Copper(II) acetate-catalyzed addition of arylboronic acids to aromatic aldehydes

Article abstract of DOI:10.1021/jo802225j

A novel copper-catalyzed protocol for the synthesis of carbinol derivatives has been developed. In the presence of copper(II) acetate and dppf, carbinol derivatives were prepared by the addition of arylboronic acids to aromatic aldehydes in good to excellent yields. Moreover, the rigorous exclusion of air or moisture is not required in these transformations.

Full text of DOI:10.1021/jo802225j

either toxic, have poor functional group compatibility, or are
sensitive to air and moisture.
Copper(II) Acetate-Catalyzed Addition of
Arylboronic Acids to Aromatic Aldehydes
Organboron reagents enjoy great prestige due to their
advantages of stability to air or moisture and good functional
group tolerance.3 In 1997, Miyaura and co-workers reported a
rhodium-catalyzed addition of aryl- and alkenyl-boronic acids
to aldehydes4 and enones.5 Since then, various synthetic methods
by rhodium-catalyzed6 and palladium-catalyzed7 approaches for
such transformations have been developed. In our previous
report, we have developed a palladium-catalyzed arylation of
aldehydes to produce secondary alcohols in good yields.8
However, palladium is very expensive compared with copper.
Furthermore, in our previous report, palladium-catalyzed alde-
hyde arylations did not tolerate bromo or formyl groups in the
substrates. We report herein that diarylmethanols can be
prepared successfully by the addition of arylboronic acids to
aromatic aldehydes with excellent yields in the presence of
copper(II) acetate.
Hanmei Zheng,† Qiang Zhang,† Jiuxi Chen,†
Miaochang Liu,† Shuanghua Cheng,† Jinchang Ding,*,†,‡
Huayue Wu,*,† and Weike Su†,§
College of Chemistry and Materials Engineering,
Wenzhou UniVersity, Wenzhou 325027, P. R. China,
Wenzhou Vocational & Technical College,
Wenzhou 325035, P. R. China, and College of
Pharmaceutical Sciences, Zhejiang UniVersity of Technology,
Zhejiang, Key Laboratory of Pharmaceutical Engineering,
Hangzhou 310014, P. R. China
djc@wzVtc.cn; huayuewu@wzu.edu.cn
ReceiVed October 6, 2008
Initially, we chose the addition of phenylboronic acid 2e to
4-nitrobenzaldehyde 1a as a model reaction using Cu(OAc)2 ·
H2O as the copper source, NaOAc as the base, and toluene as
the solvent. Considering ligands always play important roles in
metal-catalyzed chemistry,9 we first focused on ligand screening
(Chart 1). Through screening, we found that the electronic nature
and steric demands of the arylphosphine ligands played impor-
tant roles. For example, use of monodentate phosphine ligands
resulted in moderate yields (Table 1, L6-L11), and the
hindrance in the ligands or electron-poor ligands had poor
catalytic activity (Table 1,L12-L16). Bidentate phosphines L1
and L2 with smaller bite angle than L5 stopped the reaction.
To our delight, bidentate phosphines with large bite angles such
as L4, L5, and L6 were effective for this transformation. In
addition, we examined the aminophosphine ligands (Table 1,
A novel copper-catalyzed protocol for the synthesis of
carbinol derivatives has been developed. In the presence of
copper(II) acetate and dppf, carbinol derivatives were
prepared by the addition of arylboronic acids to aromatic
aldehydes in good to excellent yields. Moreover, the rigorous
exclusion of air or moisture is not required in these
transformations.
Diarylmethanols consist of an important building block in
the synthesis of natural products and pharmacological active
compounds as well as material science target molecules.1
General approaches involve the reduction of ketones and
addition of organometallic reagents to aldehydes. In recent years,
great attention has been paid to the addition of organometallic
reagents to aldehydes for the synthesis of diarylmethanols, such
as organolithium,2a,d organomagnesium,2e,g organotin,2h,i and
organozinc.2l,m However, these organometallic reagents are
(3) (a) Suzuki, A. Acc. Chem. Res. 1982, 15, 178. (b) Miyaura, N.; Suzuki,
A. Chem. ReV. 1995, 95, 2457. (c) Suzuki, A. J. Organomet. Chem. 1998, 576,
147. (d) Darses, S.; Genet, J. P. Eur. J. Org. Chem. 2003, 4313.
(4) Sakai, M.; Euda, M.; Miyaura, N. Angew. Chem., Int. Ed. 1998, 37, 3279.
(5) (a) Sakai, M.; Hayashi, H.; Miyaura, N. Organometallics. 1997, 16, 4229.
(b) Takaya, Y.; Ogasawara, M.; Hayashi, T. Tetrahedron Lett. 1998, 39, 8479.
(6) (a) Duan, H. F.; Xie, J. H.; Shi, W. J.; Zhang, Q.; Zhou, Q. L. Org. Lett.
2006, 8, 1479. (b) Son, S. U.; Kim, S. B.; Reingold, J. A.; Carpenter, G. B.;
Sweigart, D. A. J. Am. Chem. Soc. 2005, 127, 12238. (c) Pucheault, M.; Darses,
S.; Genet, J. P. Chem. Commun. 2005, 4714. (d) Focken, T.; Rudolph, J.; Bolm,
C. Synthesis 2005, 3, 429. (e) Jagt, R. B. C.; Toullec, P. Y.; Vries, J. G. D.;
Feringa, B. L.; Minnaard, A. J. Org. Biomol. Chem. 2006, 4, 773. (f) Suzuki,
K.; Kondo, K.; Aoyama, T. Synthesis 2006, 1360. (j) 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. (h) 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. J. Org. Chem. 2008, 73, 4076.
(7) (a) Gibson, S.; Foster, D. F.; Eastham, G. R.; Tooze, R. P.; Cole, H. D. J.
Chem. Commun. 2001, 779. (b) Yamamoto, T.; Ohta, T.; Ito, Y. Org. Lett. 2005,
7, 4153. (c) Suzuki, K.; Arao, T.; Ishii, S.; Maeda, Y.; Kondo, K.; Aoyama, T.
Tetrahedron Lett. 2006, 47, 5789. (d) He, P.; Lu, Y.; Dong, C. G.; Hu, Q. S.
Org. Lett. 2007, 9, 343. (e) He, P.; Lu, Y.; Hu, Q. S. Tetrahedron Lett. 2007,
48, 5283.
† Wenzhou University.
‡ Wenzhou Vocational & Technical College.
§ Zhejiang University of Technology.
(1) (a) Schmidt, F.; Stemmler, R. T.; Rudolph, J.; Bolm, C. Chem. ReV. 2006,
35, 454. (b) Fagnou, K.; Lautens, M. Chem. ReV. 2003, 103, 169. (c) Bolm, C.;
Hildebrand, J. P.; Muniz, K.; Hermanns, N. Angew. Chem., Int. Ed. 2001, 40,
3284. (d) Darses, S.; Genet, J. P. Eur. J. Org. Chem. 2003, 4313.
(2) (a) Furstner, A. Chem. ReV. 1999, 99, 991. (b) Boudier, A.; Bromm, L. O.;
Bromm, L. M.; Knochel, P. Angew. Chem., Int. Ed. 2000, 39, 4414. (c) Bolm,
C.; Rudolph, J. J. Am. Chem. Soc. 2002, 124, 14850. (d) Guijarro, D.; Yus, M.
Tetrahedron. 2000, 56, 1135. (e) Boymond, L.; Rottlander, M.; Cahiez, G.;
Knochel, P. Angew. Chem., Int. Ed. 1998, 37, 1701. (f) Abarbri, M.; Dehmel,
F.; Knochel, P. Tetrahedron Lett. 1999, 40, 7449. (g) Lee, J. S.; Velarde, O. R.;
Guijarro, A.; Wurst, J. R.; Rieke, R. D. J. Org. Chem. 2000, 65, 5428. (h) Weber,
B.; Seebach, D. Tetrahedron 1994, 50, 7473. (i) Noyori, R.; Kitamura, M. Angew.
Chem., Int. Ed. 1991, 30, 49. (j) Dosa, P. I.; Ruble, J. C.; Fu, G. C. J. Org.
Chem. 1997, 62, 444. (k) Bolm, C.; Hermanns, N.; Hildebrand, J. P.; Muniz, K.
Angew. Chem., Int. Ed. 2000, 39, 3465. (l) Ogawa, Y.; Mori, M.; Saiga, A.;
Takagi, K. Chem. Lett. 1996, 1069. (m) Kondo, Y.; Takazawa, N.; Yamazaki,
C.; Sakamoto, T. J. Org. Chem. 1994, 59, 4717.
(8) Qin, C. M.; Wu, H. Y.; Cheng, J.; Chen, X. A.; Liu, M. C.; Zhang, W. W.;
Su, W. K.; Ding, J. C. J. Org. Chem. 2007, 72, 4102.
(9) (a) Tolman, C. A. Chem. ReV. 1977, 77, 313. (b) Braga, A. A. C.; Morgon,
N. H.; Ujaque, G.; Liedos, A.; Maseras, F. J. Organomet. Chem. 2006, 691,
4459. (c) Braga, A. A. C.; Morgon, N. H.; Ujaque, G.; Maseras, F. J. Am. Chem.
Soc. 2005, 127, 9298. (d) Barder, T. E.; Walker, S. D.; Martinelli, J. R.;
Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 4685. (e) Kranenburg, M.;
vanderBurgt, Y. E. M.; Kamer, P. C. J.; van Leeuwen, P. W. N. M.
Organometallics 1995, 14, 3081. (f) Littke, A. F.; Fu, G. C. Angew. Chem., Int.
Ed. 2002, 41, 4176.
10.1021/jo802225j CCC: $40.75
Published on Web 12/09/2008
2009 American Chemical Society
J. Org. Chem. 2009, 74, 943–945 943

TABLE 2. Copper(ll) Acetate-Catalyzed Addition of Arylboronic
Acids to Aromatic Aldehydesa
CHART 1. Ligand Screening
entry
Ar1
Ar2
product yield (%)
1
2
3
4
5
6
7
8
4-NO2-C6H4 1a
1a
1a
1a
1a
1a
1a
1a
4-CF3-C6H4 2a
4-F-C6H4 2b
4-Cl-C6H4 2c
4-Br-C6H4 2d
C6H5 2e
4-Me-C6H4 2f
4-MeO-C6H4 2g 3ag
3-MeO-C6H4 2h 3ah
2-MeO-C6H4 2i
2-Me-C6H4 2j
1-nathphyl 2k
2e
2e
2e
2e
2e
3aa
3ab
3ac
3ad
3ae
3af
84
83
90
92
95
96
95
90
73
89
95
90
74
91
92
57
89
90
<5
<5
9
1a
1a
1a
3ai
3aj
3ak
3be
3ce
3de
3ee
3fe
3ge
3he
3ie
10
11
12
13
14
15
16
17
18
19
20
3-NO2-C6H4 1b
2-NO2-C6H4 1c
4-CN-C6H4 1d
4-OHC-C6H4 1e
4-MeO2C-C6H4 1f
2,4-(NO2)2-C6H3 1g 2e
4-MeO2S-C6H4 1h
C6H5 1i
2e
2e
2e
2-furyl 1j
3je
TABLE 1. Effects of Bases, Solvents, and the Amounts of Ligand
on the Copper(II) Acetate-Catalyzed Addition of Phenylboronic
Acid to 4-Nitrobenzaldehydea
a All reactions were run with aldehyde (0.2 mmol), arylboronic acid
(0.4 mmol), Cu(OAc)2 ·H20 (4.0 mg, 10 mol %), dppf ligand (15 mol
%), and NaOAc (49.2 mg, 0.6 mmol) in 3 mL of toluene at reflux for
24 h under air atmosphere. b Isolated yields reported.
catalytic reaction. Toluene appeared to be the best choice among
the common solvents such as CH3CH2NO2, DMF, DMSO,
dioxane, DCE, THF, and t-BuOMe. Cu(OAc)2 ·H2O exhibited
the highest catalytic activity compared with CuCl2 and CuCl.
Increasing the amount of L5 in the procedure afforded nearly
quantitive yield (Table 1, entries 17 and 18). In the light of
these results, we adopted conditions with 0.1 equiv of
Cu(OAc)2 ·H2O, 0.15 equiv of L5, 4-nitrobenzaldehyde, and 3
equiv of NaOAc in the present protocol.
entry
base
K2CO3
KF·2H2O
HCOONa
LiOH·H2O
DABCO
DBU
NaOAc
NaOAc
NaOAc
solvent
toluene
yieldb (%)
1
2
3
4
5
6
7
8
<5
<5
30
59
17
<5
85
15
<5
<5
<5
<5
<5
<5
91
93
95
96
toluene
toluene
toluene
toluene
toluene
toluene
CH3CH2NO2
DMF
9
10
11
12
13
14
15
16
17c
18d
NaOAc
NaOAc
NaOAc
NaOAc
DMSO
dioxane
DCE
With optimal conditions in hand, the reaction of various
arylboronic acids with different aromatic aldehydes was exam-
ined to explore the scope of the reaction (Table 2).
THF
The reaction proceeded smoothly with a variety of functional
groups and afforded diarylmethanols in excellent yields.
In our system, electronic effect on the arylboronic acids had
little influence (Table 2, entries 1-7). Electron-withdrawing
arylboronic acids, which are less nucleophilic, and hence,
transmetalate more slowly than electro-neutral analogues, are
prone to homocoupling and protodeboronation side reactions.9d
However, in our catalytic system, 4-chlorophenylboronic acid
2c and 4-bromophenylboronic acid 2d proceeded smoothly with
1a to afford 3ac and 3ad in 90% and 92% yields, respectively.
The products of 3ac and 3ad had the chloro and bromo group
untouched (Table 2, entries 3 and 4). For the aldehydes, electron-
withdrawing aromatic aldehydes reacted with 2e easily and gave
diarylmethanols in good yields (Table 2, entries 12-18). Par-
ticularly, 4-formylbenzaldehyde 1e coupled with 2e and the
product of 3ee left one formyl group untouched (Table 2, entry
15), which may be due to the electronic nature playing important
roles, CdO bond activity was decreased in the product 3ee,
and stopped addition of phenylboronic acid 2e to formal group
of 3ee. Unfortunately, the reaction was unsuccessful using
aldehydes with neutral, electron-rich groups or aliphatic aldehydes.
We further examined the steric effect in our system. A
monosubstitution group on the ortho or meta position for both
NaOAc
t-BuOMe
toluene
toluene
toluene
toluene
NaOAc (3 equiv)
NaOAc (4 equiv)
NaOAc (3 equiv)
NaOAc (3 equiv)
a AII reactions were run with 4-nitrobenzaldehyde (30 mg, 0.2 mmol),
phenylboronic acid (48.8 mg, 0.4 mmol), Cu(OAc)2 ·H2O (4.0 mg, 10
mol %), dppf ligand (10 mol %), and base (0.4 mmol) in 3 mL of
solvent at reflux for 24
h
under air atmosphere. b Isolated yields
reported. c L/Cu ) 1.5:1. d L/Cu ) 2:1.
L17-L20), which had poor activity except for ligand L18.
Finally, we chose commercial available L5 as the best ligand
in our system.
Further studies on the optimization of the reaction conditions
such as bases, solvents and the ratio of L5/Cu for phenylation
of 4-nitrobenzaldehyde are listed in Table 1. Among the bases,
NaOAc was superior to some others such as K2CO3, KF·2H2O,
LiOH·H2O, DABCO, DBU, and HCOONa. In addition, we also
studied influence of the amount of NaOAc on the reaction yields.
It was found that the yield was not significantly affected by
adding different amount of NaOAc (Table 1, entries 7, 15, and
16). The choice of solvent was also vital to the success of the
944 J. Org. Chem. Vol. 74, No. 2, 2009

3455 (-OH); MS (EI) m/z 297 (M+). Anal. Calcd for C14H10F3NO3:
C, 56.57; H, 3.39. Found: C, 56.40; H, 3.45.
arylboronic acids (Table 2, entries 7-9) and aromatic aldehydes
(Table 2, entries 5, 12, and 13) had little effect on the yields in
the reaction. For example, 1a reacted with arylboronic acids
2g, 2h, and 2i efficiently and afforded 3ag, 3ah, and 3ai in
95%, 90%, and 73% yields, respectively (Table 2, entries 7-9).
Of particular note, the reaction rate with aldehydes 1g or 1h
was faster than others (Table 2, entries 17 and 18), which may
be due to the electron-withdrawing groups increasing CdO bond
activity and accelerating the reactions. Moreover, the rigorous
exclusion of air or moisture is not required in the present
protocol.
3-Methoxyphenyl(4-nitrophenyl)methanol (3ah) (Table 2,
1
entry 8): H NMR (CDCl3, 300 MHz) δ 2.74 (s, 1H), 3.79 (s,
3H), 5.86 (s, 1H), 6.82-6.93 (m, 3H), 7.29 (d, J ) 8.2 Hz, 1H),
7.57 (d, J ) 8.1 Hz, 2H), 8.17 (d, J ) 8.1 Hz, 2H); 13C NMR
(CDCl3, 75 MHz) δ 55.2, 75.3, 112.4, 113.5, 118.9, 123.6, 127.0,
129.9, 144.2, 147.1, 150.6, 159.9; IR (KBr, cm-1) 3444 (-OH);
MS (EI) m/z 259 (M+). Anal. Calcd for C14H13NO4: C, 64.86; H,
5.05. Found: C, 64.90; H, 5.11.
2-Methoxyphenyl(4-nitrophenyl)methanol (3ai) (Table 2,
1
entry 9): H NMR (CDCl3, 300 MHz) δ 3.17 (s, 1H), 3.80 (s,
3H), 6.10 (s, 1H), 6.89-6.92 (m, 2H), 7.21-7.32 (m, 2H), 7.55
(d, J ) 8.8 Hz, 2H), 8.15 (d, J ) 8.8 Hz, 2H); 13C NMR (CDCl3,
75 MHz) δ 55.4, 71.6, 111.0, 121.1, 123.4, 127.1, 127.8, 128.2,
129.0, 129.5, 130.7, 150.9; IR (KBr, cm-1) 3438 (-OH); MS (EI)
m/z 259 (M+). Anal. Calcd for C14H13NO4: C, 64.86; H, 5.05.
Found: C, 64.79; H, 4.98.
In summary, describe here the first example of an efficient
and practical approach for the synthesis of a variety of carbinol
derivatives via the combination of an inexpensive copper(II)
acetate catalyst and air-stable dppf ligand. Work to probe the
detailed mechanism and apply the reaction in organic synthesis
is currently underway.
Naphthalen-1-yl(4-nitrophenyl)methanol (3ak) (Table 2,
1
entry 11): H NMR (CDCl3, 300 MHz) δ 2.79 (brs, 1H), 6.55 (s,
1H), 7.47-7.51 (m, 4H), 7.58 (d, J ) 8.9 Hz, 2H), 7.85-7.91 (m,
2H), 8.01-8.04 (m, 1H), 8.15 (d, J ) 8.9 Hz, 2H); 13C NMR
(CDCl3, 75 MHz) δ 73.4, 123.6, 123.7, 125.3, 125.6, 126.0, 126.6,
127.5, 129.0, 129.4, 130.5, 134.2, 137.8, 147.3, 150.3; IR (KBr,
cm-1) 3450 (-OH); MS (EI) m/z 279 (M+). Anal. Calcd for
C17H13NO3: C, 73.11; H, 4.69. Found: C, 73.18; H, 4.75.
Experimental Section
General Procedure for the Synthesis of Carbinol Deri-
vatives. Under an air atmosphere, a Schlenk tube was charged with
Cu(OAc)2 ·H2O (4.0 mg, 0.02 mmol), dppf (16.6 mg, 0.03 mmol),
arylboronic acid (0.4 mmol), aldehyde (0.2 mmol), NaOAc (49.2
mg, 0.6 mmol), and toluene (3 mL) under ice-salt (-20 °C). The
mixture was stirred for 0.5 h at room temperature, refluxed for 24 h,
and then cooled in a Schlenk tube to room temperature. The mixture
was extracted with ethyl acetate (4 × 5 mL), and the organic layers
were washed with water. The organic layers were dried over
MgSO4, concentrated, and purified by flash column chromatography
on silica gel to give the desired product.
Acknowledgment. We thank the National Key Technology
R&D Program (No. 2007BAI34B00), the National Natural
Science Foundation of China (No. 20876147 and 20676123),
and the Natural Science Foundation of Zhengjiang Province (No.
Y4080107) for financial support.
4-Nitrophenyl(4-(trifluoromethyl)phenyl)methanol(3aa)(Ta-
Supporting Information Available: Experimental proce-
dures along with copies of spectroscopic and data. This material
is available free of charge via the Internet at http://pubs.acs.org.
1
ble 2, entry 1): H NMR (CDCl3, 300 MHz) δ 2.52 (d, J ) 2.6
Hz, 1H), 5.99 (s, 1H), 7.48-7.64 (m, 6H), 8.21 (d, J ) 8.8 Hz,
2H); 13C NMR (CDCl3, 75 MHz) δ 74.9, 122.1, 123.9, 125.8, 125.9,
126.9, 127.2, 128.3, 130.3, 146.4, 147.5, 149.9; IR (KBr, cm-1
)
JO802225J
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