Palladium-catalyzed addition of arylboronic acids to N-tosylarylimines

Article abstract of DOI:10.1055/s-2008-1042932

Pd-catalyzed addition of arylboronic acids to N-tosylarylimines was described by employing easily prepared, air-stable aminophosphine ligands, cheap inorganic base, and common organic solvents, providing diarylmethylamine derivatives through one-pot synth

Full text of DOI:10.1055/s-2008-1042932

LETTER
935
Palladium-Catalyzed Addition of Arylboronic Acids to N-Tosylarylimines
P
d-Catalyze
d
Add
i
ition of
a
A
rylboron
n
ic
A
cids to
N
g
-
Tosylarylimines Zhang,a Jiuxi Chen,a Miaochang Liu,a Huayue Wu,*a Jiang Cheng,*a Changming Qin,a Weike Su,a,b
Jinchang Dinga
a
College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou, 325027, P. R. of China
Fax +86(577)88368280; E-mail: huayuewu@wzu.edu.cn; E-mail: jiangcheng@wzu.edu.cn
Key Laboratory of Pharmaceutical Engineering, College of Pharmaceutical Sciences, Zhejiang University of Technology, Zhejiang,
Hangzhou, 310014, P. R. of China
b
Received 4 December 2007
polarity of C–Pd bond is poorer than C–Rh bond, so C–Pd
Abstract: Pd-catalyzed addition of arylboronic acids to N-tosyl-
bond is harder to insert into C=N bond. Thus, such trans-
arylimines was described by employing easily prepared, air-stable
formations catalyzed by palladium were scarcely report-
ed. Lately, Lu reported cation palladium(II)-catalyzed
aminophosphine ligands, cheap inorganic base, and common organ-
ic solvents, providing diarylmethylamine derivatives through one-
pot synthesis in moderate to good yields. The efficiency of this re- addition of arylboronic acids to N-tert-butanesulfinyl imi-
no esters for the synthesis of arylglycine derivatives.11 Hu
action was demonstrated by the compatibility with nitro, trifluoro-
methyl, fluoro, chloro, and methoxy groups. Moreover, rigorous
and coworkers have reported palladacycles were highly
exclusion of air/moisture is not required in these transformations.
active catalysts for the addition reactions of arylboronic
Key words: N-tosylarylimines, arylboronic acids, palladium-cata-
acids to aldehydes, a,b-unsaturated ketones, ketoesters,
and aldimines.12 Among the conditions described above,
lyzed, aminophosphine ligands, diarylmethylamine derivatives
examples of palladium-catalyzed tuned by tertiary phos-
phine are scarce or have not been reported. The electron
In the past few years, great strides have been made in the
development of the methods of insertion unsaturated car-
bon–heteroatom multiple bonds (C=O,1 C=N,2 C≡N3) into
carbon–metal bonds. The addition of arylmetallic re-
agents to imines catalyzed by transition metal has drawn
considerable attentions.4 The addition products are impor-
tant precursors for the synthesis of many pharmacologi-
cally active compounds. For instance, the 1,1-diarylalkyl
structural segment is found in antimuscarinics,5 antide-
pressants,6 and endothelin antagonists.7 Common strate-
gies involve the catalytic asymmetric additions of
organozinc reagents to N-sulfonylimines, N-phosphinoyl-
imines, N-formylimines, and N-arylimines.8 However,
these protocols suffer from several limitations, such as the
narrow substrate scopes, the use of unusual ligands, the
inherent air- and water-sensitivity, and the tedious separa-
tion of the toxicity-containing byproducts. The develop-
ment of practical synthetic methods for the preparation of
the multifunctional diarylmethylamines and their deriva-
tives is highly desirable. The use of organoboronic re-
agents has been winning high prestige in the metal-
catalyzed C–C bond formation as a result of their relative
stability toward air and moisture, good functional group
tolerance, commercial availability, and low toxicity as
well as ease of synthesis.9 Recently, many efforts have
been made in the rhodium-catalyzed addition of orga-
noboronic reagents to imines.10 Very recently, Lin report-
ed C2-symmetrical tetrahydropentalenes as new chiral
diene ligands for highly enantioselective Rh-catalyzed
arylation of N-tosylarylimines with arylboronic acids.10a
Since Pd atom is more electronegative than Rh atom, the
density and the hindrance of the P atom on the aminophos-
phine ligand may be tuned facilely, which may have dra-
matic effect on the reactivity. Furthermore, the chiral
groups may be introduced into the phosphine ligands for
asymmetric addition of arylboronic acids to C=N. Thus, it
is of great importance to develop the tertiary phosphine-
mediated transformation. Herein, we describe an efficient
palladium-catalyzed addition of arylboronic acids to N-
tosylarylimines in the presence of i-Pr2NPPh2, providing
diarylmethylamine derivatives in moderate to good
yields.
The electron-withdrawing tosyl group on the nitrogen
atom may enhance the activity of C=N in such transfor-
mations. Thus we initially chose the addition of phenylbo-
ronic acid to N-tosylphenylimine as the model reaction by
employing PdCl2 as the palladium source, Na2CO3 as the
base, and anhydrous dioxane as the solvent; 4 Å molecular
sieve (MS) were added to inhibit the decomposition of N-
tosylarylimines in the catalytic system. Since ligands al-
ways play important roles in transition-metal-catalyzed
chemistry, we first turned our attentions to the screening
of ligands (Table 1). In our catalytic system, bidentate
phosphine ligands such as dppp, dppe, dppb, (S)-binap,
and dppf were much less effective, monodentate phos-
phine ligands L6–L14 had no catalytic activity with the
exception of P(1-naphthyl)3, which could promote the
arylation of aldehydes to furnish carbinol derivatives in
good to excellent yields,13 affording the desired product in
only 26% yield. In our previous work, the aminophos-
phine ligands were highly efficient ligands in Suzuki–
Miyaura cross-coupling reaction, as well as in copper and
amine-free Sonogashira reaction.14 Accordingly, a series
of aminophosphine ligands were tested in the model reac-
tion. To our delight, the ligand L15 provided the desired
SYNLETT 2008, No. 6, pp 0935–0939
x
x.
x
x.
2
0
0
8
Advanced online publication: 11.03.2008
DOI: 10.1055/s-2008-1042932; Art ID: W20807ST
© Georg Thieme Verlag Stuttgart · New York

936
Q. Zhang et al.
LETTER
Table 1 Ligand Screeninga
Table 2 Effects of Pd Sources, Bases, Solvents, and Ligands on the
Pd-Catalyzed Addition of Phenylboronic Acid to N-Tosylphe-
nyliminea
Ts
Ts
5 mol% PdCl2, 5 mol% L
NH
N
PhB(OH)2
+
Ts
Na2CO3, 4 Å MS, dioxane
Ts
Ph
Ph
Ph
Pd source, i-Pr2NPPh2
base, 4 Å MS, dioxane
NH
N
PhB(OH)2
+
Ligand
L1
Yield (%)
<5
Ph
Ph
Ph
dppe
Entry Pd source
Base
Solvent
L/Pd Yield
ratio (%)
L2
dppp
<5
1
2
PdCl2
Li2CO3
Na2CO3
Rb2CO3
Cs2CO3
DABCO
NaOH
Et3N
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
DMF
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
0.5
23
60
68
<5
<5
<5
<5
<5
<5
<5
10
61
49
35
23
38
46
41
65
83
83
71
L3
dppb
<5
PdCl2
L4
(S)-binap
dppf
<5
3
PdCl2
L5
<5
4
PdCl2
L6
Ph3P
<5
5
PdCl2
L7
P(2-furyl)3
P(2-tolyl)3
P(2-thienyl)3
P(4-tolyl)3
P(1-naphthyl)3
<5
6
PdCl2
L8
<5
7
PdCl2
L9
<5
8
PdCl2
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
L10
L11
<5
9
PdCl2
27
10
11
12
13
14
15
16
17
18
19
20
21
22
PdCl2
DMAC
DME
L12
L13
L14
L15
L16
P(4-FC6H4)3
<5
<5
<5
65
<5
PdCl2
P(4-MeOC6H4)3
P(4-ClC6H4)3
i-Pr2NPPh2
PdCl2
THF
PdCl2
toluene
MeCN
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
PdCl2
i-Pr2NP(2-tolyl)2
Pd(OAc)2
Pd(PPh3)2
Pd2(dba)3
PdCl2(PPh3)2
L17
<5
NHPPh2
L18
L19
<5
<5
PdCl2(MeCN)2
PdCl2(PhCN)2
PdCl2(PhCN)2
PdCl2(PhCN)2
O
N
PPh2
NH
N
PPh2
a All the reactions were run with N-tosylphenylimine (130 mg, 0.5
mmol), phenylboronic acid (122 mg, 1.0 mmol), Na2CO3 (159 mg,
1.5 mmol), PdCl2 (4.4 mg, 5 mol%), 4 Å MS (100 mg), and i-
Pr2NPPh2 (7.2 mg, 5 mol%) in dioxane (3 mL) at 80 °C for 24 h under
N2 atmosphere and anhydrous solvent with isolated yields.
a All reactions were run with N-tosylphenylimine (130 mg, 0.5
mmol), phenylboronic acid (122 mg,1.0 mmol), base (1.5 mmol), Pd
source (5 mol%), 4 Å MS (100 mg), and i- Pr2NPPh2 (5 mol%) in an-
hydrous solvent (3 mL) at 80 °C for 24 h under N2 atmosphere with
isolated yield.
crucial to the success of the catalytic system. Dioxane was
tested to be the best among the common solvents such as
DMAC, DMF, DME, toluene, THF, and MeCN,
PdCl2(PhCN)2 exhibited the highest catalytic activity
among PdCl2, Pd(OAc)2, Pd2(dba)3, PdCl2(PPh3)2,
PdCl2(PhCN)2, PdCl2(MeCN)2, and Pd(PPh3)4. Increasing
the amount of L15 in the system had little influence on the
yield, but reducing the amount of L15 caused the yield to
decrease sharply from 83% to 71%, respectively.
product in 65% yield, while others were totally ineffec-
tive.
Next, further investigations into optimization of other re-
action conditions (Table 2), such as bases, solvents, and
palladium sources as well as the ratios of Pd/L15 were
conducted. Among the bases we employed, K2CO3 was
superior to some other bases such as Li2CO3, Na2CO3,
Rb2CO3, Cs2CO3, NaOH, and K3PO4·3H2O, and the prod-
uct was isolated in 68%. The choice of solvents was also
Synlett 2008, No. 6, 935–939 © Thieme Stuttgart · New York

LETTER
Pd-Catalyzed Addition of Arylboronic Acids to N-Tosylarylimines
937
Table 3 Pd-Catalyzed Addition of Arylboronic Acids to Electron-
Deficient N-Tosylarylimines and Electron-Neutral Analoguesa
Table 4 Pd-Catalyzed Addition of Arylboronic Acids to Electron-
Rich N-Tosylarylimines and Crowded Analogues17
Ts
Ts
Ts
Ts
NH
PdCl2(PhCN)2, i-Pr2NPPh2
K2CO3, 4 Å MS, dixoane
NH
PdCl2(PhCN)2, i-Pr2NPPh2
K2CO3, 4 Å MS, dixoane
Ar1B(OH)2
Ar1B(OH)2
N
+
N
+
Ar1
Ar2
Ar2
Ar1
Ar2
Ar2
Entry
1
Ar1
Ar2
Product
Yield (%)
83 (77)
Entry Ar1
Ar2-
Product
Yield (%)
70 (57)
Ph
1a
Ph
2a
3aa
1
1a
1a
1a
1a
1a
1a
1a
1a
2-furyl
2g
3ag
3ah
3ai
2
3
1a
1a
1a
1a
1a
4-FC6H4
2b
3ab
3ac
3ad
3ae
3af
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
85 (80)
77 (70)
69 (54)
75 (70)b
60 (55)c
76
2
4-EtC6H4
2h
71 (63)
75 (70)
65 (64)
50 (45)
70 (55)
80 (75)
62 (56)
43
4-F3CC6H4
2c
3
4-MeC6H4
2i
4
4-ClC6H4
2d
4
4-MeOC6H4
2j
3aj
5
4-BrC6H4
2e
5
3,4-(OCH2O)C6H3 3ak
2k
6
4-O2NC6H4
2f
6
2-ClC6H4
2l
3al
7
4-MeOC6H4
1b
2a
2a
2a
2a
2a
2a
2a
2a
7
1-naphthyl
2m
3am
3an
3ja
3ka
3hi
3gi
8
3-MeOC6H4
1c
60
8
2,5-(Me)2C6H3
2n
9
4-MeC6H4
1d
73
9
1-naphthyl
2a
2a
2i
1j
10
11
12
13
14
4-F3CC6H4
1e
66
10
11
12
2-MeC6H4
1k
63
3-F3CC6H4
1f
65
4-FC6H4
1h
70
4-ClC6H4
1g
70
4-ClC6H4
2i
80
1g
a All reactions were run with N-tosylarylimine (0.5 mmol), arylboron-
ic acid (1.0 mmol), K2CO3 (207 mg, 1.5 mmol), PdCl2(PhCN)2 (9.6
mg, 5 mol%), i-Pr2NPPh2 (7.2 mg, 5 mol%), and 4 Å MS (100 mg) in
anhydrous dioxane (3 mL) at 80 °C for 24 h under N2 atmosphere or
air atmosphere (in parentheses).
4-FC6H4
1h
73
3-thienyl
1i
31
a All reactions were run with N-tosylarylimine (0.5 mmol), arylboron-
ic acid (1.0 mmol), K2CO3 (207 mg 1.5 mmol), PdCl2(PhCN)2 (9.6
mg, 5 mol%), i-Pr2NPPh2 (7.2 mg 5 mol%), and 4 Å MS (100 mg) in
anhydrous dioxane (3 mL) at 80 °C for 24 h with the isolated yield un-
der N2 atmosphere or air atmosphere (in the parentheses).
worthy that the chloro group of both the substrates could
keep untouched for further functionization (Table 3, en-
tries 4, 12; Table 4, entries 6, 12), while the N-tosy-
larylimines with bromo group provided the further Suzuki
coupling product 3ae in 75% yield (Table 3, entry 5).
b N-[Biphenyl-4-yl(phenyl)methyl]-4-methylbenzenesulfonamide
was obtained using 3 equiv of phenylboronic acid.
c (4-Nitrophenyl)(phenyl)methanol was obtained in 21% (20%) yield. Arylboronic acids with electron-withdrawing substitu-
ents, which are less nucleophilic, hence transmetalate
more slowly than electron-neutral analogues, are prone to
With the optimized conditions in hand, the reactions of
homocoupling and protodeboronation side reactions.15
different arylboronic acids with various N-tosylarylimines
However, 1e, 1f, and 1g were good substrates in our reac-
were examined to explore the scopes of the reaction
tion system, and 3ea, 3fa, 3ga were isolated in 66%, 65%
(Table 3 and Table 4). First, we examined the N-tosyl-
and 70% yields, respectively (Table 3, entries 10–12).
phenylimine and N-tosylarylimines with electron-with-
Thien-3-yl boronic acid 1i still worked smoothly in this
drawing substituents in our catalytic system. To our
procedure, although the yield of 3ia was decreased to
delight, the reaction proceeded smoothly in the presence
31%, which may be ascribed to the fact that heteroatoms
of a variety of functional groups including nitro, trifluo-
in the heteroarylboronic acid could coordinate to transi-
romethyl, fluoro, chloro, and bromo groups. It was note-
tion metal (Table 3, entry 14).16
Synlett 2008, No. 6, 935–939 © Thieme Stuttgart · New York

938
Q. Zhang et al.
LETTER
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Acknowledgment
We thank the National Natural Science Foundation of China (No.
20676123 and 20504023), Natural Science Foundation of Zhejiang
Province (No. Y405015 and Y405113), and Technology Program
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Synlett 2008, No. 6, 935–939 © Thieme Stuttgart · New York

LETTER
Pd-Catalyzed Addition of Arylboronic Acids to N-Tosylarylimines
939
(17) General Procedures
with N2 under salted ice (ca. –10 °C). The mixture was
A Schlenk reaction tube was charged with PdCl2(PhCN)2
stirred for 0.5 h at r.t. Then, the mixture was heated at 80 °C
for the given time. After completion of the reaction, as
indicated by TLC, the reaction mixture was concentrated in
vacuo and the residue was purified by flash column
chromatography on a silica gel to give the product.
(9.6 mg, 0.05 mmol), i-Pr2NPPh2 (7.2 mg, 0.05 mmol),
arylboronic acids (1.0 mmol), N-tosylarylimines (0.5 mmol),
K2CO3 (207 mg, 1.5 mmol), 4 Å MS (100 mg), and
anhydrous dioxane (3 mL). The reaction tube was purged
Synlett 2008, No. 6, 935–939 © Thieme Stuttgart · New York