Regioselective and stereospecific cross-coupling of primary allylic amines with boronic acids and boronates through palladium-catalyzed C-N bond cleavage

Article abstract of DOI:10.1002/anie.201109171

The NH₂ group serves as an effective leaving group in the palladium-catalyzed regioselective and stereospecific title reaction (see scheme). The reaction works well with aryl- and alkenylboronic acids and aryl-, alkenyl-, allyl-, and benzylboronates, and complete transfer of chirality has been achieved when using α-chiral primary allylic amines as the allylic electrophiles. Copyright

Full text of DOI:10.1002/anie.201109171

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Angewandte
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DOI: 10.1002/anie.201109171
Cross-Coupling
Regioselective and Stereospecific Cross-Coupling of Primary Allylic
Amines with Boronic Acids and Boronates through Palladium-
ꢀ
Catalyzed C N Bond Cleavage**
Man-Bo Li, Yong Wang, and Shi-Kai Tian*
The cross-coupling of allylic electrophiles with boronic acids
boronates. Notably, complete transfer of chirality was ach-
ieved when using a-chiral primary allylic amines as the allylic
electrophiles.
Initially, we found that 5 mol% of [Pd(PPh3)4] could
catalyze the cross-coupling of primary allylic amine 1a with
boronic acid 2a in dioxane at 1108C to give alkene 4a in 70%
yield (Table 1, entry 1). This reaction proceeded with exclu-
sive a selectivity, and no E/Z isomerization was observed for
ꢀ
and boronates is extremely useful for the formation of C C
bonds and for the introduction of the allyl moieties to target
compounds.[1,2] Allylic halides,[3] esters,[4] carbonates,[4f,g,5]
phosphates,[6] and alcohols[7] have been identified as allylic
electrophiles with significantly different reactivity and selec-
tivity. It is noteworthy that the employment of an allylic
alcohol as the allylic electrophile is very attractive with
respect to atom economy because the leaving OH group has
a mass of 17 amu, which is much smaller than that of a halo or
an OR (R ¼ H) group. Nevertheless, the coupling of an a-
chiral allylic alcohol with a boronic acid has been reported to
afford a racemic product.[7f] To our knowledge, a leaving
group with a mass smaller than 17 amu has not yet been
reported for the coupling of an allylic electrophile with an
organoboron.
Table 1: Optimization of the reaction conditions.[a]
Entry
Catalyst
Additive (equiv)
Solvent
Yield [%][b]
1
[Pd(PPh3)4]
[Pd2(dba)3]
PdII[d]
[Pd(PPh3)4]
[Pd(PPh3)4]
[Pd(PPh3)4]
[Pd(PPh3)4]
[Pd(PPh3)4]
[Pd(PPh3)4]
none
none
none
none
dioxane
dioxane
dioxane
toluene
solvent[e]
dioxane
dioxane
dioxane
dioxane
70
0
trace
62
trace
36
40
76
89
2[c]
3
In contrast to allylic halides and alcohol derivatives, allylic
amines have rarely been employed to deliver allyl moieties to
final products in the cross-coupling reactions owing to the
poor leaving ability of the amino group.[8] Notably, in 1995
Trost et al. described a nickel-catalyzed cross-coupling of
terminal tertiary allylic amines with boronic acids.[8g]
Although the reaction suffers from narrow substrate scope
4
5[c]
6[c]
7[c]
8
none
PhCO2H (1)
TsOH (1)
B(OH)3 (1)
B(OH)3 (3)
9[f]
[a] Reaction conditions: amine 1a (0. 50 mmol), boronic acid 2a
(0.60 mmol), catalyst (5 mol%), additive (if any), solvent (3.0 mL),
and poor selectivity, this study, together with our interest in
[9]
ꢀ
C N bond cleavage, prompted us to investigate the
=
1108C, 12 h. [b] Yield of the isolated product. [c] N(CH2CH CHPh)3 was
possibility of using primary allylic amines as the allylic
electrophiles. Herein, we report that the NH2 group, having
a mass of 16 amu, acts as an effective leaving group in the
palladium-catalyzed regioselective and stereospecific cross-
coupling of primary allylic amines with boronic acids and
obtained as the major product. [d] [Pd(PPh3)2Cl2] or Pd(OAc)2.
[e] Dimethyl sulfoxide, N,N-dimethylformamide, or n-butanol. [f] 5.0 mL
of dioxane was used. dba=dibenzylideneacetone, Ts=p-toluenesul-
fonyl.
=
the allyl C C bond. The major byproduct generated from
[*] M.-B. Li, Y. Wang, Prof. Dr. S.-K. Tian
Joint Laboratory of Green Synthetic Chemistry
Department of Chemistry
=
amine 1a was N(CH2CH CHPh)3, which could barely be
transformed into alkene 4a through prolonging reaction time.
The replacement of [Pd(PPh3)4] with [Pd2(dba)3] led to the
formation of N(CH2CH CHPh)3 as the major product
University of Science and Technology of China
Hefei, Anhui 230026 (China)
=
E-mail: tiansk@ustc.edu.cn
(Table 1, entry 2), and the reaction was very sluggish in the
presence of a palladium(II) catalyst (Table 1, entry 3).
Furthermore, switching solvents did not improve the yield
(Table 1, entries 4–5). On the assumption that the NH2 group
of amine 1a might serve as a better leaving group under acidic
conditions, we added a selection of acids to the reaction
mixture and found that the yield was enhanced to 89% when
using the inexpensive B(OH)3 as the additive (Table 1,
entry 9). Finally, the loading of [Pd(PPh3)4] was reduced to 2
mol% without affecting the yield significantly (88%).
Prof. Dr. S.-K. Tian
Key Laboratory of Synthetic Chemistry of Natural Substances
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
Shanghai 200032 (China)
[**] We are grateful for the financial support from the National Natural
Science Foundation of China (21172206 and 20972147), the
National Basic Research Program of China (973 Program
2010CB833300), and the Program for Changjiang Scholars and
Innovative Research Team in University (IRT1189).
Under the optimized reaction conditions, a range of
primary E-allylic amines bearing various b and g substitutents
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201109171.
2968
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Angew. Chem. Int. Ed. 2012, 51, 2968 –2971

Angewandte
Chemie
smoothly coupled with boronic acid 2a or 2b in an excellent
a-selective fashion to give alkenes 4 in good to excellent
yields and with excellent retention of alkene geometry
(Table 2, entries 1–7 and 9–11). In contrast, the reaction
with Z-allylic amine 1h gave only the E alkene 4a in 86%
yield (Table 2, entry 8).[10] On the other hand, the reaction
worked well with a variety of aryl-, heteroaryl-, and alkenyl-
boronic acids (Table 2, entries 12–22). Moreover, the scope
for the reaction was significantly extended by employing
aryl-, alkenyl-, allyl-, and benzylboronates as the carbon
nucleophiles (Table 2, entries 23–29). As demonstrated by the
results summarized in Table 2, this reaction well tolerated
a variety of functional groups, such as alkoxy, aromatic nitro,
halo, ester, vinyl, and ketone.
alkene 7a in 75% yield (Table 3, entry 1). To achieve an
effective transfer of chirality, we optimized the reaction
conditions again. Replacement of [Pd(PPh3)4] with [Pd2-
(dba)3] did not lead to racemization, but decreased the yield
to 19% (Table 3, entry 2). The yield and stereochemical
outcome were significantly affected by the ligand, and
Table 3: Optimization of reaction conditions.[a]
Entry
Pd source
Ligand
Additive
Yield [%][b]
ee [%][c]
1
2
3
4
[Pd(PPh3)4]
[Pd2(dba)3]
[Pd2(dba)3]
[Pd2(dba)3]
[Pd2(dba)3]
[Pd2(dba)3]
[Pd2(dba)3]
none
none
binap
binol
(CH2OH)2
TMEDA
TMEDA
B(OH)3
B(OH)3
B(OH)3
B(OH)3
B(OH)3
B(OH)3
none
75
19
73
25
30
46
59
0
95
48
95
95
95
95
Such reaction conditions were applied to a-chiral primary
allylic amine 6a (95% ee), and the reaction gave racemic
5
6
Table 2: Cross-coupling of primary allylic amines with boronic acids and
7[d]
boronates.[a,b]
[a] Reaction conditions: amine 6a (0. 50 mmol), boronic acid 2a
(0.60 mmol), Pd source (2 mol%), ligand (8 mol%), additive (if any,
3.0 equiv), dioxane (5.0 mL), 1108C, 12 h. [b] Yield of the isolated
product. [c] Determined by HPLC analysis on a chiral stationary phase.
[d] The reaction was run in 2.0 mL of dioxane for 24 h. binap=2,2’-
bis(diphenylphosphino)-1,1’-binaphthyl, binol=1,1’-binaphthol,
TMEDA=N,N,N’,N’-tetramethylethylenediamine.
Entry 1, R1, R2, R3
2 or 3, R
2a, Ph
Product
Yield
[%][d]
(4/5)[c]
1
2
3
4
5
1a, Ph, H, H
4a (>99:1) 88
4b (>99:1) 88
4c (>99:1) 87
4d (>99:1) 84
4e (>99:1) 80
4 f (>99:1) 72
4g (94:6)[e] 76
4a (>99:1) 86
4h (>99:1) 92
4i (>99:1) 93
gratifyingly, the use of TMEDA as the ligand improved the
yield to 46% and completely inverted the chiral center
(Table 3, entry 6). Finally, the yield was enhanced to 59% by
removing B(OH)3, increasing the concentration of the
reaction mixture, and prolonging the reaction time (Table 3,
entry 7).
In the presence of 2 mol% of [Pd2(dba)3] and 8 mol% of
TMEDA, a range of a-chiral primary allylic amines 6
smoothly coupled with boronic acids to give optically active
alkenes 7 in moderate yields (Table 4).[11] As summarized in
Table 4, the chiral centers of amines 6 were completely
inverted and there was no loss of optical purity during the
reaction.
1b, 4-MeOC6H4, H, H 2a, Ph
1c, 2-MeOC6H4, H, H 2a, Ph
1d, 2-NO2C6H4, H, H 2a, Ph
1e, 3-pyridinyl, H, H 2a, Ph
6
1 f, 3-thienyl, H, H
2a, Ph
7
1g, cyclohexyl, H, H 2a, Ph
8
9
10
1h, H, Ph, H
1i, Ph, H, Me
1j, Ph, Ph, H
2a, Ph
2a, Ph
2a, Ph
2b,
11[f] 1k, H, H, H
4j
84
9-phenanthrenyl
2c, 4-FC6H4
2d, 4-ClC6H4
2e, 4-(MeO2C)C6H4 4m (>99:1) 84
2 f, 4-PhC6H4 4n (>99:1) 89
2g, 3-(MeO2C)C6H4 4o (>99:1) 86
2h, 3,5-(CF3)2C6H3 4p (>99:1) 85
2i, 2,6-Me2C6H3
2j, 2-furyl
2k, 2-naphthyl
2l, 1-naphthyl
2m, (E)-PhCH CH 4u (>99:1) 88
3a, Ph
3b, 4-MeOC6H4
3c, 4-vinylphenyl
3d, 4-PhCOC6H4
3e, (E)-PhCH CH 4u (>99:1) 76
3 f, CH2 =CHCH2
3g, PhCH2
12
13
14
15
16
17
1a, Ph, H, H
1a, Ph, H, H
1a, Ph, H, H
1a, Ph, H, H
1a, Ph, H, H
1a, Ph, H, H
4k (>99:1) 80
4l (>99:1) 66
ESI-MS analysis of the reaction mixture for the [Pd-
(PPh3)4]-catalyzed cross-coupling of amine 1a with boronic
18[g] 1a, Ph, H, H
19[g] 1a, Ph, H, H
4q (>99:1) 68
4r (>99:1) 60
4s (>99:1) 88
4t (>99:1) 91
=
acid 2a allowed us to identify the intermediate [Pd(CH2CH
CHPh)(PPh3)2]+ according to the high resolution mass data
(C45H39P2Pd+ calcd 747.1556, found 747.1545). This result
20
21
22
23
24
25
26
27
28
29
1a, Ph, H, H
1a, Ph, H, H
1a, Ph, H, H
1a, Ph, H, H
1a, Ph, H, H
1a, Ph, H, H
1a, Ph, H, H
1a, Ph, H, H
1a, Ph, H, H
1a, Ph, H, H
ꢀ
suggests that the C N bond of the primary allylic amine is
=
cleaved and an allylpalladium complex is formed during the
reaction.
4a (>99:1) 66
4v (>99:1) 71
4w (>99:1) 70
4x (>99:1) 60
Based on our results and the general mechanism for
palladium catalysis,[1,2] we propose the reaction pathways
depicted in Scheme 1 for the cross-coupling of a-chiral
primary allylic amines with boronic acids. The NH2 group of
=
4y (>99:1) 71
4z (>99:1) 83
ꢀ
amine 6 is activated by boronic acid 2 and the allylic C N
[a] Reaction conditions: amine 1 (0. 50 mmol), boronic acid 2
(0.60 mmol) or boronate 3 (0.75 mmol), [Pd(PPh3)4] (2 mol%), B(OH)3
(3 equiv), dioxane (5.0 mL), 1108C, 12 h. [b] Unless otherwise stated,
only the E-alkene product was obtained. [c] Determined by 1H NMR
spectroscopic analysis. [d] Yield of the isolated product. [e] 96:4 E/Z.
[f] The reaction was run in a sealed tube. [g] The reaction was run for
24 h.
bond is cleaved by the palladium(0) catalyst with inversion of
configuration to give p-allylpalladium 9a. When TMEDA is
used as the ligand, complex 9a undergoes transmetallation
followed by reductive elimination to give alkene 7 and
regenerate the palladium(0) catalyst. However, racemization
of complex 9a takes place when a phosphine is used as the
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Communications
1.50 mmol), and amine 1 (0.50 mmol) in dioxane (5.0 mL) was
heated at 1108C under nitrogen for 12 h. The mixture was cooled to
room temperature, and purified by preparative thin layer chroma-
tography (petroleum ether) to give alkene 4.
Table 4: Cross-coupling of a-chiral primary allylic amines with boronic
acids.[a]
Received: December 27, 2011
Published online: February 14, 2012
Entry 6, R1, R2
ee 2, R
[%]
7
Yield ee
[%][b] [%][c]
ꢀ
1
2
3
4
5
6
7
8
9
6a, Ph, Me
95 2a, Ph
95 2c, 4-FC6H4
95 2d, 4-ClC6H4
95 2e, 4-(MeO2C)C6H4 7d 56
95 2n, 2,6-(MeO)2C6H3 7e 55
92 2a, Ph
7a 59
7b 60
7c 46
95
95
95
95
95
92
90
91
90
Keywords: allylic compounds · C N bond cleavage ·
cross-coupling · boron · palladium
.
6a, Ph, Me
6a, Ph, Me
6a, Ph, Me
6a, Ph, Me
6b, Ph, Et
7 f 61
7g 56
7h 60
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6c, 2-naphthyl, Me 90 2a, Ph
6d, 4-ClC6H4, Me 91 2a, Ph
6c, 2-naphthyl, Me 90 2m, (E)-PhCH CH 7i 58
=
[a] Reaction conditions: amine 6 (0. 50 mmol), boronic acid 2
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a portion of amine 6 into alkene ent-7.
In summary, we have developed an unprecedented
palladium-catalyzed regioselective and stereospecific cross-
coupling of primary allylic amines with boronic acids and
boronates, wherein the NH2 group serves as an effective
leaving group. A range of primary allylic amines bearing b
and g substitutents smoothly couple with boronic acids in an
excellent a-selective fashion to give alkenes in good to
excellent yields and with excellent E selectivity. The reaction
works well with aryl- and alkenylboronic acids and aryl-,
alkenyl-, allyl-, and benzylboronates, and tolerates functional
groups such as alkoxy, aromatic nitro, halo, ester, vinyl, and
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General procedure (Table 2):
A mixture of boronic acid 2
(0.60 mmol), [Pd(PPh3)4] (11.6 mg, 2 mol%), B(OH)3 (92.7 mg,
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[10] The Z/E isomerization can be attributed to the generation of a p-
allylpalladium intermediate during the reaction (see below).
[11] The major side reaction with amines 6 is the formation of the
corresponding tertiary amines.
Angew. Chem. Int. Ed. 2012, 51, 2968 –2971
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