic acids as reaction partners. In most instances
the anticipated products were obtained in good to excellent iso-
lated yields (Table 2).13 Aromatic aldehydes with different types
of halogen substituents afforded excellent product yields (Table
2, entries 2–7). Electron-rich aldehydes such as 3-methoxy-, 4-
methoxy-, and 3,4-dimethoxybenzaldehyde (Table 2, entries 9–
12) provided similar high yields while for 3-methyl- and 4-methyl-
benzaldehyde the reaction time had to be increased to 30 min in
order to obtain acceptable yields (Table 2, entries 13 and 14). On
the other hand, electron-deficient aldehydes, such as 4-cyanobenz-
aldehyde (Table 2, entry 8), did not participate in the reaction in
agreement with previous literature reports.9 Employing aliphatic
aldehydes the desired benzyl alcohols were also obtained in mod-
erate yields, however self-aldol condensation of the aldehyde com-
ponent had a negative impact on the overall reaction yield,
requiring the use of longer reaction times and catalyst loadings
(Table 2, entries 15 and 16). The use of substituted arylboronic
acids revealed significant electronic effects, with electron-rich
arylboronic acids generally providing lower yields compared to
their electron-deficient counterparts (Table 2, entries 17–22).
Gratifyingly, it was also demonstrated that the microwave-as-
sisted protocol introduced herein was readily scalable. Thus, the
Ni-catalyzed addition of phenylboronic acid to benzaldehyde (Ta-
ble 2, entry 1) was performed on a 10 mmol scale (20 mL solvent)
in the same single-mode microwave reactor under otherwise iden-
tical conditions, but using a larger reaction vial (30 mL). From this
experiment 1.36 g (74%) of diphenylmethanol was obtained, in a
very similar yield and product purity as in the 1.0 mmol scale
experiment.
This work was supported by a grant from the Christian Doppler
Research Foundation (CDG). C.W. thanks the China Scholarship
Council (CSC) for the scholarship.
References and notes
1. Schmidt, F.; Stemmler, R.; Rudolph, J.; Bolm, C. Chem. Soc. Rev. 2006, 35, 454–
470.
2. Sakai, M.; Euda, M.; Miyaura, N. Angew. Chem., Int. Ed. Engl. 1998, 37, 3279–
3281.
3. (a) Yigit, M.; Oezdemir, I.; Cetinkaya, E.; Cetinkaya, B. Transition. Met. Chem.
2007, 32, 536–540; (b) Jagt, R. B. C.; Toullec, P. Y.; Schudde, E. P.; De Vries, J. G.;
Feringa, B. L.; Minnaard, A. J. J. Comb. Chem. 2007, 9, 407–414; (c) Gois, P. M. P.;
Trindade, A. F.; Veiros, L. F.; Andre, V.; Duarte, M. T.; Afonso, C. A. M.; Caddick,
S.; Cloke, F. G. N. Angew. Chem., Int. Ed. 2007, 46, 5750–5753; (d) Tuerkmen, H.;
Denizalti, S.; Oezdemir, I.; Cetinkaya, E.; Cetinkaya, B. J. Organomet. Chem. 2008,
693, 425–434; (e) Trindade, A. F.; Gois, P. M. P.; Veiros, L. F.; Andre, V.; Duarte,
M. T.; Afonso, C. A. M.; Caddick, S.; Cloke, F. G. N. J. Org. Chem. 2008, 73, 4076–
4086; (f) Xing, C.-H.; Liu, T.-P.; Zheng, J. R.; Ng, J.; Eposito, M.; Hu, Q.-S.
Tetrahedron Lett. 2009, 50, 4953–4957; (g) White, J. R.; Price, G. J.; Plucinski, P.
K.; Frost, C. G. Tetrahedron Lett. 2009, 50, 7365–7368.
4. (a) Yamamoto, T.; Ohta, T.; Ito, Y. Org. Lett. 2005, 7, 4153–4155; (b) Suzuki, K.;
Arao, T.; Ishii, S.; Maeda, Y.; Kondo, K.; Aoyama, T. Tetrahedron Lett. 2006, 47,
5789–5792; (c) Lin, S.; Lu, X. J. Org. Chem. 2007, 72, 9757–9760; (d) Qin, C.; Wu,
H.; Cheng, J.; Chen, X.; Liu, M.; Zhang, W.; Su, W.; Ding, J. J. Org. Chem. 2007, 72,
4102–4107; (e) He, P.; Lu, Y.; Dong, C.-G.; Hu, Q.-S. Org. Lett. 2007, 9, 343–346;
(f) Yu, A.; Cheng, B.; Wu, Y.; Li, J.; Wei, K. Tetrahedron Lett. 2008, 49, 5405–5407;
(g) Kuriyama, M.; Shimazawa, R.; Shirai, R. J. Org. Chem. 2008, 73, 1597–1600;
(h) Yamamoto, T.; Iizuka, M.; Takenaka, H.; Ohta, T.; Ito, Y. J. Organomet. Chem.
2009, 694, 1325–1332.
5. (a) Tomita, D.; Kanai, M.; Shibasaki, M. Chem. Asian J. 2006, 1, 161–166; (b)
Zheng, H.-M.; Zhang, Q.; Chen, J.-X.; Liu, M.-C.; Cheng, S.-H.; Ding, J.-C.; Wu, H.-
Y.; Su, W.-K. J. Org. Chem. 2009, 74, 943–945.
6. Zou, T.; Pi, S.-S.; Li, J.-H. Org. Lett. 2009, 11, 453–456.
7. Takahashi, G.; Shirakawa, E.; Tsuchimoto, T.; Kawakami, Y. Chem. Commun.
2005, 1459–1461.
8. (a) Hirano, K.; Yorimitsu, H.; Oshima, K. Org. Lett. 2005, 7, 4689–4691; (b) Arao,
T.; Kondo, K.; Aoyama, T. Tetrahedron Lett. 2007, 48, 4115–4117; (c) Yamamoto,
K.; Tsurumi, K.; Sakurai, F.; Kondo, K.; Aoyama, T. Synthesis 2008, 3585–3591;
(d) Bouffard, J.; Itami, K. Org. Lett. 2009, 11, 4410–4413; (e) Xing, C.-H.; Hu, Q.-S.
Tetrahedron Lett. 2010, 51, 924–927.
9. Zhou, L.; Du, X.; He, R.; Ci, Z.; Bao, M. Tetrahedron Lett. 2009, 50, 406–408.
10. For recent reviews on microwave-assisted organic synthesis, see: (a) Kappe, C.
O.; Dallinger, D. Mol. Divers. 2009, 13, 71–193; (b) Nilsson, P.; Olofsson, K.;
Larhed, M. Top. Curr. Chem. 2006, 266, 103–144; (c) Prasad, A.; Van der Eycken,
E. Eur. J. Org. Chem. 2008, 1133–1155.
11. For the importance of internal temperature measurement in microwave
chemistry and a description of the microwave reactor, see: Obermayer, D.;
Kappe, C. O. Org. Biomol. Chem. 2010, 8, 114. and references cited therein. See
also Ref. 12.
12. (a) Obermayer, D.; Gutmann, B.; Kappe, C. O. Angew. Chem., Int. Ed. 2009, 48,
8321–8324; (b) Gutmann, B.; Obermayer, D.; Reichart, B.; Prekodravac, B.;
Irfan, M.; Kremsner, J. M.; Kappe, C. O. Chem. Eur. J. 2010, 16, 12182–12194.
13. General procedure for the Ni-catalyzed arylation of aldehydes with arylboronic
acids (Table 2): Aldehyde (1.0 mmol), arylboronic acid (1.5 mmol, 1.5 equiv),
K2CO3 (138 mg, 1.0 mmol, 1 equiv), and Ni(acac)2 (2.6 mg, 0.01 mmol, 1 mol %)
were added to a 10 mL microwave processing vial containing a Teflon coated
stir bar. After the vial was sealed dry toluene (2 mL) was transferred to the vial
and mixture was pre-stirred for 5 min. The vial was placed in the microwave
cavity and heated for 10 min at 180 °C (fixed hold time). After cooling, diethyl
ether or ethyl acetate (10 mL) was added and the crude reaction mixture was
subsequently washed with 25% aqueous NH3 (2 Â 10 mL). The aqueous
ammonium layer was reextracted again with diethyl ether or ethyl acetate
(2 Â 10 mL). The combined organic phase was dried over MgSO4 and the
residue after evaporation purified by flash chromatography using a petroleum
ether/ethylacetate (10:1–2.5:1) as eluent phase. All products are literature
known and were identified by 1H NMR and MS spectroscopy.
In conclusion, we have developed a rapid and efficient proto-
col for the Ni-catalyzed arylation of aromatic and aliphatic alde-
hydes with arylboronic acids providing the corresponding
benzylic alcohol derivatives. The transformations are conve-
niently carried out using 1–2 mol % of inexpensive Ni(acac)2 in
the presence of 1–2 equiv of K2CO3 as a base without the need
for an inert atmosphere. Employing sealed vessel microwave
heating at 180 °C under carefully controlled conditions the 1,2-
addition reactions are completed within 10–30 min providing
good to excellent product yields in most instances. The reactions
are easily scalable up to gram scale (10 mmol) using larger
microwave vessels.