FeCl3-catalyzed 1,2-addition reactions of aryl aldehydes with arylboronic acids

Article abstract of DOI:10.1021/ol802529p

(Chemical Equation Presented) A novel protocol for the 1,2-addition reactions of electron-deficient aryl aldehydes with arylboronic acids using an inexpensive and environmentally benign iron catalyst is reported. In the presence of FeCl₃ and 2-

Full text of DOI:10.1021/ol802529p

ORGANIC
LETTERS
2009
Vol. 11, No. 2
453-456
FeCl3-Catalyzed 1,2-Addition Reactions
of Aryl Aldehydes with Arylboronic
Acids
Tao Zou,† Sha-Sha Pi,† and Jin-Heng Li*,†,‡
College of Chemistry and Materials Science, Wenzhou UniVersity, Wenzhou 325035,
China, and Key Laboratory of Chemical Biology & Traditional Chinese Medicine
Research, Hunan Normal UniVersity, Changsha 410081, China
jhli@hunnu.edu.cn
Received November 6, 2008
ABSTRACT
A novel protocol for the 1,2-addition reactions of electron-deficient aryl aldehydes with arylboronic acids using an inexpensive and environmentally
benign iron catalyst is reported. In the presence of FeCl3 and 2-(di-tert-butylphosphino)biphenyl, 1,2-addition reactions of various electron-
deficient aryl aldehydes with arylboronic acids provided the corresponding biaryl methanols in moderate to excellent yields.
Rhodium-catalyzed 1,2-addition of aldehydes with orga-
noboronic acids was first reported by Miyaura in 1998.
Shortly after, other transition-metal-catalyzed versions of
this transformation emerged, and the method quickly
became a valuable tool for carbon-carbon bond forma-
tion.1-6 However, these transformations are often used
highly expensive transition metal catalysts, such as rhodi-
um,1,2 palladium,3 platinum,4 and nickel5 complexes. Only
one paper has reported on the use of inexpensive copper
catalyst.6 In view of both economy and environment, a great
challenge still remains regarding the use of some inexpensive
and environmentally benign catalysts for the 1,2-addition
reaction. Recently, iron, an inexpensive and environmentally
benign catalyst, has been proven to be efficient for the
formation of carbon-carbon and carbon-heteroatom bonds.7
A representative example is that iron displayed highly
† Wenzhou University.
‡ Hunan Normal University.
(1) For reviews, see: (a) Li, C.-J. Acc. Chem. Res. 2002, 35, 533. (b)
Fagnou, K.; Lautens, M. Chem. ReV. 2003, 103, 169. (c) Hayashi, T.;
(3) (a) Yamamoto, T.; Ohta, T.; Ito, Y. Org. Lett. 2005, 7, 4153. (b)
Suzuki, K.; Arao, T.; Ishii, S.; Maeda, Y.; Kondo, K.; Aoyama, T.
Tetrahedron 2006, 47, 5789. (c) He, P.; Lu, Y.; Dong, C.-G.; Hu, Q.-S.
Org. Lett. 2007, 9, 343. (d) Lin, S.; Lu, X. J. Org. Chem. 2007, 72, 9757.
(e) Qin, C.; Wu, H.; Cheng, J.; Chen, X.; Liu, M.; Zhang, W.; Su, W.;
Ding, J. J. Org. Chem. 2007, 72, 4102. (f) Qin, C.; Chen, J.; Wu, H.; Cheng,
J.; Zhang, Q.; Zou, B.; Su, W.; Ding, J. Tetrahedron Lett. 2008, 49, 1884.
(g) Qin, C.; Wu, H.; Chen, J.; Liu, M.; Cheng, J.; Su, W.; Ding, J. Org.
Lett. 2008, 10, 1537. (h) Kuriyama, M.; Shimazawa, R.; Shirai, R. J. Org.
Chem. 2008, 73, 1597. (i) Kuriyama, M.; Shimazawa, R.; Enomoto, T.;
Shirai, R. J. Org. Chem. 2008, 73, 6939.
Yamasaki, K. Chem. ReV. 2003, 103, 2829
.
(2) For selected papers, see: (a) Sakai, M.; Ueda, M.; Miyaura, N. Angew.
Chem., Int. Ed. 1998, 37, 3279. (b) Ueda, M.; Miyaura, N. J. Org. Chem.
2000, 65, 4450. (c) Pourbaix, C.; Carreaux, F.; Carboni, B. Org. Lett. 2001,
3, 803. (d) Hayashi, T.; Takahashi, M.; Takaya, Y.; Ogasawara, M. J. Am.
Chem. Soc. 2002, 124, 5052. (e) Krug, C.; Hartwig, J. F. J. Am. Chem.
Soc. 2002, 124, 1674. (f) Pucheault, M.; Darses, S.; Genet, J.-P. J. Am.
Chem. Soc. 2004, 126, 15356. (g) Son, S. U.; Kim, S. B.; Reingold, J. A.;
Carpenter, G. B.; Sweigart, D. A. J. Am. Chem. Soc. 2005, 127, 12238. (h)
Duan, H.-F.; Xie, J.-H.; Shi, W.-J.; Zhang, Q.; Zhou, Q.-L. Org. Lett. 2006,
8, 1479. (i) Suzuki, K.; Ishii, S.; Kondo, K.; Aoyama, T. Synlett 2006,
648. (j) Suzuki, K.; Kondo, K.; Aoyama, T. Synthesis 2006, 1360. (k) 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. (l) Noe¨l, T.; Vandyck, K.;
Van der Eycken, J. Tetrahedron 2007, 63, 12961. (m) Gois, P. M.; Trindade,
A. F.; Veiros, L. F.; Andre´, V.; Duarte, M. T.; Afonso, C. A. M.; Caddick,
(4) Liao, Y.-X.; Xing, C.-H.; He, P.; Hu, Q.-S. Org. Lett. 2008, 10,
2509.
(5) (a) Takahashi, G.; Shirakawa, E.; Tsuchimoto, T.; Kawakami, Y.
Chem. Commun. 2005, 1459. (b) Arao, T.; Kondo, K.; Aoyama, T.
Tetrahedron Lett. 2007, 48, 4115. (c) Arao, T.; Kondo, K.; Aoyama, T.
Tetrahedron 2007, 63, 5261.
S.; Cloke, F. G. N. Angew. Chem., Int. Ed. 2007, 46, 5750
.
(6) Tomita, D.; Kanai, M.; Shibasaki, M. Chem. Asian J. 2006, 1, 161.
10.1021/ol802529p CCC: $40.75
Published on Web 12/15/2008
2009 American Chemical Society

catalytic activation in the addition reactions of carbonyl
compounds with normal O-, N-, S-, P-, or C-nucleophiles.7,8
Prompted by these results, we decided to evaluate the
feasibility of iron-catalyzed 1,2-addition reactions of alde-
hydes with nucleophilic organoboronic acids. To our delight,
we found that FeCl3 combined with 2-(di-tert-butylphosphi-
no)biphenyl was an efficient catalytic system for the 1,2-
addition reactions of electron-deficient aryl aldehydes with
arylboronic acids. Here, we wish to report our preliminary
results on the first example of iron-catalyzed 1,2-addition
of aldehydes with organoboronic acids.
Table 1. Iron-Catalyzed 1,2-Addition of 4-Nitrobenzaldehyde
(1a) with Phenylboronic Acid (2a)a
The effect of several ligands was initially tested in the
1,2-addition reaction of 4-nitrobenzaldehyde (1a) with
phenylboronic acid (2a) using FeCl3 as the catalyst (Table
1). Without ligands, treatment of substrate 1a with boronic
acid 2a, FeCl3, and K2CO3 afforded a trace amount of the
target product 3 determined by GC-MS analysis (entry
1). The yield of 3 was enhanced sharply to 97% in the
presence of 2-(di-tert-butylphosphino)biphenyl (L1) (entry
2). However, other ligands L2-L8 were less active
(entries 3-9). Subsequently, both bases and solvents were
evaluated (entries 10-14). We found that another base,
CsF, decreased the yield (entry 10), and other solvents,
including dioxane, benzene, or MeCN, were unsuitable
media for the reaction (entries 12-14). It is noted that
no reaction takes place without either bases or iron
catalysts (entries 11 and 15). The controlled experiments
showed that other Fe catalysts, such as FeF3, Fe(SO4)3,
Fe(NO3)3, and FeCl2, were less efficient than FeCl3 (entries
16-19). Although the yield was reduced to some extent,
both FeF3 and Fe(SO4)3 are still highly active. However,
Fe(NO3)3 and FeCl2 have no effect on the reaction. Finally,
amounts of FeCl3, ligand, and phenylboronic acid were
examined (entries 20-22). We were happy to find that a
good yield of 3 was still achieved even at a loading of 5
mol % FeCl3 (entry 20), and the increased loading of L1
did not affect the yield (entry 21). However, the yield
was reduced to 60% in the presence of 1.2 equiv of
phenylboronic acid (2a) (entry 22). A good yield was still
obtained using a Rh(PPh3)3Cl/L1 catalytic system (entry
23).
entry
[Fe]
FeCl3
ligand
solvent
base
yield (%)b
1
2
3
4
5
6
7
8
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
dioxane
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
CsF
trace
97
trace
trace
8
trace
trace
trace
trace
85
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
L1
L2
L3
L4
L5
L6
L7
L8
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
9
10
11
12
13
14
15
16
17
18
19
20c
21d
22e
23f
0
K2CO3
trace
5
trace
0
92
82
trace
trace
91
98
60
benzene K2CO3
MeCN
THF
THF
THF
THF
THF
THF
THF
THF
THF
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
FeF3
Fe(SO4)3
Fe(NO3)3
FeCl2
FeCl3
FeCl3
FeCl3
Rh(PPh3)3Cl
80
a Reaction conditions: 1 (0.25 mmol), 2a (2 equiv), FeCl3 (10 mol
%), ligand (10 mol %), and base (2 equiv) in solvent (2 mL) at 90 °C
for 22-24 h. b Isolated yield. c FeCl3 (5 mol %). d L1 (20 mol %) was
added. e 1.2 equiv of PhB(OH)2 2a was added. f Rh(PPh3)3Cl (2 mol%)
instead of FeCl3.
As shown in Table 2, both aryl aldehydes and arylbo-
ronic acids were surveyed to investigate the scope of the
reaction under the standard reaction conditions. The results
showed that an electronic effect of the functional groups
both in aryl aldehydes and arylboronic acids plays an
important role in the reaction. We found that only electron-
deficient aryl aldehydes could undergo the reaction with
either electron-rich or electron-neutral arylboronic acids
in moderate to excellent yields, but with electron-deficient
arylboronic acids the reaction gave low yields. Initially,
a variety of arylboronic acids were examined by reacting
with 4-nitrobenzaldehyde (1a), FeCl3, and L1 (entries
1-7). To our delight, a number of functional groups,
including methyl, methoxy, fluoro, chloro, and acetyl
groups, were tolerated well. Boronic acids 2a and 2c
bearing a p- or o-methyl group, for instance, were reacted
with substrate 1a, FeCl3, and L1 smoothly in excellent
yields (entries 1 and 3), and boronic acids 2c having a
m-methyl group gave a moderate yield (entry 2). The
reaction conditions are also compatible with ether, halide,
and acetyl groups that could be readily substituted and
decomposed under harsh conditions (entries 4-7). While
boronic acid 2f containing a p-fluoro group, for example,
was treated with substrate 1a, FeCl3, and L1 successfully
in quantitative yield (entry 5), two other electro-deficient
(7) (a) Bolm, C.; Legros, J.; Le Paih, J.; Zani, L. Chem. ReV. 2004,
104, 6217. (b) Fu¨rstner, A.; Martin, R. Chem. Lett. 2005, 34, 624. (c) Iron
Catalysis in Organic Chemistry: Reactions and Applications; Plietker, B.,
Ed.; Wiley-VCH: Weinheim, 2008. (d) Correa, A.; Manchen˜o, O. G.; Bolm,
C. Chem. Soc. ReV. 2008, 37, 1108. (e) Sherry, B. D.; Fu¨rstner, A. Acc.
Chem. Res. 2008, 41, 1500
.
(8) For detailed iron-catalyzed carbonyl compounds with C-nucleophiles,
see: Christoffers, J.; Frey, H.; Rosiak, A. In Iron Catalysis in Organic
Chemistry: Reactions and Applications; Plietker, B. Ed.; Wiley-VCH:
Weinheim, 2008; pp 217-243.
454
Org. Lett., Vol. 11, No. 2, 2009

Table 2. FeCl3-Catalyzed 1,2-Addition of Aryl Aldehyde (1)
with Arylboronic Acid (2) in the Presence of
2-(Di-tert-butylphosphino)biphenyl (L1)a
Scheme 1. Possible Mechanism
arylboronic acids 2g and 2h provided low yields under
the same conditions (entries 6 and 7). Next, a series of
the other aryl aldehydes were investigated, and the results
indicated that only electron-deficient aryl aldehydes were
suitable substrates for the reaction (entries 8-22). Aryl
aldehyde 1d bearing two trifluoromethyl groups, for
instance, underwent the 1,2-addition reaction with aryl-
boronic acids 2a, 2b, 2e, 2i, or 2j, FeCl3, and L1 smoothly
in excellent yields (entries 14-18). However, the reaction
between substrate 1d and the electron-deficient arylboronic
acid 2k afforded the target product 22 in a low yield (entry
19). Unfortunately, the reactions of benzaldehyde (1f),
4-methoxybenzaldehyde (1g), or chalcone (1h) with
phenylboronic acid (2a) were unsuccessful under the
standard conditions (entries 21-23).
The electronic effect presented in the above results
suggested that the present reaction underwent a nucleo-
philic attack process. Based on reported papers,1-7
a
working mechanism as outlined in Scheme 1 is proposed.
First, complexation of FeCl3 with ligand affords FeCl3Ln.
Subsequently, coordination of FeCl3Ln with aldehyde 1
readily occurs to afford intermediate A,7c followed by
transmetalation of intermediate A with boronic acid 2 to
generate an Ar′-Fe intermediate B. Insertion of CdO into
the Fe-C bond in intermediate B then takes place to give
intermediate C. Intermediate C undergoes hydrolysis with
water to yield the target product and regenerate the active
Fe catalyst.
In summary, we describe here the first example of 1,2-
addition of aryl aldehydes with arylboronic acids using a
FeCl3 and 2-(di-tert-butylphosphino)biphenyl catalytic sys-
tem. In the presence of FeCl3 and 2-(di-tert-butylphosphi-
no)biphenyl, a variety of electron-deficient aryl aldehydes
were found to be suitable substrates for the reaction with
arylboronic acids in moderate to excellent yields. It is
noteworthy that the electronic effect of the functional groups
both in arylaldehydes and arylboronic acids is found to play
a crucial role in the present reaction. Work to probe the
detailed mechanism and apply the Fe catalytic system in
organic synthesis is currently underway.
a Reaction conditions: 1 (0.25 mmol), 2 (2 equiv), FeCl3 (10 mol %),
L1 (10 mol %), and K2CO3 (2 equiv) in THF (2 mL) at 90 °C for 22 h.
b Isolated yield. c For 37 h.
Org. Lett., Vol. 11, No. 2, 2009
455

Acknowledgment. We thank the New Century Excellent
Talents in University (no. NCET-06-0711), National
Natural Science Foundation of China (nos. 20572020
and 20872112), and Zhejiang Provincial Natural
Science Foundation of China (no. Y407116) for financial
support.
Supporting Information Available: Analytical data and
spectra (1H and 13C NMR) for all the products, and typical
procedure for FeCl3-catalyzed addition of aryl aldehydes with
arylboronic acids. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL802529P
456
Org. Lett., Vol. 11, No. 2, 2009