A mild, one-pot synthesis of arylamines via palladium-catalyzed addition of aryl aldehydes with amines and arylboronic acids in water

Article abstract of DOI:10.1002/adsc.200800680

A mild, one-pot synthesis of diarylmethylamines via the palladium-catalyzed addition of aryl aldehydes with amines and arylboronic acids is reported. Best results were obtained in neat water with ammonium chloride as additive, affording diarylmethylamine

Full text of DOI:10.1002/adsc.200800680

FULL PAPERS
DOI: 10.1002/adsc.200800680
A Mild, One-Pot Synthesis of Arylamines via Palladium-
Catalyzed Addition of Aryl Aldehydes with Amines and
Arylboronic Acids in Water
Ajuan Yu,a Yangjie Wu,a,* Baoli Cheng,a Kun Wei,a and Jingya Lia
a
Chemistry Department, Henan Key Laboratory of Chemical Biology and Organic Chemistry, Key Laboratory of Applied
Chemistry of Henan Universities, Zhengzhou University, Zhengzhou 450052, Peopleꢀs Republic of China
Fax : (+86)-371-6797-9408; e-mail: wyj@zzu.edu.cn
Received: November 5, 2008; Revised: February 25, 2009; Published online: March 17, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200800680.
Abstract: A mild, one-pot synthesis of diarylmethyl- ammonium chloride as additive, affording diarylme-
amines via the palladium-catalyzed addition of aryl thylamine derivatives as the main products.
aldehydes with amines and arylboronic acids is re-
ported. Best results were obtained in neat water with Keywords: aldehydes; amines; arylboronic acids; cat-
alysis; cyclopalladated complexes
Introduction
nificant practical improvement over existing condi-
tions and expanding the scope of the substrates for
The addition of carbon nucleophiles to carbon-hetero- such transformations. Herein, we report the results of
ACHTUNGTRENNUNGatom multiple bonds such as those of imines is a com- our studies regarding the cyclopalladated complexes-
monly employed strategy in organic synthesis for the catalyzed reaction of aryl aldehydes with arylamines
formation of carbon-carbon bonds,[1] as the resulting and arylboronic acids in a single-vessel, three-compo-
product amines are important precursors for the syn- nent catalytic procedure that obviates the need to use
thesis of many pharmacologically active compounds.[2] imines as starting substrates separately synthesized by
However, due to the poor electrophilicity of the azo- the reaction of aldehydes with amines (Scheme 1).
methine carbon, this addition is often plagued by
competitive enolization, deprotonation or coupling re-
actions.[3] Many efforts have been made in the rhodi-
um-catalyzed addition of organometallic reagents to
imines.[4] Despite many reports, only recently have
several examples of Pd-complex catalysts been devel-
oped. Boronic acids have been shown to undergo ad-
dition to imines, as demonstrated by Luꢀs cationic pal-
Scheme 1.
ladium complex-catalyzed addition of arylboronic
acids to N-tert-butanesulfinyl iminoacetates for the Results and Discussion
synthesis of arylglycine derivatives,[5] and Huꢀs phos-
phinite- and phosphite-based type I palladacycle-cata- Initial experiments were carried out by the reaction
lyzed additions of arylboronic acids with aldehydes, of benzaldehyde, aniline and phenylboronic acid in
a,b-unsaturated ketones, a-keto esters and ald- the presence of cat. 2 (5 mol%; Scheme 2) in water.
ACHTUNGTRENNUNG
imines.[6] Very recently, Wu[7] described the Pd-cata- Very gratifyingly, the addition product, N-phenyl-1,1-
lyzed addition of arylboronic acids to N-tosyl-aryl- diphenylmethylamine 4aaa, was smoothly obtained in
imines by employing aminophosphine ligands. Al- 75% yield (Table 1, entry 1). In addition, when ald-
though a variety of methods has been developed, the imines derived from benzaldehyde and aniline with
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
reaction is not general, and the imine substrates phenylboronic acid were used as substrates, 4aaa was
which can be applied in this addition are limited. Our also isolated in 75% yield (Table 1, entry 2). Unex-
interest focused on the possibility of developing a sig- pectedly, when diphenylmethanol and aniline were
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Ajuan Yu et al.
FULL PAPERS
tries 13 and 14). It is worth noting that PdACHTUNGTRENNUNG(OAc)2
combined with bipyridine could be used for this trans-
formation (Table 1, entry 15), but the yield is lower.
So cat. 2 emerged as the best choice of catalyst pre-
cursors.
A variety of acids (e.g., acetic acid, benzoic acid,
phenol, ammonium chloride and NaH2PO4·2H2O)
were investigated, and NH4Cl was found to give the
best yields (Table 2, entries 1–5). A series of bases
was also examined, and the results were not satisfac-
tory (Table 2, entries 6–10). The addition of NH4Cl to
the reaction mixture is not essential for the transfor-
mation to proceed, but the reproducibility in the
chemical yield of 4aaa was higher in the presence of
ammonium chloride than in its absence (Table 2,
entry 11). The weak acid, NH4Cl, may be the effective
protonolysis reagent for the palladium amide species
in water.[8] The influence of the loading of cat. 2 could
be reduced to 3.0 mol% with no change in the yield
(Table 2, entries 12–14). When reducing the reaction
temperature, the yield dropped sharply (Table 2,
entry 15). In addition, the yields of amine decreased
with decreasing amount of phenylboronic acid
(Table 2, entry 16). The excess amounts of phenylbor-
onic acid were consumed due to the homo-coupling
reaction to form the biphenyl. Thus, PhCHO
Scheme 2.
Table 1. Optimization of reaction conditions for the addition
of benzaldehyde and aniline to phenylboronic acid.[a]
Entry Pd catalyst Solvent
Yield[b] [%]
1
cat. 2
cat. 2
cat. 2
cat. 2
cat. 2
cat. 2
cat. 2
cat. 2
cat. 2
cat. 2
cat. 2
cat. 1
cat. 1
cat. 3
H2O
H2O
H2O
THF
CH3NO2
HOAc
dioxane
i-PrOH
DMF
75
75
trace
16
NR
NR
NR
trace
trace
trace
2[c]
3[d]
4
5
6
7
8
9
10
11
12
13[e]
14
15[f]
DMSO
CH3NO2/dioxane (8:1, v/v) trace
H2O
H2O
H2O
NR
22
8
Pd
(OAc)2 H2O
54
(0.5 mmol),
PhNH2
(0.5 mmol),
PhB(OH)2
[a]
Reaction conditions: PhCHO 0.5 mmol, PhNH2
0.5 mmol, PhB(OH)2 1.5 mmol, PhOH 1.5 mmol, sodium
dodecyl sulfonate 0.5 mmol, 5.0 mol% of catalyst in
2.0 mL of solvent at 1008C for 12 h.
(1.5 mmol), cat. 2 (3.0 mol%), NH4Cl (1.5 mmol) and
Table 2. Screening of the reaction conditions.[a]
[b]
[c]
Isolated yield.
Entry Catalyst
loading [Pd
Additive
Temperature Yield[b]
N-Benzylideneaniline and phenylboronic acid (1:1) were
used as the substrates. N-Benzylideneaniline was derived
from benzaldehyde and aniline in water.
Diphenylmethanol and aniline (1:1) were used as the
substrates. Diphenylmethanol was derived from benzal-
dehyde and phenylboronic acid under these reaction con-
ditions.
[8C]
[%]
mol%]
[d]
1
2
3
4
5
6
7
8
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
4.0
3.0
2.5
3.0
CH3COOH
PhCOOH
PhOH
NH4Cl
NaH2PO4·2H2O 100
KF·2H2O
Na2CO3
K2CO3
K3PO4·7H2O
t-BuONa
–
100
100
100
100
49
5
75
79
42
69
NR
14
15
NR
58
79
79
65
36
56
[e]
[f]
Cat. 1:bpy (1:2) was used as the catalyst.
PdACHTUNGTRENNUNG(OAc)2:bpy (1:2) was used as the catalyst.
100
100
100
100
100
100
100
100
100
80
subjected to our reaction conditions, only a trace
amount of 4aaa resulted (Table 1, entry 3). The rigor-
ous exclusion of air/moisture was not required in
these transformations. The results of this initial sol-
vent screening are summarized in Table 1.
After screening the solvents, we found that the neat
water appeared to be the best among the common
solvents. The aldimine which was formed from ben-
zaldehyde and aniline was the main product, which
became substantial when the reaction was carried out
in solvents other than water (Table 1, entries 4–11).
When the cat. 1was used in this reaction, the reaction
mixtures became dark quickly and no reaction was
observed (Table 1, entry 12). However, when cat. 1
with bipyridine or cat. 3 was subjected to the reaction,
low yields of the products were obtained (Table 1, en-
9
10
11
12
13[c]
14
15
NH4Cl
NH4Cl
NH4Cl
NH4Cl
16[d] 3.0
NH4Cl
100
[a]
Reaction conditions: PhCHO 0.5 mmol, PhNH2
0.5 mmol, PhB(OH)2 1.5 mmol, additive 1.5 mmol,
sodium dodecyl sulfonate 0.5 mmol, cat. 2 in 2.0 mL of
water for 12 h.
[b]
[c]
Isolated yield.
The expected product 4aaa was obtained along with bi-
phenyl in 8% yield.
The amount of PhB(OH)2 was 1.0 mmol.
[d]
768
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A Mild, One-Pot Synthesis of Arylamines via Palladium-Catalyzed Addition
FULL PAPERS
Table 3. Pd-catalyzed addition of aryl aldehydes with aniline
Table 4. Pd-catalyzed addition of benzaldehyde with aryl-
ACHTUNGTRENNUNG
amines and phenylboronic acid.[a]
and phenylboronic acid.[a]
Entry
Ar1
Ar2
Ar3
Product Yield[b]
[%]
Entry Ar1 Ar2
Ar3 Product Yield[b] [%]
1
2
3
4
5
6
7
1a 2b 3-MeC6H4
1a 2c 4-MeC6H4
1a 2d 4-MeOC6H4
1a 2e 3-BrC6H4
1a 2f 4-ClC6H4
1a 2g 3-O2NC6H4
3a 4aba
3a 4aca
3a 4ada
3a 4aea
3a 4afa
3a 4aga
50
75
79
77
81
58
0
1
2
3
4
5
6
7
8
9
1a Ph
2a Ph 3a Ph 4aaa
79
68
64
50
61
62
74
96
46
37
1b 2-ClC6H4
1c 2-BrC6H4
1d 4-FC6H4
1e 4-ClC6H4
1f 4-BrC6H4
1g 2-O2NC6H4 2a
1h 3-O2NC6H4 2a
1i 2-MeOC6H4 2a
1j 4-MeOC6H4 2a
2a
2a
2a
2a
2a
3a
3a
3a
3a
3a
3a
3a
3a
3a
4baa
4caa
4daa
4eaa
4faa
4gaa
4haa
4iaa
1a 2h 4-MeC6H4SO2 3a 4aha
[a]
Reaction conditions: benzaldehyde 0.5 mmol, arylamine
0.5 mmol, PhB(OH)2 1.5 mmol, NH4Cl 1.5 mmol, sodium
dodecyl sulfonate 0.5 mmol, 3.0 mol% of cat. 2 in 2.0 mL
of water for 12 h.
10
4jaa
[a]
[b]
Reaction conditions: aryl aldehyde 0.5 mmol, PhNH2
0.5 mmol, PhB(OH)2 1.5 mmol, NH4Cl 1.5 mmol, sodium
dodecyl sulfonate 0.5 mmol, 3.0 mol% of cat. 2 in 2.0 mL
of water for 12 h.
Isolated yield.
Table 5. Pd-catalyzed addition of benzaldehyde with aryl-
AHCTUNGTRENNUNG
amines and arylboronic acids.[a]
[b]
Isolated yield.
Entry Ar1 Ar2
Ar3
Product Yield[b] [%]
sodium dodecyl sulfonate (0.5 mmol) in water
(2.0 mL) at 1008C for 12 h were chosen as the opti-
mized conditions (Table 2, entry 13).
With the optimized conditions in hand, the reac-
tions of different aryl aldehydes and arylamines with
various arylboronic acids were examined to explore
the scope of the reaction. First, we examined the
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
2f
2f
2a
2f
2f
2f
2f
2f
2f
2a
3b 2-MeC6H4
3c 3-MeOC6H4 4afc
3d 4-MeC6H4 4aad
3e 4-MeOC6H4 4afe
3f 4-Me3CC6H4 4aff
3g 4-F3COC6H4 4afg
3h 3-ClC6H4
3i 4-BrC6H4
3j 3-thienyl
3k 1-naphthyl
4afb
31
74
94
89
95
66
45
55
47
52
4afh
4afi
benzACHTUNGTRENNUNGaldehyde derivatives with electron-withdrawing
4afj
4aak
substituents in this catalytic system. To our delight,
the reaction proceeded smoothly in the presence of a
variety of functional groups including fluoro, chloro,
bromo and nitro groups (Table 3, entries 1–8). How-
ever, the reaction yields were sensitive to electronic
effects on the benzaldehyde, and electron-donating
groups at the ortho or para position of aryl aldehydes
gave much lower yields (Table 3, entries 9 and 10).
The reaction was not significantly affected by the
electronic effect of the amines because both electron-
10
[a]
[b]
Reaction conditions: benzaldehyde 0.5 mmol, arylamine
0.5 mmol, arylboronic acid 1.5 mmol, NH4Cl 1.5 mmol,
sodium dodecyl sulfonate 0.5 mmol, 3.0 mol% of cat. 2 in
2.0 mL of water for 12 h.
Isolated yield.
rich and electron-deficient arylamines could give simi- were obtained (Table 5, entries 7 and 8). 3-Thienyl-
larly moderate or good results (Table 4, entries 1–6). boronic acid 3j still worked smoothly in this proce-
No reaction was observed when a p-toluenesulfon- dure, although the yield of 4afj was decreased to
ACHTUNGTRENNUNGamide was subjected to our optimized reaction condi- 47%, which may be ascribed to the fact that hetero-
tions (Table 4, entry 7), which is in sharp contrast to
ACHTUNGTRENNUNG
the existing reports.[4–7]
A contrasting electronic effect was observed when hindrance in arylboronic acid 3k had also little nega-
substituted arylboronic acids were used. Arylboronic tive effect on the reaction, and 4aak was obtained in
acids with electron-donating substituents, which are 52% yield (Table 5, entry 10).
more nucleophilic, and hence transmetalate more
The possible mechanism for the addition of aryl al-
quickly than electron-neutral analogues, are not dehydes with amines and arylboronic acids was pro-
prone to homocoupling and protodeboronation side posed as shown in Scheme 3. First, the Pd(II) complex
reactions,[9] and gave excellent yields of the addition was pre-activated to form a. Transmetalation will gen-
products (Table 5, entries 2–6). However, the sterical- erate the arylpalladium species b. Because of the
ly hindered ortho-substitued arylboronic acid was vacant coordination site on the palladium, the ald-
proved to be problematic for this catalyst system
ACHTUNGTRENiNGNU mine could coordinate with it very easily to generate
(Table 5, entry 1). For arylboronic acids with electron- intermediate c. It was followed by insertion of the C=
withdrawing groups, lower yields of addition products N bond into the palladium-carbon bond to produce d.
Adv. Synth. Catal. 2009, 351, 767 – 771
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Ajuan Yu et al.
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Scheme 3.
cubated in a oil bath at 1008C for 12 h. After cooling, the
reaction mixture was diluted with 10 mL brine. The aqueous
layer was extracted with dichloromethane and dried over
Na2SO4. After evaporation of the solvent, the residue was
subjected to TLC (petroleum-dichloromethane) to give the
product 4aaa; yield: 79%.
The protonolysis of d gave e and regenerated the pal-
ladium catalyst a.
Conclusions
In summary, a highly practical method for the synthe-
sis of a-branched amines has been developed. Imine
synthesis and arylboronic acids addition can be ac-
complished in one pot. The procedure is very simple,
cheap and offers other distinct advantages over the
existing methods. Further studies on probing the de-
tailed mechanism and the application to asymmetric
synthesis are currently underway.
Analyses
Melting points were measured on a WC-1 microscopic appa-
ratus and are uncorrected. IR spectra were recorded on a
Bruker VECTOR22 spectrophotometer. 1H NMR, and
13C NMR spectra were recorded on a Bruker DPX-400 spec-
trometer in CDCl3 with TMS as an internal standard. Mass
spectra were measured on an LC-MSD-Trap-XCT instru-
ment. High-resolution mass spectra were measured on a
Waters Q-T of Micro spectrometer.
Experimental Section
Materials
Acknowledgements
All the chemicals are commercially available. Aniline and
organic solvents have been purified prior to use. The cata-
lysts cat. 1 to cat. 3 were prepared according to our previous
work.[11]
We thank the National Science Foundation of China (No.
20472074, 20772114), the Innovation Fund for Outstanding
Scholar of Henan Province (No. 0621001100) and Fund of
Zhengzhou University (No. 000000533011) for financial sup-
port. We thank Dr. Weiguo Zhu, Mr. Jianxun Kang for their
excellent analytical support.
Typical Procedure for the Addition of Aryl
Aldehydes with Amines and Arylboronic Acids
A
reaction vessel was charged with benzaldehyde
(0.5 mmol, 53 mg), aniline (0.5 mmol, 47 mg), phenylboronic References
acid (1.5 mmol, 183 mg), NH4Cl (1.5 mmol, 81 mg), sodium
dodecyl sulfonate (0.5 mmol, 136 mg), and Pd cat.
(0.015 mmol, 9.2 mg) in 2.0 mL of water and the mixture in-
2
[1] a) M. Beller, C. Bolm, Transition Metals for Organic
Synthesis: Building Blocks and Fine Chemicals, Wiley-
770
asc.wiley-vch.de
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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A Mild, One-Pot Synthesis of Arylamines via Palladium-Catalyzed Addition
FULL PAPERS
VCH, New York, 1998; b) K. Fagnou, M. Lautens,
Chem. Rev. 2003, 103, 169.
Chem. Soc. 2005, 127, 1092; k) P. B. C. Jagt, P. Y. Toul-
lec, D. Geerdink, J. G. Devries, B. L. Feringa, A. J. Min-
naard, Angew. Chem. 2006, 118, 2855; Angew. Chem.
Int. Ed. 2006, 45, 2789; l) H. F. Duan, Y. X. Jia, L. X.
Wang, Q. L. Zhou, Org. Lett. 2006, 8, 2567; m) M. A.
Beenen, D. J. Weix, J. A. Ellman, J. Am. Chem. Soc.
2006, 128, 6304; n) K. Ueura, S. Miyamura, T. Satoh,
M. Miura, J. Organomet. Chem. 2006, 691, 2821;
o) Z. Q. Wang, C. G. Feng, M. H. Xu, G. Q. Lin, J. Am.
Chem. Soc. 2007, 129, 5336.
[2] a) W. M. Welch, A. R. Kraska, R. Sarges, K. B. Coe, J.
Med. Chem. 1984, 27, 1508; b) P. C. Astles, T. J. Brown,
F. Halley, C. M. Handscombe, N. V. Harris, T. N. Majid,
C. Mccarthy, I. M. Mclay, A. Morley, B. Porter, A. G.
Roach, C. Sargent, C. Smith, R. J. A. Walsh, J. Med.
Chem. 2000, 43, 900.
[3] R. Bloch, Chem. Rev. 1998, 98, 1407.
[4] For reactions catalyzed by rhodium species, see: a) M.
Ueda, N. Miyaura, J. Organomet. Chem. 2000, 595, 31;
b) J. R. Porter, J. F. Traverse, A. H. Hoveyda, M. L.
Snapper, J. Am. Chem. Soc. 2001, 123, 10409; c) N.
Hermanns, S. Dahmen, C. Bolm, S. Brase, Angew.
Chem. 2002, 114, 3844; Angew. Chem. Int. Ed. 2002, 41,
3692; d) A. A. Boezio, J. Pytkowicz, A. Cote, A. B.
Charette, J. Am. Chem. Soc. 2003, 125, 14260; e) N. To-
kunaga, Y. Otomaru, K. Okamoto, K. Ueyama, R.
Shintani, T. Hayashi, J. Am. Chem. Soc. 2004, 126,
13584; f) M. Kuriyama, T. Soeta, X. Hao, Q. Chen, K.
Tomioka, J. Am. Chem. Soc. 2004, 126, 8128; g) T. Hay-
ashi, M. Kawai, N. Tokunaga, Angew. Chem. 2004, 116,
6251; Angew. Chem. Int. Ed. 2004, 43, 6125; h) Y. Bol-
shan, R. A. Batey, Org. Lett. 2005, 7, 1481; i) Y. Oto-
maru, N. Tokunaga, R. Shintani, T. Hayashi, Org. Lett.
2005, 7, 307; j) D. J. Weix, Y. Shi, J. A. Ellman, J. Am.
[5] H. X Dai, X. Y. Lu, Org. Lett. 2007, 9, 3077.
[6] P. He, Y. Lu, Q. S. Hu, Tetrahedron Lett. 2007, 48, 5283.
[7] Q. Zhang, J. X. Chen, M. C. Liu, H. Y. Wu, J. Cheng,
C. M. Qin, W. K. Su, J. C. Ding, Synlett 2008, 6, 935.
[8] a) S. Miyamura, T. Satoh, M. Miura, J. Org. Chem.
2007, 72, 2255; b) K. Ueura, S. Miyamura, T. Satoh, M.
Miura, J. Organomet. Chem. 2006, 691, 2821.
[9] T. E. Barder, S. D. Walker, J. R. Martinelli, S. L. Buch-
wald, J. Am. Chem. Soc. 2005, 127, 4685.
[10] F. Menard, T. M. Chapman, C. Dockendorff, M. Laut-
ens, Org. Lett. 2006, 8, 4569.
[11] a) S. Q. Huo, Y. J. Wu, C. X. Du, Y. Zhu, H. Z. Yuan,
X. A. Mao, J. Organomet. Chem. 1994, 483, 139;
b) A. J. Yu, J. Y. Li, M. J. Cui, Y. J. Wu, Synlett 2007,
19, 3063; c) A. J. Yu, B. L. Cheng, Y. J. Wu, J. Y. Li, K.
Wei, Tetrahedron Lett. 2008, 49, 5405.
Adv. Synth. Catal. 2009, 351, 767 – 771
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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