Dual Catalysis Using Boronic Acid and Chiral Amine: Acyclic Quaternary Carbons via Enantioselective Alkylation of Branched Aldehydes with Allylic Alcohols

Article abstract of DOI:10.1021/jacs.6b06101

A ferrocenium boronic acid salt activates allylic alcohols to generate transient carbocations that react with in situ-generated chiral enamines from branched aldehydes. The optimized conditions afford the desired acyclic products embedding a methyl-aryl quaternary carbon center with up to 90% yield and 97:3 enantiomeric ratio, with only water as the byproduct. This noble-metal-free method complements alternative methods that are incompatible with carbon-halogen bonds and other sensitive functional groups.

Full text of DOI:10.1021/jacs.6b06101

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Dual Catalysis Using Boronic Acid and Chiral Amine:
Acyclic Quaternary Carbons via Enantioselective
Alkylation of Branched Aldehydes with Allylic Alcohols
Xiaobin Mo, and Dennis G Hall
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 12 Aug 2016
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Dual Catalysis Using Boronic Acid and Chiral Amine:
Acyclic Quaternary Carbons via Enantioselective Alkylation of
Branched Aldehydes with Allylic Alcohols
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Xiaobin Mo, Dennis G. Hall*
Department of Chemistry, Centennial Centre for Interdisciplinary Science, University of Alberta, Edmonton,
Alberta, Canada, T6G 2G2
Supporting Information Placeholder
co-workers prepared acyclic quaternary carbon centers with
a clever combination of palladium, Brønsted acid, and amine
catalysis (Figure 1a).6b Similarly, Carreira and co-workers
employed dual iridium and amine catalysis as a complemen-
tary strategy to obtain the branched products of allylic alkyl-
ation in high enantio- and diastereoselectivity (Figure 1b).6d
ABSTRACT: A ferrocenium boronic acid salt activates allylic
alcohols to generate transient carbocations that react with in
situ generated chiral enamines from branched aldehydes.
The optimized conditions afford the desired acyclic products
embedding a methyl-aryl quaternary carbon centre with up
to 90 % yield and 97:3 enantioselectivity ratio, with only wa-
ter as the by-product. This noble metal-free method com-
plements alternative methods that are incompatible with C–
halogen bonds and other sensitive functional groups.
Previous work
(a) List; Pd + amine + chiral acid (ref. 6b)
O
O
[Pd] + amine
chiral phosphoric acid
R2
HO
Ar
Me
H
R2
H
R1
R1, R2 = H, Me, Ph
R1
Me Ar
66-98% yield
up to 99.8:0.2 er
linear product
(b) Carreira; Ir + amine + acid (ref. 6d)
The advent of new strategies for the catalytic activation of
organic molecules creates new opportunities to design un-
conventional bond forming processes. In dual catalysis, two
mutually compatible catalysts are combined to independent-
ly activate two different substrates and expand the scope of
reactions with substrates that are unreactive under tradition-
al conditions.1 In this perspective, the concept of boronic
acid catalysis (BAC), which exploits the ability of boronic
acids to form reversible covalent bonds with hydroxyl func-
tionalities, was examined by our group and others in the
catalytic direct activation of carboxylic acids and alcohols.2
For instance, we recently reported direct boronic acid-
catalyzed Friedel-Crafts alkylations of neutral arenes with
readily available allylic and benzylic alcohols as a way to cir-
cumvent the use of toxic organohalide electrophiles.3 With a
view to extend this strategy towards other classes of nucleo-
philes such as carbonyl enolates, we envisaged the possibility
of merging BAC with chiral amine catalysis to achieve alkyla-
tion of enamines with carbocations via dual activation of
aldehydes and alcohols, respectively.4,5 A priori, the com-
bined use of Lewis acidic and Brønsted basic catalysts poses
challenging issues of chemoselectivity, including the threat
of catalysts’ inter-annihilation. Moreover, the use of alcohols
as precursors of reactive carbocations can lead to side-
reactions like homoetherification or alkylation of the amine
catalyst. Cozzi and co-workers overcame these challenges by
employing InBr3 and imidazolidinone catalysts to alkylate
linear aldehydes with secondary allylic alcohols in high enan-
tioselectivities.4b Similar approaches to asymmetric allylation
of branched aldehydes with allylic alcohols engaging transi-
tion metals6 as co-catalysts were reported. In 2011, List and
[Ir] + amine
chiral ligand
acid activator
O
O
H
Ar
OH
Ar
H
H
Ar
42-86% yield
>99.5:0.5 er, >20:1 dr
Me
Me Ar
branched product
This work
(c) Boronic acid + chiral amine
O
Ar
O
Ar
boronic acid + chiral amine
HO
Ar
Ar
Me
H
Ar
H
Me Ar
54-90% yield
up to 97:3 er
noble-metal free,
benign by-
product (H2O)
stereogenic
quaternary
carbon centers
complementary
functional group
tolerance
further product
transformations,
e.g. oxidative cleavage
Figure 1. Methods for dual catalytic asymmetric allylation of
branched aldehydes with allylic alcohols
As highlighted through these key contributions, the prepara-
tion of acyclic quaternary all-carbon centers remains an im-
portant objective in organic synthesis.7 For instance, methyl-
aryl quaternary carbons are present in a number of bioactive
natural products and drug candidates (Figure 2).8 Although
several methods exist based on the use of chiral auxiliaries,9
there are relatively few strategies available through asymmet-
ric catalysis. Furthermore, preparative methods based on
palladium catalysis are not orthogonal with functionalities
like aryl halides and are often incompatible with nitro or
other basic functional groups. Herein, we describe a concep-
tually novel, noble metal-free methodology based on dual
BAC and amine catalysis that is compatible with these func-
tional groups and provides methylated quaternary carbon
centers in high enantioselectivity (Figure 1c).
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The enantioselectivity of the allylation was examined by
Me
Ph
Cl
Cl
1
2
3
4
5
6
7
8
O
N
screening over 30 different chiral amines, based on condi-
tions of the optimized racemic reaction (see SI). Chiral pri-
mary amines were investigated first because they are less
sterically hindered for branched aldehydes.12 Unfortunately,
these amines generally provided poor performance, as exem-
plified with A213 affording a 76.5:23.5 er (Table 1, entry 2). The
more common chiral secondary amines were evaluated even
though α-functionalization of branched aldehydes catalyzed
by secondary amines is generally more challenging and less
successful.14 When diphenylprolinol trimethylsilyl ether A315
was employed, the reaction provided no product (Table 1,
entry 3). We hypothesized that this failure may be due to the
nucleophilic secondary amine center, which could deactivate
the ferrocenium boronic acid B1. To our satisfaction, upon
using the less nucleophilic diarylprolinol silyl ether A4, the
desired product was observed in high enantioselectivity
(87.5:12.5 er) albeit with low yield (20%). Encouraged by this
result, we eventually identified A8 as the best amine catalyst
providing 47% yield and 90:10 er (Table 1, entry 8). With this
optimal chiral amine in hand, we turned our attention to the
optimization of other reaction parameters. A brief solvent
screening identified toluene/HFIP (v:v=10:1), at a concentra-
tion of 0.25 M, as the solvent system providing the highest
enantioselectivity albeit, in 32% yield (see SI). Additives (wa-
ter, acetic acid16) provided no improvement. According to
Bräse and co-workers, the use of microwave irradiation can
accelerate enamine formation for branched aldehydes.17 By
applying the same strategy with a catalyst loading of 30
mol%, the yield of 3a near doubled. Catalysts ratio other than
1:1 B1:A8 led to no improvement (see SI). At this stage, a re-
optimization of the allylic alcohol showed that 2b can serve
as a cheaper and more effective allylation agent providing a
higher yield of 60% while maintaining the enantioselectivity.
The remainder of the mass balance consists mostly of unre-
acted aldehyde and transposed alcohol.
O
H
N
OMe
N
H2N
N
Me
Ph Me
2TFA
O
Me
Me
LY426965
serotonin antagonist
N
(+)-cuparene
F
O
O2N
O
N
Me
O O
S
N
O
O
N
N
Me
Me
NK1/NK3 receptor
antagonist
CCR5 antagonist
9
10
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45
46
47
48
49
50
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52
53
54
55
56
57
58
59
60
Figure 2. Examples of biologically active compounds contain-
ing stereogenic methylated quaternary carbon centers
The initial optimization was performed on the racemic reac-
tion and focused on selecting the best boronic acid co-
catalyst and allylic alcohol partner with aldehyde 1a and ben-
zhydrylamine A16d (see SI). This effort identified the most
promising conditions with ferrocenium boronic acid B1 and
alcohol 2a in a dichloromethane/hexafluoroisopropanol mix-
ture (v:v=10:1) at 40 °C for 48 h, affording product 3a in 88%
yield (Table 1, entry 1). The use of HFIP was critical to in-
crease the solubility of ferrocenium boronic acid B1 as well as
stabilizing the putative carbocation intermediate.10 Allylic
alcohol 2a with para fluorine substituents was employed to
best suppress the boronic acid-catalyzed 1,3-rearrangement
of allylic alcohols, a process competing with the desired al-
lylation.11 Even though a limited number of allylic alcohols
were suitable (see SI), it is often inconsequential because one
of the most compelling synthetic transformation of the diaryl
alkene moiety of products like 3a is oxidative cleavage.
Table 1. Chiral Amine Optimization in the Dual Cata-
lytic Asymmetric Allylationa
O
O
Ar
B1 (20 mol%)
Ar
amine (20 mol%)
Ph
HO
Ar
H
H
Ar
DCM:HFIP = 10:1,
40 °C, 48 h, 0.125 M
Me Ph
Me
1a
The scope of aldehyde substrate was assessed under
the optimal conditions of (Scheme 1). Branched aldehydes
with an aryl group bearing electron-donating substituents (-
OMe, -Me) provided products 4b and 4c in slightly lower
yield and enantioselectivity compared to 4a. While existing
methods6b also reported high yield and high enantioselectivi-
ty for select aldehydes containing simple aryl substituents (-
OMe, -Me, -F), we were delighted to observe a wider func-
tional group tolerance with our reaction system, especially
for electron withdrawing aryl substituents. Branched alde-
hydes with bromo/chloro aryl substituents, which are partic-
ularly useful for derivatization by cross-coupling chemistry,
were well tolerated and gave high yield and high enantiose-
lectivity in the preparation of products 4d-f.18 Highly enanti-
oselective catalytic α-functionalization of aldehydes 1g-j has
been shown to be challenging with other methods.6f,14d,19 In
contrast, with our system, polar basic functional groups such
as -CO2Me, -NO2, and CF3 fared well affording products 4g-
j.20 An aldehyde with a naphthyl group afforded product 4k
in good yield and enantioselectivity. The auspicious applica-
bility of this method towards heterocyclic substrates is high-
lighted with indolyl product 4l, which despite a lower yield,
was obtained in high er. Unfortunately, the α-ethyl aldehyde
1m was not readily applicable. The absolute configuration of
the allylation products 4a-m was assigned as (S) based on the
derivatization of 4a into a known compound (see SI).21
2a: Ar = 4-F-C6H4
3a
F3C
CF3
CF3
CF3
B(OH)2
Ph
NH2
A1
Ph
+
N
Fe
N
N
O
O
R
NH2
H
H
SbF6
TMS
B1
A4-8
A2
A3
entry
amine
A1
R
yield (%)b
erc
50:50
1
-
-
88
86
n.r.
20
34
51
2
3
4
5
6
7
8
A2
76.5:23.5
n.d.
A3
-
A4
-SiMe3
-SiEt3
-Si(i-Pr)3
-SiPh3
-Si(t-Bu)Me2
87.5:12.5
83.5:16.5
85.5:14.5
85.5:14.5
90:10
A5
A6
A7
31
A8
47
aReactions conditions: 0.25 mmol of aldehyde and 0.50 mmol
of alcohol in a solvent mixture of dichloromethane (2.0 mL)
and hexafluoroisopropanol (0.2 mL) under nitrogen at 40 °C
b
1
for 48 h. Yields were determined by H NMR analysis of the
reaction mixture with 1,4-dinitrobenzene as internal stand-
c
ard. Determined by chiral HPLC analysis of the correspond-
ing alcohol product of aldehyde reduction (see SI).
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Ph
Scheme 1. Substrate Scope of Dual Catalytic Asym-
metric Allylationa
1. B1 (30 mol%), A8 (30 mol%)
Cl
Cl
HO
Ph
Cl
1
2
3
4
5
6
7
8
O
toluene:HFIP = 10:1,
0.250 M, µw 60 °C, 12 h,
Ph
Me
HO
Ph
H
2. NaBH4 (10.0 equiv)
DCM:MeOH = 10:1, 0 °C
F3C
CF3
Me
1f
Cl
O
R2
4f
CF3
CF3
2b
(9.90 mmol)
(1.00 g, 4.95 mmol)
B(OH)2
(67%, 96:4 er)
H
R1
+
SbF6 Fe
N
O
Ph
Cl
Cl
H
Ph
O
N
1a-k
TBS
H
N
1. TBSCl (1.1 equiv),
imidazole (2.0 equiv)
DCM, rt, 16 h (96%)
1. B1 (30 mol%), A8 (30 mol%)
HO
Ph
H2N
OH
TBSO
Me
R1
O
Me
Me
Ph
toluene:HFIP = 10:1,
0.250 M, µw 60 °C, 12 h,
HO
2TFA
R2
R2N
Cl
Ph
2. i. O3, DCM, -78 °C
ii. NaBH4 (10.0 equiv)
9
2. NaBH4 (10.0 equiv)
DCM:MeOH = 10:1, 0 °C
NK1/NK3 receptor antagonist
(see full structure in Scheme 1)
4a-m
2b
Cl
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
5 (89%)
Ph
Ph
Ph
Ph
Mechanistic control experiments were conducted. Ferroceni-
um boronic acid B1 was shown to be a superior acid catalyst
compared to TFA,4a InBr3,4b and p-TsOH5b for the asymmet-
ric allylation (Scheme 3, top). Though it provides a signifi-
cantly lower yield, the ferrocenium catalyst devoid of a bo-
ronyl group, CpFe(III)CpSbF6, is also active (Scheme 3, top).
This result indicates that cooperative activation involving
both Lewis acidic sites of B1 cannot be ruled out. In the pres-
ence of HFIP, with none or trace water, a complex dynamic
equilibrium is likely to establish consisting of the free bo-
ronic acid, the bis(hexafluoroisopropoxide), the hydroxy
(hexafluoroisopropoxide) hemiester, and the corresponding
anionic species (Scheme 3). Formation of boronic anhydrides
was not detected by mass spectrometry. The possible exist-
ence of inter-catalyst interactions was examined by NMR
spectroscopy in the reaction solvent (10:1 d8-toluene:HFIP).
In the presence of the amine catalyst, a new 11B NMR reso-
nance appears at ~5 ppm, possibly indicative of reversible
catalyst interactions as a tetrahedral amine-borate, or, more
HO
Ph
HO
Ph HO
Ph HO
Ph
Me
Me
Me
Me
Br
OMe
Me
4c
62% (57%)
93:7 er
4a
4d
4b
60%b (60%)c
94:6 erd
77% (70%)
95.5:4.5 er
54% (42%)
92.5:7.5 er
Ph
Ph
Ph
HO
Ph HO
Ph
HO
Ph
4h: EWG = NO2
82% (79%)
97:3 ere
Me
Me
Me
Cl
Cl
EWG
Br
4e
4g: EWG = CO2Me
69% (58%)
4f
4i: EWG = CF3
90% (80%)
96:4 er
73% (68%)
96:4 er
87% (82%)
96.5:3.5 er
95:5 er
Ph
Ph
Ph
Ph
HO
Ph HO
Ph
HO
Ph HO
Ph
Me
Me
Me
Et
CF3
N
Ts
F3C
4j
4k
4l
4m
70% (70%)
95.5:4.5 er
76% (71%)
96:4 er
52% (49%)
94:6 er
24% (19%)
80:20 er
likely
a
base-promoted
formation
of
the
tri(hexafluoroisopropoxy)borate complex observed by MS
(see SI). According to 11B NMR analysis, catalyst B1 appears
largely transformed at the end of the reaction. Although a
slow destructive interaction between the Fe(III) ion and nu-
cleophilic reagents cannot be ruled out,22 reversible interac-
tion of the catalyst with the water by-product or unreacted
substrates is also possible and would require further studies.
Altogether, based on these preliminary experiments and pre-
vious work3b with catalyst B1, an SN1 mechanism is proposed
with the dual-catalyzed cycles depicted in Scheme 3. Face-
selective attack of the in situ formed chiral enamine (H) to
the reactive carbocation (E) results in the allylation product.
Substitution of boronic acid B1 for a mixture of 2,3,4,5-
F4HC6B(OH)2 and Cp2Fe(III)SbF6 provided a lower yield
(32%), which lends further support to an ion redistribution
mechanism that is possible only with ionic boronic acid B1.
aReactions conditions: 0.25 mmol of aldehyde and 0.50 mmol
of alcohol in 1.1 mL of solvent in a microwave reactor under
nitrogen at 60 °C for 12 h. bYield of first step were determined
by 1H NMR analysis of the reaction mixture with 1,4-
dinitrobenzene as internal standard. Isolated yield over two
steps, of the alcohol product of aldehyde reduction. Deter-
c
d
mined by chiral HPLC analysis of the alcohol products 4 (see
SI). Enantiomeric ratio of 4i was obtained by Mosher’s acid
e
analysis of the reduced alcohol product.
To demonstrate the practicality of this method, a gram scale
reaction with aldehyde 1f was performed (Scheme 2). Even
though a lower yield was observed compared to the explora-
tory scale of Scheme 1, the enantioselectivity was maintained.
Oxidative cleavage of the double bond of product 4f afforded
compound 5 as a key building block possessing correctly
differentiated side chains for the quaternary carbon fragment
of Servier’s NK1/NK3 receptor antagonist,8d which could not
be prepared previously in catalytic asymmetric fashion.
In summary, we have disclosed the first application of BAC in
asymmetric dual catalysis. This noble metal-free method for
allylation of branched aldehydes provides moderate to high
yields with high enantioselectivity, and it displays broad
functional group tolerance. The reliability of this asymmetric
allylation was demonstrated on a gram-scale for the prepara-
tion of a quaternary carbon fragment of Servier’s NK1/NK3
receptor antagonist. A dual catalyzed SN1 mechanistic cycle
was proposed. We envision that more dual catalyzed trans-
formations of synthetic interest can be developed based on
the BAC concept.
Scheme 2. Application of Dual Catalytic Allylation
Scheme 3. Mechanistic Controls and Proposed Cata-
lytic Cycle of Dual Catalytic Asymmetric Allylation
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(1) (a) Shao, Z.; Zhang, H. Chem. Soc. Rev. 2009, 38, 2745. (b) Zhong,
C.; Shi, X. Eur. J. Org. Chem. 2010, 2999. (c) Allen, A. E.; MacMillan,
D. W. C. Chem. Sci. 2012, 3, 633.
Control experiments with other acid catalysts
1
2
3
4
5
6
7
8
O
O
Ar
Ar
Ph
HO
Ar
acid catalysts, A8
H
H
Ar
(2) (a) Maki, T.; Ishihara, K.; Yamamoto, H.; Tetrahedron 2007, 63,
8645. (b) Georgiou, I.; Ilyashenko, G.; Whiting, A.; Acc. Chem. Res.
2009, 42, 756. (c) Zheng, H.; Hall, D. G. Aldrich. Acta. 2014, 47, 41.
(3) (a) Ricardo, C. L.; Mo, X.; McCubbin, J. A.; Hall, D. G. Chem. -
Eur. J. 2015, 21, 4218. (b) Mo, X.; Yakiwchuk, J.; Dansereau, J.;
McCubbin, J. A.; Hall, D. G. J. Am. Chem. Soc. 2015, 137, 9694.
(4) (a) Cozzi, P. G.; Benfatti, F.; Zoli, L. Angew. Chem. Int. Ed. 2009,
48, 1313. (b) Capdevila, M. G.; Benfatti, F.; Zoli, L.; Stenta, M.; Cozzi,
P. G. Chem. - Eur. J. 2010, 16, 11237.
(5) For an example of catalytic enantioselective SN1 benzylation of
branched aldehydes with benzyl bromides, see: (a) Brown, A. R.;
Kuo, W. -H.; Jacobsen, E. N. J. Am. Chem. Soc. 2010, 132, 9286. For an
example of catalytic racemic allylation of branched aldehydes with
allylic alcohols, see: (b) Xu, L. -W.; Gao, G.; Gu, F. -L.; Sheng, H.; Li,
L.; Lai, G. -Q.; Jiang. J. -X. Adv. Synth. Catal. 2010, 352, 1441.
(6) For examples of enantioselective allylation of branched aldehydes
by transition metal/amine catalysis, see: (a) Usui, I.; Schmidt, S.;
Breit, B. Org. Lett. 2009, 11, 1453. (b) Jiang, G.; List, B. Angew. Chem.
Int. Ed. 2011, 50, 9471. (c) Yoshida, M.; Terumine, T.; Masaki, E.; Ha-
ra, S. J. Org. Chem. 2013, 78, 10853. (d) Krautwald, S.; Sarlah,
D.; Schafroth, M. A.; Carreira, E. M. Science. 2013, 340, 1065. (e) Huo,
X.; Yang, G.; Liu, D.; Liu, Y.; Gridnev, I. D.; Zhang, W. Angew. Chem.
Int. Ed. 2014, 53, 6776. (f) Wang, P. -S.; Lin, H. -C.; Zhai, Y. -J.; Han,
Z. -Y.; Gong, L. -Z. Angew. Chem. Int. Ed. 2014, 53, 12218.
Me Ph
Me
1a
B1: up to 60%, 94:6 er
CpFe(III)CpSbF6
conditions
2a or 2b
3a or 4a
CpFe(III)CpSbF6
2,3,4,5-F4HC6B(OH)2:
up to 32%, 94:6 er
InBr3: up to 21%, 93:7 er
p-TsOH : < 5%, er n.d.
TFA: up to 18%, 88:12 er
+
:
up to 35%, 93:7 er
Proposed catalytic cycle
9
B(OR)3
Ph
HO
Ph
+
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
SbF6 Fe
Ph
Ph
C (tetra-ion)
Ion Exchange
B(OR)2
B(OH)2
+
B(OR)3
+
Fe
Fe
+
SbF6
SbF6
Fe
Boronic Acid Cycle
HFIP
D (zwitterion)
B1 (R = H or CH(CF3)2)
B1
Ph
SbF6
Ph
O
Ph
E (carbocation)
H
Ph
Me Ar
R1 R2
N
+
H2O
Me
H
(7) (a) Quasdorf, K. W.; Overman, L. E. Nature, 2014, 516, 181. (b)
Marek, I.; Minko, Y.; Pasco, M.; Mejuch, T.; Gilboa, N.; Chechik, H.;
Jaya P. Das, J. P. J. Am. Chem. Soc. 2014, 136, 2682.
Ar
R1 R2
N
F3C
CF3
H (chiral enamine)
R1 R2
CF3
CF3
Me
H
N
H
Chiral Amine Cycle
(8) (+)-cuparene: (a) Enzell, C.; Erdtman, H.; Tetrahedron, 1958, 4,
361. LY426965: (b) Rasmussen, K.; Calligaro, D. O.; Czachura, J. F.;
Dreshfield-Ahmad, L. J.; Evans, D. C.; Hemrick-Luecke, S. K.; Kall-
man, M. J.; Kendrick, W. T.; Leander, J. D.; Nelson, D. L.; Overshiner,
C. D.; Wainscott, D. B.; Wolff, M. C.; Wong, D. T.; Branchek, T. A.;
Zgombick, J. M.; Xu, Y.-C. J. Pharmacol. Exp. Ther. 2000, 294, 688.
CCR5 antagonist: (c) Shah,S. K.; Chen, N.; Guthikonda, R. N.; Mills,
S. G.; Malkowitz, L.; Springer, M. S.; Gould, S. L.; Julie A. DeMartino,
J. A.; Carella, A.; Carver, G.; Holmes, K.; Schleif, W. A.; Danzeisen, R.;
Hazuda, D.; Kessler, J.; Lineberger, J.; Miller,M.; Emini E. A.; Mac-
Coss, M. Bioorg. Med. Chem. Lett. 2005, 15, 977. NK1/NK3 receptor
antagonist: (d) Hanessian, S.; Jennequin, T.; Boyer, N.; Babonneau,
V.; Soma, U.; la Cour, C. M.; Millan, M. J.; De Nanteuil, G. ACS Med.
Chem.Lett. 2014, 5, 550.
(9) For sexample, see: Kummer, D. A.; Chain, W. J.;Morales, M. R.;
Quiroga, O.; Myers, A. G. J. Am. Chem. Soc. 2008, 130, 13231; and
references cited therein.
(10) Shuklov, I. A.; Dubrovina, N. V.; Börner, A. Synthesis 2007, 2925.
(11) Zheng, G.; Lejkowski, M.; Hall, D. G. Chem. Sci. 2011, 2, 1305.
(12) Melchiorre, P. Angew. Chem. Int. Ed. 2012, 51, 9748.
(13) Zhang, L.; Fu, N.; Luo, S. Acc. Chem. Res. 2015, 48, 986.
(14) (a) Sánchez, D.; Bastida, D.; Burés, J.; Isart, C.; Pineda, O.; Jaume
Vilarrasa, J.; Org. Lett. 2012, 14, 536. (b) Kempf, B.; Hampel, N.; Ofial,
A. R.; Mayr, H. Chem. - Eur. J. 2003, 9, 2209. For reviews on asym-
metric enamine catalysis, see: (c) Mukherjee, S.; Yang, J. W.; Hoff-
mann, S.; List, B. Chem. Rev. 2007, 107, 5471. (d) Desmarchelier, A.;
Coeffard, V.; Moreau, X.; Greck, C. Tetrahedron, 2014, 70, 2491.
(15) (a) Jensen, K. L.; Dickmeiss, G.; Jiang, H.; Albrecht, Ł.; Jørgensen.
K. A. Acc. Chem. Res. 2012, 45, 248.
(16) The addition of acetic acid is known to promote a faster E/Z
enamine equilibrium for branched aldehydes, see: Burés, J.; Arm-
strong, A.; Blackmond. D. G. Chem. Sci. 2012, 3, 1273.
(17) Baumann, T.; Bächle, M.; Hartmann, C.; Bräse, S. Eur. J. Org.
Chem. 2008, 2207.
Ar
A8
N
O
G (imine)
H
TBS
A8
R2
H2O
O
R1
N OH
Ar
Me
Ar
H
H
Me
F
ASSOCIATED CONTENT
Supporting Information
Experimental details, analytical and spectral reproductions
for the prepared compounds. The Supporting Information is
available free of charge on the ACS Publications website.
AUTHOR INFORMATION
Corresponding Author
*E-mail: dennis.hall@ualberta.ca
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
This research was funded by the Natural Science and Engi-
neering Research Council of Canada (Discovery Grant to
D.G.H.) and the University of Alberta. X.M. thanks Alberta
Innovate − Health Solutions for a Graduate Studentship. We
thank Dr. Angelina Morales-Izquierdo for help with mass
spectrometric analyses, and Dr. Tristan Verdelet for sugges-
tions on the manuscript.
(18) To the best of our knowledge, dual catalytic asymmetric Tsuji-
Trost type allylation with Pd/amine catalysis on aldehydes with aryl
groups bearing bromo substituents has not been achieved, see: ref. 6.
(19) For a comparison of substrate 1h under Pd/amine/chiral phos-
phoric acid catalysis similar to ref. 6b, a lower enantioselectivity 67%
ee was observed, see: ref. 6f.
REFERENCES
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(20) The racemic background enol allylation did not undermine the
enantioselectivity as proposed by Bräse and co-workers.17
(21) Sonawane, R. P.; Jheengut, V.; Rabalakos, C.; Larouche-Gauthier,
R.; Scott, H. K.; Aggarwal, V. K. Angew. Chem. Int. Ed. 2011, 50, 3760.
(22) Prins, R.; Korswagen, A. R.; Kortbeek, A. G. T. G. J. Organomet.
Chem. 1972, 39, 335.
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Boronic Acid Catalysis
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up to 90% yield
up to 97:3 er
Chiral Amine Catalysis
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