Enantioselective Aminomethylamination of Conjugated Dienes with Aminals Enabled by Chiral Palladium Complex-Catalyzed C-N Bond Activation

Article abstract of DOI:10.1021/jacs.6b00976

A novel highly enantioselective aminomethylamination of conjugated dienes with aminals catalyzed by a chiral palladium complex ligated with BINOL-derived chiral diphosphinite has been successfully developed. This reaction proceeds via a Pd-catalyzed cascade C-N bond activation, aminomethylation, and asymmetric allylic amination reaction under mild reaction conditions, providing a unique and efficient strategy for the synthesis of enantiomerically pure allylic 1,3-diamines.

Full text of DOI:10.1021/jacs.6b00976

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Communication
Enantioselective Aminomethylamination of Conjugated Dienes with Aminals
Enabled by Chiral Palladium Complex-Catalyzed C-N Bond Activation
Yang Liu, Yinjun Xie, Hongli Wang, and Hanmin Huang
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b00976 • Publication Date (Web): 21 Mar 2016
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Enantioselective Aminomethylamination of Conjugated Dienes with Aminals Ena-
bled by Chiral Palladium Complex-Catalyzed C-N Bond Activation
Yang Liu, +,ǂ,§ Yinjun Xie,+,§ Hongli Wang,+ and Hanmin Huang*,+
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+State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy
of Sciences, Lanzhou 730000, P. R. China
ǂ University of Chinese Academy of Sciences, Beijing 100049, P. R. China
Supporting Information Placeholder
the aminal to furnish the corresponding allylic 1,3-diamine
ABSTRACT: A novel highly enantioselective aminome-
and regenerated the active palladium complex (Scheme 1-1).
thylamination of conjugated dienes with aminals catalyzed by
This reaction is operative for a wide range of substituted
a chiral palladium complex ligated with BINOL-derived chiral
allenes, affording the achiral allylic 1,3-diamines in good to
diphosphinite has been successfully developed. This reaction
excellent yields. Considering the olefin insertion involving
proceeds via a Pd-catalyzed cascade C-N bond activation,
1,3-diene likely benefits from a similar incipient π bond, it
aminomethylation and asymmetric allylic amination reaction
was of interest to determine whether the cyclopalladated
under mild reaction conditions, providing a unique and effi-
cient strategy for the synthesis of enantiomerically pure allylic
1,3-diamines.
complex I efficient for insertion of allene would be effective
in catalytic synthesis of 1,3-diamine with conjugated dienes.
We anticipated that once an effective chiral ligand was
identified, the chiral allylic 1,3-diamines would be obtained
from the proposed catalytic system. Herein, we report the first
highly
enantioselective
1,2-aminomethylamination
of
The chiral 1,3-diamine is an important structural element in
various bioactive natural products and pharmaceuticals. It is
also a key core of chiral ligands and auxiliaries used for
asymmetric transformations.1 Among these, the alkenyl-
substituted ones are especially versatile because the vinylic
and allylic moieties in the product exhibit orthogonal
reactivity and can be transformed into a wide range of
functionalities, thereby facilitating further elaboration.
Although several approaches based on Mannich reaction,
intramolecular diastereoselective C-H amination, and the
diastereoselective reduction of ketimines are available for
synthesis of normal chiral 1,3-diamines,2 the catalytic
approach to chiral allylic 1,3-diamines from simple alkenes
remains a largely unsolved problem. Thus, development of an
efficient enantioselective protocol to chiral alkenyl-substituted
1,3-diamines is highly desired.
conjugated 1,3-dienes with aminals via transition-metal-
catalyzed C-N bond activation (Scheme1-2), which provided
an efficient approach to chiral allylic 1,3-diamines from
simple alkenes and aminals.
Scheme 1. A New Strategy for Synthesis of 1,3-Diamines
The selective insertion of a double bond of 1,3-dienes to
element-element bond is a powerful tool for the synthesis of
1,2- or 1,4-difunctionalization products.3 In this context, the
insertion of such kind of double bond to C-N bond for the
formation of one C-C and C-N bonds is a promising protocol
for synthesis of nitrogenated molecules.4 However, highly
enantioselective difunctionalization reactions of 1,3-dienes, in
particular, the protocols access to chiral 1,3-diamines, have
never been realized. We recently developed a new type of C-N
To validate our hypothesis, we commenced our studies by
attempting the proposed difunctionalization of 1,3-diene 1a
with stoichiometric amounts of xantphos-ligated cyclopalla-
dated complex I (confirmed by X-ray analysis)4a and Bn2NLi
(Scheme 2-1) at room temperature. To our delight, the reaction
-
took place smoothly and the aminomethyl moiety (R2NCH2 )
bond activation reaction, which provided
a
unique
contained in the cyclopalladated complex I and the amino
nucleophile (R2N-) have been indeed successfully incorporated
into the 1,3-diene 1a. The desired 1,2-difunctional product
3aa and an unexpected 1,1-difunctional product 4aa were
obtained in 22% yield with 27:73 ratio. The structures of 3aa
and 4aa were fully characterized and confirmed by their X-ray
crystallographic analysis.6 This result indicated that the π-
allylic-Pd intermediate III indeed formed via the insertion of
the double bond to the C-Pd bond and was nucleophilic at-
tacked by Bn2N- to form the racemic 3aa. Moreover, the prod-
cyclopalladated complex benefited from the facile C-N bond
-
cleavage of aminals.4 The aminomethyl moiety (R2NCH2 )
contained in the cyclopalladated complex I and the amino
nucleophile (R2N-) released from the C-N bond activation
process have been successfully incorporated into the
unsaturated double bond of allenes under the palladium
catalysis.5 Detailed mechanistic studies suggested this reaction
proceeds by migratory insertion of terminal alkene into the Pd-
C bond of the cyclopalladated complex I and a π-allylic-Pd
complex was formed, which was then nucleophilic attacked by
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ditions, a variety of commercially available chiral ligands,
uct 4aa was most likely produced from the intermediate IV
which derived from intermediate III via β-hydride elimination
and reinsertion (Scheme 2-2).7
1
2
3
4
5
6
7
8
such as diphosphine, monophosphine, chiral phosphine-
oxazoline-type P,N ligands, which were highly efficient in the
Pd-catalyzed asymmetric allylic alkylations,8 were initially
evaluated. However none of these ligands gave good results.
Further screening disclosed that BINAPO (5a)9 derived from
BINOL could deliver the difunctional products 3aa and 4aa in
81% isolated yield and the desired 1,3-diamines 3aa was ob-
tained in 25% ee with lower regioselectivity (Table 1, entry 1).
Inspired by this promising result, a series of modified
BINAPO ligands (5b-5l), bearing substituents at 3,3’-positions
of the binaphthyl scaffold and the phenyl ring of the phos-
phine, were prepared and assessed (the structure of 5i was
confirmed by X-ray analysis).6 The screening experiments
demonstrated that the sterically congested ligands were found
to be crucial for obtaining high enantioselectivity and regiose-
lectivity (Table 1, entries 2-12). Among these, 5h was the
most effective ligand which could deliver the desired 1,3-
diamine 3aa in 84% yield with 84% ee and good regioselec-
tivity (Table 1, entry 8). The impact of the counter ions over
the reactivity and selectivity of this process was investigated,
Scheme 2. Stoichiometric Reaction of Cyclopalladated-
Complex I and 1,3-Diene
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-
Table 1. Optimization of Reaction Conditions a
and it was discovered that ClO4 remained the optimal choice
(see Supporting Information). Finally, the ee value was in-
creased to 90%, but with lower regioselectivity and reactivity
when the reaction temperature decreased to 0 °C (Table 1,
entry 14). Prolonging the reaction time to 48 h and conducting
o
the reaction at 10 C, high yield with good enantioselectivity
and regioselectivity was obtained (Table 1, entry 13 vs 15).
Table 2. Substrate Scope of Aminals a
ratio
entry
ligand T (°C )
yield (%)
ee (%)b
(3/4)c
52:48
61:39
>20:1
70:30
89:11
79:21
>20:1
94:6
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15d
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5h
5h
5h
25
25
25
25
25
25
25
25
25
25
25
25
10
0
81
85
78
86
88
46
64
84
81
56
43
54
77
69
91
-25
30
72
50
83
86
83
84
83
76
58
75
87
90
87
ee
(%)b
87
88
84
93
91
94
96
78
55
56
59
ratio
(3/4)c
>20:1
93:7
>20:1
>20:1
>20:1
>20:1
76:24
>20:1
>20:1
>20:1
>20:1
Entry
R
yield (%)
1
2
3
4
5
6
7
8
9
C6H5CH2
4-FC6H4CH2
2-ClC6H4CH2
4-ClC6H4CH2
2-BrC6H4CH2
4-BrC6H4CH2
4-CF3C6H4CH2
4-CH3OC6H4CH2
CH3CH2
3aa (91)
3ab (92)
3ac (93)
3ad (91)
3ae (85)
3af (82)
3ag (68)
3ah (46)
3ai (40)
3aj (56)
3ak (62)
93:7
82:18
82:18
>20:1
92:8
85:15
>20:1
10
11
CH3CH2CH2
CH3CH2CH2CH2
aReaction conditions: 1a (0.24 mmol),
2
(0.2 mmol),
10
aReaction conditions: 1a (0.24 mmol), 2a (0.2 mmol),
[Pd(allyl)Cl]2 (2.5 mol%), ligand (5.5 mol%), AgClO4 (5.5 mol%),
CH2Cl2 (0.5 mL), 24 h, isolated yield for 3 and 4. bDetermined by
HPLC analysis and the ee value is for 3. cDetermined by 1H NMR
analysis. d48 h.
[Pd(allyl)Cl]2 (2.5 mol%), 5h (5.5 mol%), AgClO4 (5.5 mol%),
b
CH2Cl2 (0.5 mL), 10 °C , 48 h, isolated yield for 3 and 4. Deter-
mined by HPLC analysis and the ee value is for 3. cDetermined by
1H NMR analysis.
With the optimized reaction conditions identified, we then
investigated the reaction of aminals with (E)-buta-1,3-dien-1-
ylbenzene 1a. As shown in Table 2, the benzyl aminals with
both electron-withdrawing and -donating groups on the phenyl
ring were well tolerated with good to excellent yields and se-
lectivities under this protocol. It was noted that the electronic
nature on the phenyl ring of the aminals had a strong influence
on the reactivities, enantio- and regioselectivities. The aminals
bearing halides (2b-2f) flourished the corresponding chiral
1,3-diamines in high yields with excellent enantioselectivities
The above results intrigued us to investigate the enantiose-
lective catalytic aminomethylamination of conjugated 1,3-
dienes with aminals according to the proposed reaction path-
way. (E)-buta-1,3-dien-1-ylbenzene 1a was chosen as a model
substrate to react with N,N,N’,N’-tetrabenzylmethanediamine
2a for identifying a suitable chiral catalyst and reaction condi-
tions (Table 1). The reaction carried out with 5 mol% catalyst
loading in CH2Cl2 at 25 oC for 24 h. The catalyst was prepared
in situ by mixing 2.5 mol% of [Pd(allyl)Cl]2 and 5.5 mol% of
AgClO4 with the ligand in CH2Cl2. Under these reaction con-
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as >20:1 regioselectivity. It is noteworthy that the arylbutadi-
as well as good regioselectivities (Table 2, entries 2−6). How-
1
2
3
4
5
6
7
8
enes with a variety of substituents, such as alkyl, methoxyl,
trifluoromethoxyl, fluoro, chloro, bromo and nitro, were all
compatible with this protocol. Obviously, both the reactivities
and regioselectivities suffer from the steric hindrance of the
alkenes. For instance, the sterically hindered ortho-substituted
arylbutadienes 1f and 1r were subjected to the catalytic system
to afford the desired products in 86% and 99% ee, respectively,
but with a relatively lower regioselectivities and yields (Table
3, entries 6 and 18). This lower regioselectivities probably due
to the fact that ortho-substituted groups influenced the stabil-
ity of the π-allyl-Pd intermediates I, thereby accelerated the
steps of β-hydride elimination and reinsertion to form the unu-
sual 1,2-diamines. In addition, naphthyl substituted arylbuta-
diene 1m and 1n were also compatible with this reaction, af-
fording the corresponding 1,3-diamines with high regio- and
enantioselectivities (up to 92% ee, Table 3, entry 14). In addi-
tion, the products 3df, 3ef, 3pf were isolated with higher ee
values when aminal 2f instead of 2d was used as the reaction
partner (Table 3, entries 19-21). Moreover, the challenging
alkyl substituted butadienes 1s and 1t can also be transformed
into the desired products in moderate yields with high regiose-
lectivities and good enantioselectivities when 5c was utilized
as a chiral ligand. Furthermore, the heteroaromatic 2-(buta-
1,3-dien-1-yl)furan also worked well in the reaction, generat-
ing the desired product in good yield and excellent enantiose-
lectivity (96% ee for 3ud and 85% ee for 4ud , Table 3, entry
24). It was important to mention that the reactivity regio- and
enantioselectivity of this reaction were not affected by the (E/Z)
ratio of the corresponding dienes (see Supporting Information).
Pleasingly, the reaction underwent smoothly on 10 mmol scale,
affording the desired product with high yield and excellent
stereoselectivity (5.98 g of 3ad was obtained in 89% yield,
with 92%ee and >20:1 regioselectivity, see Supporting Infor-
mation). The absolute configuration of 3qd was determined as
(S) by its X-ray crystallographic analysis, and the other prod-
ucts were tentatively assigned as (S) by analogy.
ever, the reaction with strong electron-withdrawing aminal (2g)
provided lower yield and regioselectivity due to the lower
nucleophilicity of the corresponding amine, but a higher enan-
tioselectivity (Table 2, entry 7). Comparing with the results of
the substrates bearing an electron-withdrawing group, the
presence of an electron-donating group such as methoxyl (2h)
led to a moderate yield with good regio- and enantioselectivity
(Table 2, entry 8). Aminals derived from simple aliphatic
amines (2i-2k) were incorporated into the conjugated diene
with this catalytic system, however, the corresponding 1,3-
diamine products were obtained with moderate yields and
moderate ee values (Table 2, entries 9−10), albeit excellent
regioselectivities were observed.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 3. Substrate Scope of 1,3-Butadienes a
ratio
entry
R1
yield (%) ee (%)b
(3/4)c
>20:1
93:7
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19d
20d
21d
22e
23e
24
C6H5
3-MeC6H4
4-MeC6H4
4-tBuC6H4
4-FC6H4
2-ClC6H4
3-ClC6H4
4-ClC6H4
4-BrC6H4
3ad (91)
3bd (86)
3cd (75)
3dd (79)
3ed (81)
3fd (40)
3gd (72)
3hd (81)
3id (84)
3jd (86)
3kd (82)
3ld (84)
3md (48)
3nd (91)
3od (74)
3pd (76)
3qd (73)
3rd (26)
3df (71)
3ef (68)
3pf (70)
3sd (33)
3td (56)
3ud (65)
93
92
95
88
88
86
83
81
87
83
81
93
89
92
96
88
92(79)
99(92)
94
92
91
80
77
96(85)
>20:1
>20:1
>20:1
76:24
92:8
>20:1
>20:1
88:12
75:25
89:11
>20:1
91:9
>20:1
>20:1
48:52
62:38
88:12
91:9
90:10
>20:1
>20:1
47:53
4-CF3OC6H4
4-NO2C6H4
4-PhC6H4
1-naphthyl
2-naphthyl
3,4-(Me)2C6H3
3,5-(Me)2C6H3
3,4-(OMe)2C6H3
2,3-(Me)2C6H3
4-tBuC6H4
4-FC6H4
To rationalize the observed enantioselectivity of the present
reaction, a Pd(II) complex of chiral ligand 5e has been isolated
and characterized by X-ray crystallography to have the formu-
la of [Pd(R-5e)(allyl)]ClO4 (Figure 1). The cationic complex
contains one ligand 5e, coordinated to Pd through the P atom.
All four phenyl rings attached to the P atom of the ligand lo-
cate at four different quadrants, respectively. On the basis of
the catalyst structure and the absolute configuration of the
products, we proposed the chiral induction model shown in
Figure 1. Assuming all of the diastereomeric π-allylic-Pd in-
termediates are in equilibrium by reversible β-H elimination,
the allylic moiety adopted the exo-syn-syn configuration (W-
type) and is attacked by R2N- from the less-hindered Si face,
affording the product with an S configuration.
3,5-(Me)2C6H3
PhCH2CH2
n-Oct
2-furyl
aReaction conditions: 1 (0.24 mmol), aminal 2 (0.2 mmol),
[Pd(allyl)Cl]2 (2.5 mol%), 5h (5.5 mol%), AgClO4 (5.5 mol%),
CH2Cl2 (0.5 mL), 10 °C , 48 h, isolated yield for 3 and 4. Deter-
b
c
mined by HPLC analysis, the data in bracket were for 4. Deter-
mined by 1H NMR analysis. d 2f was used. e 5c was used as ligand.
Figure 1. Structure of the Cationic Pd-Complex and Chiral
Induction Model
We next examined the scope with respect to the dienes (Ta-
ble 3). The substrate scope of 1,3-diene was explored by reac-
tion of a variety of substituted butadienes 1 with aminal 2d. In
theory, four kinds of regiomers could be generated from the
reaction. However, thanks to the efficient catalytic protocol,
the application of the optimized reaction conditions to the
reaction of different conjugated dienes with 2d was quite suc-
cessful and almost only two regiomers (1,3-diamine and 1,2-
diamine) were observed. As shown in Table 3, the desired
chiral 1,3-diamines were obtained in high enantioselectivities
ranging from 77% to 99% ee and up to 91% yield as well
In order to gain some insights into the mechanism of this
novel reaction, isotope effect experiments were conducted by
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(2) (a) Zhao, C.-H.; Liu, L.; Wang, D.; Chen, Y.-J. Eur. J. Org.
the reaction of d2-3,4-dimethoxylphenylbutadiene (1q-d2) with
aminal 2d. Similar to the results obtained by Gong,7v the deu-
terium migration was observed in the regiomer 4qd-d2. In
addition, the regioselectivity of the reaction was improved
from 48:52 to 75:25. The reason may be attributed to that the
β-deuteride elimination and reinsertion steps underwent much
more slowly than the similar reactions with 1q, thus result in
the formation of allylic-Pd intermediate IV is much more
slowly than III. On the basis of these results, we speculated
that β-hydride elimination and reinsertion to form allylic-Pd
intermediate were most likely involved in this reaction.
Chem. 2006, 2977; (b) Lu, S.-F.; Du, D.-M.; Xu, J.; Zhang, S.-W. J.
Am. Chem. Soc. 2006, 128, 7418; (c) Wang, J.; Li, H.; Zu, L.; Jiang,
W.; Wang, W. Adv. Synth. Catal. 2006, 348, 2047; (d) Giampitro, N.
C.; Wolfe, J. P. J. Am. Chem. Soc. 2008, 130, 12907; (e) Anderson, J.
C.; Blake, A. J.; Mills, M.; Ratcliffe, P. D. Org. Lett. 2008, 10, 4141;
(f) Rabalakos, C.; Wulff, W. D. J. Am. Chem. Soc. 2008, 130, 13524;
(g) Yang, X.; Zhou, X.; Lin, L.; Chang, L.; Liu, X.; Feng, X. Angew.
Chem., Int. Ed. 2008, 47, 7079; (h) Kurokawa, T.; Kim, M.; Du Bois,
J. Angew. Chem., Int. Ed. 2009, 48, 2777; (i) Trost, B. M.; Malhotra,
S.; Olson, D. E.; Maruniak, A.; Du Bois, J. J. Am. Chem. Soc. 2009,
131, 4190; (j) Dagousset, G.; Drouet, F.; Masson, G.; Zhu, J. Org.
Lett. 2009, 11, 5546.
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Scheme 3. Experimental Studies on Isotope Effect
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In summary, we have developed a new type of Pd-catalyzed
enantioselective aminomethylamination of conjugated dienes
with aminals via C-N bond activation. The palladium complex
coordinated with BINAPO-type ligand efficiently catalyzed
the difunctionalization reaction with high regioselectivity and
enantioselectivity, where a series of synthetically useful chiral
1,3-diamines were obtained as the reaction products. The pre-
sent transformation is the first example of an enantio- and
regioselective difunctionalization of conjugated dienes via C-
N bond activation. Further exploring efficient chiral catalysts
for regio- and enantioselectively providing the chiral 1,2-
diamines with this novel catalytic protocol and applying this
cyclopalladated complex in other asymmetric catalysis are in
progress.
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(6) CCDC 1447748(5i), 1450135(3aa), 1450186(3qd) and
1450134 {[Pd(R-5e)(allyl)]ClO4} contain the supplementary crys-
tallographic data for this paper. This data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
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ASSOCIATED CONTENT
Supporting Information. Experimental details and full spectroscopic
data for all new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
* hmhuang@licp.cas.cn
Author Contributions
§Y. L. and Y. X. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This research was supported by the Chinese Academy of Sciences,
the National Natural Science Foundation of China (21222203 and
21133011).
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