Catalytic Asymmetric Construction of Halogenated Stereogenic Carbon Centers by Direct Vinylogous Mannich-Type Reaction

Article abstract of DOI:10.1021/jacs.8b09484

A catalytic asymmetric vinylogous Mannich-type reaction of γ-halo-α,β-unsaturated N-acylpyrazoles and N-Boc-aldimines was disclosed, which afforded an array of halogenated (F-, Cl-, and Br-) allylic stereogenic carbon centers in high yields with good to high regio-, diastereo-, and enantioselectivities. The brominated product served as a suitable electrophile for common S_N2 nucleophilic substitution and copper-mediated S_N2′ allylic alkylation with metal reagents. The utility of present methodology was demonstrated by the asymmetric synthesis of a common intermediate toward the synthesis of two chiral 2,3-disubstituted piperidine pharmaceuticals.

Full text of DOI:10.1021/jacs.8b09484

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Communication
Catalytic Asymmetric Construction of Halogenated Stereogenic
Carbon Centers by Direct Vinylogous Mannich-Type Reaction
Feng Zhong, Wen-Jun Yue, Hai-Jun Zhang, Cheng-Yuan Zhang, and Liang Yin
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 01 Nov 2018
Downloaded from http://pubs.acs.org on November 1, 2018
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Catalytic Asymmetric Construction of Halogenated Stereogenic
Carbon Centers by Direct Vinylogous Mannich-Type Reaction
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Feng Zhong, Wen-Jun Yue, Hai-Jun Zhang, Cheng-Yuan Zhang, and Liang Yin*
CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Center for Excellence in Molecular Synthesis, Shanghai
Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling
Road, Shanghai 200032, China
Supporting Information Placeholder
Scheme 1. Catalytic Asymmetric Direct Vinylogous Mannich-
Type Reaction (DVMR) of -Halogenated ,-Unsaturated N-
Acylpyrazoles Catalyzed by a Copper(I) Complex
ABSTRACT: A catalytic asymmetric vinylogous Mannich-type
reaction of -halo-,-unsaturated N-acylpyrazoles and N-Boc-
aldimines was disclosed, which afforded an array of halogenated (F-,
Cl-, and Br-) allylic stereogenic carbon centers in high yields with
good to high regio-, diastereo- and enantioselectivity. The brominated
product served as a suitable electrophile for common SN2 nucleophilic
substitution and copper-mediated SN2' allylic alkylation with metal
reagents. The utility of present methodology was demonstrated by the
asymmetric synthesis of a common intermediate towards the synthesis
of two chiral 2,3-disubstituted piperidine pharmaceuticals.
(a) Reported Catalytic Asymmetric Direct Vinylogous Mannich-Type Reaction (DVMR)
[Cu(I)]
organic base
O
NHBoc

O
NBoc
H

+
Y
R
Y
Y
Y = 3,5-Ph2-pyrazole
R


H
low pKa
(b) This Work: DVMR of -Halogenated
, -Unsaturated Amides
 

[Cu(I)]
organic base
O
NHBoc
O
NBoc

X
*
Y
R
*



Y = 3,5-Ph2-pyrazole
R
H
H
X
addressing problems:
regioselectivity
diastereoselectivity
enantioselectivity
Halogenated stereogenic carbon centers are found in naturally
occurring compounds.1 Although the chiral carbon centers bearing
fluorine or iodine in natural products are few, the molecules
containing chlorine or bromine are much more. For examples, one
chiral quaternary center containing chlorine and one chiral tertiary
carbon center with bromine present in (+)-halomon, an anticancer
lead.2 Clindamycin, used to treat a variety of bacterial infections,
owns a chiral chlorinated tertiary carbon center as well.2 In manmade
bioactive molecules, the chiral carbon centers with fluorine are much
more frequently encountered.3 Some of them exhibited significant
bioactivity, such as LY-5034304 (used to treat Parkinson’s disease).
Actually, halogenation, as well as the stereochemistry of the halogen-
bearing carbons, can significantly alter the bioactivity of molecules.2
Moreover, halogen atoms have a profound effect on the bonding
through halogen bonding interactions.2 Therefore, exploring effective
stereoselective construction of halogenated chiral carbon centers is an
important synthetic task.5
highly functionalized
synthetic intermediates
low pKa
X = F, Cl, Br
The catalytic asymmetric construction of halogenated chiral carbon
centers consists of two pathways. One is catalytic asymmetric
introduction of a halogen into prochiral compounds, including
electrophilic halofunctionalization of alkenes12 and halogenation of
various nucleophiles and electrophiles.13 Denmark,12b,12d Burns14 and
many others15 are pioneers in the former case. In the latter case,
methods for enantioselective -chlorination or -bromination of
carbonyl compounds and related reactions have rapidly progressed in
the last decade.16 The other is the catalytic asymmetric
functionalization of a halogenated prochiral carbon, comprising of
enantioselective transformation with halogenated alkenes,5b,17
asymmetric allylation with halogenated allyl metal reagents,18
asymmetric -functionalization of -halo enolsilanes or enolates,19
and asymmetric -elimination of trihalides.20 However, to the best of
our knowledge, the chemistry of -halo dienolates has never been
investigated in literature. Herein, we disclosed a copper(I)-catalyzed
direct asymmetric vinylogous Mannich-type reaction of -halo(F, Cl
or Br)-,-unsaturated N-acylpyrazoles and N-Boc-aldimines,
constructing chiral halogenated allylic carbon centers in high yields
with good to high regio-, diastereo-, and enantioselectivity.
Alkyl halides are among the most versatile compounds in synthetic
chemistry and regularly employed in alkylation reactions, radical
cascades, and alkyl cross-coupling chemistry.2b,6 As one special type
of alkyl halides, allyl halides attract the most attention of synthetic
community due to its high reactivity and abundant transformation
chemistry. First, allyl halides were employed in transition metal-free
asymmetric allylic alkylation using Grignard reagents.7 Second, allyl
halides were utilized in transition metal-catalyzed asymmetric allylic
substitution with various nucleophiles.8 Third, allyl halides were
utilized in nickel-catalyzed asymmetric Negishi cross-coupling and
palladium-catalyzed enantioselective allyl-allyl cross-coupling.9
Moreover, asymmetric Nozaki-Hiyama-Kishi allylation of carbonyl
compounds afforded synthetically versatile homoallylic alcohols,
which can go further structure elaboration if multiply halogenated
allylic halides were utilized.10 However, the allyl halides employed in
literature mainly focused on the racemic compounds or the ones
without stereogenic carbon center. The preparation of chiral allyl
halides would offer a new opportunity for the asymmetric allylation
of various nucleophiles with or without transition metal catalysts.11
Previously, we reported a copper(I)-catalyzed direct catalytic
asymmetric vinylogous Mannich-type reaction of ,-unsaturated N-
acylpyrazole and various aldimines (Scheme 1a).21 Combination of an
N-acyl-3,5-Ph2-pyrazole and a bulky bisphosphine ligand ((R)-
DTBM-SEGPHOS) was found to be the key to perfectly control the
regioselectivity. It was envisioned that a weakly electron-withdrawing
halogen (F, Cl and Br) would acidify the -protons but would not
reduce the nucleophilicity of the -carbon significantly, which would
allow an atom-economic22 vinylogous Mannich-type reaction to
construct halogenated stereogenic carbon centers in the presence of a
copper catalyst23 (Scheme 1b).
Table 1. Optimization of the Reaction Conditionsa
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Journal of the American Chemical Society
Page 2 of 6
Cu(CH3CN)4PF6 (5 mol %)
ligand (5 mol %)
reaction (3u-3y). However, -addition inevitably occurred and -
adducts were observed as side products. A terminal olefin presented
in the product offers the opportunity for further functional group
manipulation to afford more complex molecules. The relative
configuration of product 3 was determined to be syn by virtue of X-
ray crystallographic analysis of 3b (for details, see SI), which is in
conformity with 6a.
O
NHBoc

O
base (5 mol %)
NBoc
H
F
1
2
3
4
5
6
7
8
N
N
N
N
Ph
+
Ph
Ph



THF (0.1 M), T oC, 24 h
Ph
F
Ph
1
Ph
2a, 2 equiv
base
3a
T
rt
rt
rt
rt
rt
rt
rt
rt
rt
0
total yieldb
dr (syn/anti)b
ee (%)c
/b
entry
1
ligand
(R)-BINAP
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
iPr2NEt
Cy2NMe
Et3N
Et3N
-
39
20
<5
<5
69
29
36
66
75
87
83
61
76
0
1/2
1/2.7
-
23/28
1/1
1.5/1
-
2
(R)-TOL-BINAP
(R)-SEGPHOS
(R)-QUINAP
-10/18
Table 2. Substrate Scope of N-Boc-Aldimines 2 in the
3
-
-
Vinylogous Mannich-Type Reaction with 1a
4
-
-
Cu(CH3CN)4PF6 (5 mol %)
5
(R)-DIFLUORPHOS
(R,R)-QUINOXP*
(R,R)-Ph-BPE
1/2.3
<1/20
1/2
53/21
-/4
1/1.8
1/3
(R)-DTBM-SEGPHOS (5 mol %)
9
O
NHBoc

O
Et3N (5 mol %)
NBoc
H
6
F
+
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
Y
R
Y
THF (0.1 M), 0 oC, 12 h
Y = 3,5-Ph2-pyrazole

7
-37/-46
11/66
98
1/3
R


F
3
8
(R,Rp)-TANIAPHOS
(R)-DTBM-SEGPHOS
(R)-DTBM-SEGPHOS
(R)-DTBM-SEGPHOS
(R)-DTBM-SEGPHOS
(R)-DTBM-SEGPHOS
-
3/1
>20/1
>20/1
>20/1
>20/1
>20/1
>20/1
-
1
2
, 2 equiv for aromatic
4 equiv for aliphatic
/
= >20/1
 
9
>20/1
>20/1
>20/1
>20/1
>20/1
-
b
3a
R = H,
, 81%, >20/1 dr, >99% ee
, 82%, >20/1 dr, >99% ee
, 83%, >20/1 dr, 97% ee
, 88%, 8/1 dr, >99% ee
, 81%, >20/1 dr, 98% ee
10d
11
12
13
14e
15
>99
98
R = OMe, 3b
NHBoc
F
O
R = Me,
R = F,
R = CF3,
3c
3d
3e
0
Y
0
99
R = CO Me,
R = OTf,
R = BPin,
3f, 90%, 15/1 dr, 98% ee
3g
2
-20
0
98
R
, 83%, 14/1 dr, >99% ee
3h, 76%, 15/1 dr, 95% ee
-
(R)-DTBM-SEGPHOS
NHBoc
0
0
-
-
-
R
O
O
3i
3j
3k
R = OMe,
R = F,
R = Cl,
R = Br,
,
,
86%, 10/1 dr, 97% ee
86%, 10/1 dr, >99% ee
, 86%, 12/1 dr, >99% ee
85%, 11/1 dr, 99% ee
a1: 0.1 mmol, 2a: 0.2 mmol. bDetermined by 1H NMR analysis of reaction crude mixture using CH3NO2 as an
internal standard. cDetermined by chiral-stationary-phase HPLC analysis. dIsolated yield. ePerformed without
Y
Y
3l
,
F
copper(I)-complex.
NHBoc
3m
3n
3o
R = OMe,
R = F,
R = Cl,
R = Br,
,87%, >20/1 dr, >99% ee
, 81%, >20/1 dr, >99% ee
, 78%, >20/1 dr, 96% ee
O
tBu
R
Ph
PPh2
H
Ph
R
NMe2
PPh2
R
N
N
P
O
O
PAr2
PAr2
PAr2
PAr2
PPh2
Me
tBu
P
P
Fe
N
R
R
P
Ph
3p, 88%, >20/1 dr, 97% ee
F
Ph
O
Me
Ar = Ph,
(R)-BINAP;
Ar = Tol,
(R)-TOL-
BINAP
(
)-SEGPHOS
(R,R)-Ph-BPE
(R,R)-QUINOXP*
(R)-QUINAP
R = H, Ar = Ph,
R
;
(
,
R Rp
)-TANIAPHOS
NHBoc
F
NHBoc
O
O
NHBoc
O
R = F, Ar = Ph, (R)-DIFLUORPHOS;
R = H, Ar = 3,5-tBu2-4-OMe-Ph,
(R)-DTBM-SEGPHOS
Y
Y
Y
F
F
O
3r
3s
, 94%, >20/1 dr, >99% ee
, 81%, 15/1 dr, >99% ee
3q
, 86%, >20/1 dr, 94% ee
We began our investigation by using -F-,-unsaturated
compound 1 and N-Boc-aldimine 2a as model substrates for
optimization of reaction conditions (Table 1). (R)-BINAP, (R)-TOL-
BINAP, (R)-SEGPHOS, (R)-QUINAP, (R)-DIFLUORPHOS, (R,R)-
QUINOXP* and (R,R)-Ph-BPE proved to be not suitable ligands in
this reaction (entries 1-7). (R,Rp)-TANIAPHOS was found to be a
good ligand in terms of excellent regioselectivity although both
diastereo- and enantioselectivity were not high (entry 8). As
previously reported,21 bulky (R)-DTBM-SEGPHOS outperformed to
give the vinylogous product 3a in 75% yield with >20/1
regioselectivity, >20/1 diastereoselectivity and 98% ee (entry 9).
Decreasing the temperature to 0 oC resulted in an increased yield
(entry 10). Study of organic bases identified triethylamine as the best
in terms of the reaction performance and its low price (entries 10-12).
Further decreased reaction temperature led to extenuated reactivity
(entry 13). Both copper(I) complex and organic base were
indispensable for this reaction as no reaction occurred in the absence
of either of them (entries 14-15).
NHBoc
O
NHBoc
O
NHBoc
O
Y
Y
Y
O
F
S
F
F
c,d
c
3t
3u
3v
, 82%, >20/1 dr, >99% ee
, 99%, >20/1 dr, 98% ee
, 75%, >20/1 dr, 95% ee
NHBoc
F
O
NHBoc
O
NHBoc
O
Y
Y
Y
F
F
, 69%, 3/1 dr, 96% ee
c,e
c,f
c,g
3y
3w
3x
, 74%, 12/1 dr, 96% ee
, 79%, >20/1 dr, 97% ee
a1: 0.2 mmol, 2: 0.4 mmol. Isolated yield reported. Regioselectivity and diastereoselectivity
determined by 1H NMR analysis of reaction crude mixture. Enantioselectivity determined by
chiral-stationary-phase HPLC analysis. bGram-scale reaction. : 0.2 mmol, : 0.8 mmol.
c1
2
d: = 6/1. e: = 8/1. f: = 3/1. g: = 5/1.
The present catalytic system was also suitable to -Cl and -Br-,-
unsaturated compounds (4 and 5) (Table 3). As for chlorinated
compound 4, 3 mol % copper(I) complex and 3 mol % Et3N were
enough to catalyze the Mannich-type reaction of both aromatic
aldimines and heteroaromatic aldimine. Both the yield and the
enantioselectivity were generally excellent. However, the
diastereoselectivity was moderate in some cases (6d, 6f, 6g, 6i, 6j,
6m, 6n and 6p). Aliphatic aldimines exhibited lower reactivity as 10
mol % copper(I) complex and 10 mol % Cy2NMe were required to
achieve satisfactory results. Moreover, instead of (R)-DTBM-
SEGPHOS, (R,Rp)-TANIAPHOS was employed due to its better
performance at low temperature.21a As for brominated compound 5,
the same reaction tendency was observed. Although the
diastereoselectivity was moderate in some cases, both regioselectivity
and enantioselectivity were excellent. Even though allyl bromides are
more useful synthetic intermediates, there are fewer reports in
literature on the enantioselective construction of brominated chiral
carbon centers containing a vinyl group.
With optimized reaction conditions in hand, the catalytic
asymmetric vinylogous Mannich-type reaction of 1 and various N-
Boc-aldimines 2 was examined (Table 2). Aromatic imines reacted
with 1 smoothly to deliver the vinylogous products in uniformly good
results. Both electron-donating and withdrawing groups on the
aromatic imines were well tolerated. The position of the substituents
on the phenyl ring seemed to have little effect on both yield and
enantioselectivity. However, sterically congested ortho-substituted
aromatic imine led to inferior diastereoselectivity (3i-3l). A variety of
functional groups, including methoxyl, methyl, fluoride, chloride,
bromide, ester, triflate (OTf) and pinacolatoboron (BPin), were well
tolerated. Particularly, the products with Cl, Br, OTf and BPin on the
phenyl ring are noteworthy, as these functional groups allow for late-
stage transition metal-catalyzed cross-coupling reaction.
The phenyl ring in aldimines 2 could be replaced by 1-naphthyl, 2-
naphthyl, 3-furanyl, and 3-thienyl with the desired products obtained
in high yield, regio-, diastereo- and enantioselectivity (3q-3t).
Remarkably, aliphatic imines containing acidic -protons and thus
sensitive to basic conditions were also competent substrates in this
The gram-scale reaction of 3a, 6a and 7a proceeded smoothly to
give constant results, highlighting the robustness of the present
methodology. The two stereogenic carbon centers in 6a were
determined to be R and R by means of X-ray diffraction analysis (for
details, see SI). The configurations of other vinylogous products (3,
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Journal of the American Chemical Society
6b-6p and 7a-7g) were assigned by analogy. Since the ligand
Scheme 2. Transformations of Vinylogous Products
employed for the generation of 6q-6s and 7h was changed from (R)-
DTBM-SEGPHOS to (R,Rp)-TANIAPHOS, the stereochemistry in
these products required additional assignment. The X-ray
crystallographic analysis of 7h identified the absolute configurations
of the two stereogenic carbon centers to be R and R (for details, see
SI). Analogically, the absolute configurations of 6q-6s were assigned
tentatively.
NHBoc
NHBoc
O
O
1
2
3
4
5
6
7
8
(1) PPh3, THF/H2O, rt;
(2) (Boc)2O, KOH (aq.), rt
PhSH, Et3N, THF, rt
Ph
Ph
OMe
Ph
OMe
X= Br
SPh
13, 86%
NHBoc
12, 78% (two steps)
NHBoc
O
NHBoc
NHBoc
O
O
H2SO4 (10 mol %)
NaN3,
Ph
OMe
Y
Ph
OMe
CH3OH, 60 o
Y = 3,5-Ph2-pyrazole
C
acetone, rt
X= Br
N3
X
X
11, 99%
X = F, 3a (>20/1 dr)
Cl, 6a (>20/1 dr)
Br, 7a (>20/1 dr)
X = F, 8, 93%
Cl, 9, 96%
Br, 10, 97%
Table 3. Substrate Scope of N-Boc-Aldimines 2 in the Vinylogous
Mannich-Type Reaction with 4 and 5a
NaBH4, THF/H2
0 oC to rt
O
CuCN, AlMe3
CuCN, ZnEt2
DMF, -50 o
DMF, 0 o
C
C
Cu(CH3CN)4PF6 (x mol %)
9
(
)-DTBM-SEGPHOS (x mol %)
Et3N (x mol %)
R
NHBoc
NHBoc
NHBoc
O
O
O
NHBoc

O
NBoc
H
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
Ph
OH
Ph
OMe
Ph
OMe
X
+
Y
R
Y
F
THF (0.067 M), -40 o
Y = 3,5-Ph2-pyrazole
, x = , 12 h , 2 equiv for aromatic
C

Me
15
Et
16
R


14
X
86%
X = Cl, 99%, >20/1 dr
X = Br, 95%, >20/1 dr
X = Cl, 99%, >20/1 dr
X = Br, 72%, 10/1 dr
X
Cl
Br
4
5
3
2
X
Cl 6
= ,
=
,
,
5
/
= >20/1
Br
7
, x = , 48 h 4 equiv for aliphatic
,
 
b
Structure elaboration of the optically enriched vinylogous product
6a
R = H,
, 93%, 13/1 dr, >99% ee
, 82%, 13/1 dr, >99% ee
, 94%, 13/1 dr, >99% ee
, 95%, 7/1 dr, >99% ee
, 83%, 12/1 dr, 98% ee
NHBoc
O
R = OMe, 6b
ent-7a opens a pathway for further transformations to chiral 2,3-
disubstituted piperidines with -hydroxyl or -amino functional
groups (Scheme 3), which are common subunits in numerous natural
products, as well as in pharmaceutically active compounds.25 For
example, (+)-L-733,06026 and (+)-CP-99,99427 are potent and
selective nerokinin-1 substance P receptor antagonists, both of which
can be accessed from a common intermediate 20 according to
reported procedures.28 The silver-mediated intramolecular substitution
of ent-7a proceeded smoothly to give intermediate 17 in 92% yield,
which afforded 18 in 77% yield for two steps through the protection
with (Boc)2O and the following opening of the oxazolidin-2-one
moiety. TBS-protection of the secondary alcohol and fully reduction
of the ,-unsaturated moiety gave 19 in 75% yield for three steps.
Then, cyclization and removal of the TBS group led to the common
intermediate 20 in 69% yield for three steps.
R = Me,
R = CF3,
6c
6d
Y
R = CO Me, 6e
Cl
2
R
R
R = OTf,
6f
,
95%, 8/1 dr, >99% ee
NHBoc
R
O
O
6g
6h
R = F,
R = Cl,
R = Br,
, 92%, 8/1 dr, >99% ee
, 90%, 13/1 dr, >99% ee
92%, 8/1 dr, >99% ee
Y
Y
6i
,
Cl
NHBoc
6j
6k
6l
R = OMe,
R = F,
R = Cl,
R = Br,
,
94%, 8/1 dr, >99% ee
, 91%, 11/1 dr, >99% ee
89%, 10/1 dr, >99% ee
,
6m
,98%, 9/1 dr, >99% ee
Cl
O
NHBoc
Cl
NHBoc
O
NHBoc
O
Y
Y
Y
Cl
Cl
S
6n
6o
6p
, 92%, 8/1 dr, 95% ee
, 97%, 8/1 dr, >99% ee
, 97%, 15/1 dr, >99% ee
NHBoc
O
NHBoc
O
NHBoc
O
Scheme 3. Synthetic Application of Vinylogous Product ent-7a
Y
Y
O
Y
NHBoc
O
NHBoc
(1) (Boc)2O, Et3N
DMAP, DCM, rt;
O
HN
O
Cl
Cl
Cl
O
AgTFA
c
c
c
Ph
OMe
Ph
Y
Ph
Y
6q
6r
6s
, 98%, >20/1 dr, 92% ee
, 99%, >20/1 dr, 90% ee
, 88%, >20/1 dr, 94% ee
CH3CN, 50 o
C
(2) Cs2CO3, MeOH, rt
OH
Br
b,d
7a
R = H,
R = OMe, 7b
R = Me,
7c
R = CF3O, 7d
R = Br,
7e
, 89%, 13/1 dr, >99% ee
, 81%, 6/1 dr, >99% ee
, 94%, 12/1 dr, >99% ee
, 78%, 8/1 dr, >99% ee
, 95%, 11/1 dr, >99% ee
ent
-7a (>20/1 dr)
17, 92%
18, 77% (two steps)
NHBoc
O
(1) TBSOTf, 2,6-lutidine, DCM, 0 oC;
(2) Pd/C, H2, MeOH, rt;
(3) LiBH4, MeOH, THF, 0 o
Y = 3,5-Ph2-pyrazole
Y
(+)-CP-99,994
R = 2-OMe-C6H4CH2
C
Br
R
NHBoc
NHR
OR'
OH
Ph
(1) MsCl, Et3N, CH2Cl2, -78 oC;
NHBoc
NHBoc
NHBoc
O
O
ref 28
O
or
Ph
OH
(2) KOtBu, THF, 0 oC;
MeO
N
Ph
N
Ph
N
Boc
Y
Y
Y
H
H
OTBS
19, 75% (three steps)
(3) 3 M HCl (aq.), THF, rt
Br
Br
Br
7h
, 87%, 13/1 dr, >99% ee , 93%, >20/1 dr, 91% ee
20, 69% (three steps)
(+)-L-733,060
R' = 3,5-(CF3)2-C6H3CH2
c
7f
7g
, 90%, 8/1 dr, 99% ee
In summary, by introducing a halogen (F, Cl or Br) at the -position
of ,-unsaturated N-acylpyrazole, we achieved a copper(I)-catalyzed
direct catalytic asymmetric vinylogous Mannich-type reaction for the
first time, which constructed a series of halogenated chiral stereogenic
carbon centers in high enantioselectivity. The reaction showed
advantages, such as mild reaction conditions, broad substrate scope,
good tolerance of functional groups, and good to excellent regio- and
stereoselectivity. The produced chiral allyl bromide was successfully
employed as a chiral electrophile in common SN2 reaction and
copper-catalyzed SN2' reaction. Moreover, the present methodology
was applied to the synthesis of a common intermediate towards the
synthesis of two chiral piperidine pharmaceuticals. Further efforts
regarding the expansion of the present methodology and its
application in the synthesis of bioactive natural products are in
progress.
a4 5
2
-
:
0.2 mmol,
:
0.4 mmol. Isolated yield reported. Regioselectivity and
diastereoselectivity determined by 1H NMR analysis of reaction crude mixture.
Enantioselectivity determined by chiral-stationary-phase HPLC analysis. bGram-scale
c4 5
2
4'
5'
reaction.
Ph2-pyrazole-amides
- : 0.2 mmol. : 0.8 mmol. 3,5-Tol2-pyrazole-amides ( and ) instead of 3,5-
4
5
) used. 10 mol
(
and
%
Cu(CH3CN)4PF6, 10 mol % (R,Rp)-
TANIAPHOS and 10 mol % Cy2NMe employed. 48 h. d3 mol % Cu(CH3CN)4PF6, 3 mol %
(R)-DTBM-SEGPHOS and 3 mol % Et3N employed.
The transformations of vinylogous products were presented in
Scheme 2. The alcoholysis of 3a, 6a and 7a afforded esters 8, 9 and
10 in excellent yields. SN2 reaction of 10 with NaN3 led to 11 in 99%
yield. The Staudinger reduction of azide group in 11 and the
subsequent protection of newly generated amine with (Boc)2O led to
chiral diamine derivative 12 in 78% yield for two steps. Moreover,
SN2 reaction of 10 with PhSH generated thioether 13 in 86% yield.
The full reduction of 3a was achieved to furnish 14 in 86% yield. The
reported conditions for the SN2' substitution of allyl halides promoted
by copper(I) salt were slightly modified.24 In the presence of CuCN,
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website at:
o
the reactions of 9 and 10 with AlMe3 were set up in DMF at 0 C,
which afforded 15 in excellent yields with >20/1 dr. The reaction of 9
with ZnEt2 in DMF at -50 oC proceeded in excellent results while the
reaction of 10 with ZnEt2 provided 16 in 72% yield with 10/1 dr. The
newly generated stereogenic center in 15 was determined to be R by
further transformation (For details, see SI) and the one in 16 was
assigned to be R tentatively by analogy.
Crystallographic data for 3b, 6a and 7h (CIF)
Experimental procedures, characterizations and analytical data
of new compounds, X-ray diffraction data for 3b, 6a and 7h,
and spectra of NMR and HPLC for new compounds (PDF)
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Transition-metal catalysis of nucleophilic substitution reactions: a
radical alternative to SN1 and SN2 processes. ACS Cent. Sci. 2017, 3,
692–700. More references cited in these papers.
AUTHOR INFORMATION
1
2
3
4
5
6
7
Corresponding Author
*liangyin@sioc.ac.cn
(7) For two selected very recent examples, see: (a) Grassi, D.; Alexakis,
A. Transition metal-free asymmetric and diastereoselective allylic
alkylation using Grignard reagents: construction of vicinal
Stereogenic centers via kinetic resolution. Chem. Sci. 2014, 5, 3803–
3807. (b) Grassi, D.; Alexakis, A. Improvements and applications of
the transition metal-free asymmetric allylic alkylation using
Grignard reagents and magnesium alanates. Adv. Synth. Catal. 2015,
357, 3171–3186. More references cited in these papers.
ORCID
Liang Yin: 0000-0001-9604-5198
Notes
The authors declare no competing financial interests.
8
9
(8) For two selected very recent examples, see: (a) Hethcox, J. C.;
Shockley, S. E.; Stoltz, B. M. Iridium-catalyzed stereoselective
allylic alkylation reactions with crotyl chloride. Angew. Chem. Int.
Ed. 2016, 55, 16092–16095. (b) Goh, S. S.; Guduguntla, S.; Kikuchi,
T.; Lutz, M.; Otten, E.; Fujita, M.; Feringa, B. L. Desymmetrization
ACKNOWLEDGMENT
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
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34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
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54
55
56
57
58
59
60
We gratefully acknowledge the financial support from the “Thousand
Youth Talents Plan”, the National Natural Science Foundation of
China (No. 21672235 and No. 21871287), the Strategic Priority
Research Program of the Chinese Academy of Sciences (No.
XDB20000000), CAS Key Laboratory of Synthetic Chemistry of
Natural Substances and Shanghai Institute of Organic Chemistry.
of
meso-dibromocycloalkenes
through
copper(I)-catalyzed
asymmetric allylic substitution with organolithium reagents. J. Am.
Chem. Soc. 2018, 140, 7052–7055. More references cited in these
papers.
(9) For two selected recent examples, see: (a) Son, S.; Fu, G. C. Nickel-
catalyzed asymmetric Negishi cross-couplings of secondary allylic
chlorides with alkylzincs. J. Am. Chem. Soc. 2008, 130, 2756–2757.
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compounds and imines. Chem. Rev. 2011, 111, 7774–7854. (b) Tian,
Q.; Zhang, G. Recent advances in the asymmetric Nozaki–Hiyama–
Kishi reaction. Synthesis 2016, 48, 4038–4049.
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Ueno, M. Chiral zinc-catalyzed asymmetric -alkylallylation and -
chloroallylation of aldehydes. Angew. Chem. Int. Ed. 2011, 50,
12262–12265. (b) van der Mei, F. W.; Miyamoto, H.; Silverio, D. L.;
Hoveyda, A. H. Lewis acid catalyzed borotropic shifts in the design
of diastereo- and enantioselective -additions of allylboron moieties
to aldimines. Angew. Chem. Int. Ed. 2016, 55, 4701–4706. (c) Tekle-
Smith, M. A.; Williamson, K. S.; Hughes, I. F.; Leighton, J. L.
Direct, mild, and general n-Bu4NBr-catalyzed aldehyde
allylsilylation with allyl chlorides. Org. Lett. 2017, 19, 6024–6027.
(19) For some selected recent examples, see: (a) Liu, W. B.; Reeves, C.
M.; Stoltz, B. M. Enantio-, diastereo-, and regioselective iridium-
selective nonpeptide substance P receptor antagonist radioligand. J.
Med. Chem. 1993, 36, 3197–3201.
(28) (a) Calvez, O.; Langlois, N. Stereoselective synthesis of (2S,3S)-3-
hydroxy-2-phenylpiperidines, precursors of non-peptidic substance P
antagonists. Tetrahedron Lett. 1999, 40, 7099–7100. (b) Garrido, N.
M.; García, M.; Sánchez, M. R.; Díez, D.; Urones, J. G.
Enantioselective synthesis of (+)-L-733,060 and (+)-CP-99,994:
application of an Ireland-Claisen rearrangement/Michael addition
domino sequence. Synlett 2010, 387–390. (c) Liu, Y.-W.; Mao, Z.-Y.;
Ma, R.-J.; Yan, J.-H.; Si, C.-M.; Wei, B.-G. Divergent syntheses of
L-733, 060 and CP-122721 from functionalized piperidinones made
by one-pot tandem cyclization. Tetrahedron 2017, 73, 2100–2108.
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Cu(CH3CN)4PF6 (3-10 mol %)
bisphosphine ligand (3-10 mol %)
O
NHBoc

O
NBoc
H
Et3N or Cy2NMe (3-10 mol %)
X
+
Y
R
Y
R
THF, -40 or 0 oC, 12-48 h
Y = pyrazole



X
52 examples
69%-99%
= 3/1~>20/1
/
 
F
Cl
Br
X =
3/1~>20/1 dr
90%~>99% ee
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