Direct Asymmetric Vinylogous and Bisvinylogous Mannich-Type Reaction Catalyzed by a Copper(I) Complex

Article abstract of DOI:10.1021/jacs.6b13042

A direct catalytic asymmetric vinylogous Mannich-type reaction has been disclosed in good yield, excellent regio-, diastereo- and enantioselectivity. The key to control the regioselectivity is the combination of a bulky N-acylpyrazole and a bulky bisphosphine ligand. The catalytic system was extended to a bisvinylogous Mannich-type reaction by changing the ligand. The synthetic utility of the vinylogous products was demonstrated by several transformations.

Full text of DOI:10.1021/jacs.6b13042

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Communication
Direct Asymmetric Vinylogous and Bisvinylogous
Mannich-Type Reaction Catalyzed by a Copper(I) Complex
Hai-Jun Zhang, Chang-Yun Shi, Feng Zhong, and Liang Yin
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b13042 • Publication Date (Web): 31 Jan 2017
Downloaded from http://pubs.acs.org on January 31, 2017
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Direct Asymmetric Vinylogous and Bisvinylogous Mannich-Type Re-
action Catalyzed by a Copper(I) Complex
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Hai-Jun Zhang, Chang-Yun Shi, Feng Zhong, Liang Yin*
Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences, 345 Lingling Road, Shanghai 200032, China.
Supporting Information Placeholder
are three possible regio-isomers, including α-adduct, γ-adduct
and ε-adduct in theory. Secondly, the enantioselectivity is very
difficult to control because the ε-position is far from the carbon-
yl functional group. To the best of our knowledge, there was
only one example on the catalytic asymmetric bisvinylogous
aldol reaction, which employed trienolsilanes as the nucleo-
philes.6b Control of the regioselectivity proved to be very chal-
lenging with a regioselectivity less than 5/1(ε/α) in many cases.
Moreover, the enantioselectivity was not satisfactory generally,
which allowed room for further improvement. We were planning
to develop both vinylogous and bisvinylogous direct catalytic
asymmetric Mannich-type reaction with both high regioselectiv-
ity and enantioselectivity.
ABSTRACT: A direct catalytic asymmetric vinylogous Mannich-
type reaction has been disclosed in good yield, excellent regio-,
diastereo- and enantioselectivity. The key to control the regiose-
lectivity is the combination of a bulky N-acylpyrazole and a
bulky bisphosphine ligand. The present catalytic system was
successfully extended to a bisvinylogous Mannich-type reaction
simply by changing the ligand. The synthetic utility of the vi-
nylogous products was demonstrated by several transformations.
Optically active δ-amino-α,β-unsaturated carbonyl com-
pounds serve as important structural motifs in biologically active
compounds and also as versatile synthetic intermediates.1 One of
the easiest methods to access these compounds is the catalytic
asymmetric vinylogous Mannich reaction between imines and
dienolate species.2 The cyclic dienolates usually lead to the for-
mation of γ-adducts exclusively whenever the dienolsilanes or
metal dienolates were utilized.3,4 Among the linear dienolate
species, the dienolsilanes are the most frequently employed nu-
cleophiles,5 possibly due to their natural tendency to favor γ-
addition.6 Although metal dienolates would be more practical
from a synthetic perspective, the α-addition product is the typi-
cal mode of reactivity in the Mannich reaction giving an aza-
Morita-Baylis-Hillman-type product after the isomerization of
the double bond.7
Scheme 1. Generation of Copper(I)-Dienolates and Its Pos-
sible Reaction Pathways with N-Boc Imine 2a.
(a) Vinylogous Mukaiyama Mannich-Type Reaction
phosphoric acid
OTBS
NPMP
NHPMP
O
catalysis
+
ref 5b
OEt
R
H
R
OEt
(b) Direct Vinylogous Mannich-Type Reaction
O
N
R = Me, 1a
R = Ph, 1b
N
R
[Cu*] = copper(I)-bisphosphine complex
H
R
harsh
P
NHBoc
O
-addition
N
R = Me, 4a
R = Ph, 5a
Ph
N
R
NBoc
P
Although the vinylogous Mukaiyama reaction has established
its historic position in organic synthesis,2,6c,8 it still suffers from
some limitations. First, the unstable dienolsilanes usually need
to be prepared at a separate step. This leads to undesirable waste
(silica gel, solvent, stoichiometric chlorosilanes, etc.), which is
conflict with the principle of atomic economy in modern green
chemistry.9 Control of the geometry of dienolsilanes is another
concern and usually the inseparable mixture of 1-(E)- and 1-(Z)-
dienolsilanes was obtained in the standard preparation.10 There-
fore, it is highly desirable to develop a direct catalytic asymmet-
ric vinylogous Mannich reaction with high regioselectivity.2
[Cu]
R
O
Ph
H
2a
this work
N
N
R
BocHN
Ph
O
N
R
-addition
N
R = Me, 4a'
R = Ph, 5a'
R
mild
N
R
O
similar -additions reported in ref 7
N
R = Me, 3a
R = Ph, 3b
R
H
R
It was envisioned that increasing the steric hindrance of metal
dienolates or trienolates would be of value to control the regi-
oselectivity. As illustrated in the Scheme 1, by introducing a
bulky pyrazole, together with employing a bulky copper(I) com-
plex, γ-addition would be favored. The approach of electrophiles
to the α-position of the dienolate was shielded by employing this
strategy. An N-acylpyrazole functional group was also helpful to
stabilize the corresponding copper(I) enolate, which might aid
in the control of diastereoselectivity and enantioselectivity.
Moreover, N-acylpyrazole was reported to be a versatile func-
tional group, which can be easily transformed to ester, amide,
carboxylic acid and alcohol functionalities.13 Since the direct
In 2010, Maruoka group disclosed an impressive alkenylation
of aldimines with vinylogous aza-enamines.11 Control of the ge-
ometry of the conjugated double bond in the product was prov-
en to be difficult. Furthermore, the vinylogous aza-enamines
with a C3-substituent were not applicable due to the generation
of a mixture of regioisomers. In 2013, Chi group also reported a
NHC-catalyzed asymmetric Mannich reaction of α,β-
unsaturated esters and activated aldimines.12 Although the
direct vinylogous Mannich reaction was explored, the direct
bisvinylogous Mannich reaction remains unknown, possibly
due to the formidable challenges encountered. Firstly, there
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and 86% ee, with the regioselectivity up to >20/1. Increasing the
vinylogous Michael reactions with α,β-unsaturated compounds
have been reported with success,14,15 the reaction between α,β-
unsaturated N-acylpyrazole 1 and N-Boc imine 2a was investigat-
ed in the presence of copper(I) complex and common organic
base.
1
2
3
steric hindrance of the acylpyrazole (using 3b instead of 3a) fur-
ther increased both the yield and enantioselectivity with main-
tained high regioselectivity. Lowering the temperature from
room temperature to ̶
40 oC led to 98% ee. Further lowering the
4
5
6
7
8
9
temperature gave extenuated reactivity. Et3N was determined to
be the choice due to its relatively cheaper price.
Unfortunately, the above reaction afforded only trace product
with 1 being intact. The high pKa value of the γ-protons was be-
lieved to lead to the inertness of 1 under the current weakly basic
conditions. It was reported that β,γ-unsaturated carbonyl com-
pounds were more easily transformed to the corresponding met-
al dienolate relative to α,β-unsaturated carbonyl compounds
because of the relatively lower pKa value of its α-protons.7a,16
Thus, β,γ-unsaturated N-acylpyrazole 3 was employed as the
model substrate, which was prepared by coupling the commer-
cially available but-3-enoic acid and pyrazoles in reasonable
yield.
Table 2. Substrate Scope of the Direct Catalytic Asymmetric
Vinylogous Mannich-Type Reaction of 3b and N-Boc Imines
2a
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Table 1. Optimization of the Reaction Conditions with
3a/3b and N-Boc Imine 2aa
Cu(CH3CN)4PF6 (5 mol%)
ligand (5 mol%)
O
NHBoc
O
base (5 mol%)
NBoc
H
N
N
N
N
+
Ph
R
R
0.05 M, THF, T oC, 8 h
Ph
R
R
R = Me, 4a
R = Ph, 5a
3, 1 equiv.
R
2a, 1.5 equiv.
entry
1
ligand
T
rt
base
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
TEA
total yieldb 4a(5a)/4a'(5a')
0.6/1
ee of 4a(5a) (%)c
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
Ph
Ph
Ph
Ph
(R)-BINAP
99
99
95
88
61
82
24
89
88
99
98
43
99
99
16
21
24
20
<5
21
-10
-39
86
96
98
99
98
98
2
(R)-TOL-BINAP
rt
0.8/1
0.8/1
0.6/1
0.6/1
0.3/1
0.5/1
10/1
3
(R)-SEGPHOS
rt
4
(R)-DIFLUORPHOS
(R,R)-QUINOXP*
rt
5
rt
6
(R,R)-Ph-BPE
rt
7
(R)-QUINAP
rt
8
(R,Rp)-TANIAPHOS
(R)-DTBM-SEGPHOS
(R)-DTBM-SEGPHOS
(R)-DTBM-SEGPHOS
(R)-DTBM-SEGPHOS
(R)-DTBM-SEGPHOS
(R)-DTBM-SEGPHOS
rt
9
rt
>20/1
>20/1
>20/1
>20/1
>20/1
>20/1
10
11
12d
13
rt
- 40
- 60
- 40
- 40
14e
a
TEA
3: 0.1 mmol, 2a: 0.15 mmol. b Determined by 1H NMR analysis of reaction crude mixture using
CH3NO2 as an internal standard. c Determined by chiral-stationary-phase HPLC analysis. d 24 h. e 1
mol % Cu(CH3CN)4PF6, 1 mol % TEA and 2 equiv. 2a were employed. The concentration of 3b was
0.2 M. DIPEA = diisopropyl ethyl amine. TEA = Triethyl amine.
O
tBu
R
R
Ph
PPh2
Ph
NMe2
PPh2
N
N
P
O
O
PAr2
PAr2
PAr2
PAr2
PPh2
Me
tBu
P
P
Fe
H
N
With the optimized reaction conditions in hand, the substrate
scope was investigated (Table 2). In regard to aromatic imines,
both electron-donating and withdrawing substituents were well
tolerated (entry 1-11). This reaction was not very sensitive to the
position of a substituent on the phenyl ring of the aromatic
imine. However, sterically congested ortho-substituted aromatic
imine required lower temperature and longer reaction time to
obtain the good yield and enantioselectivity. The reaction condi-
tions were also applicable to hetero-aromatic imines, giving the
products (5l, 5m and 5n) in excellent yield, regioselectivity and
enantioselectivity. Moreover, both 2-naphthyl imine and 1-
naphthyl imine reacted with 3b to afford the products (5o and
5p) in excellent yield, regioselectivity and enantioselectivity.
Remarkably, aliphatic imines containing acidic α-protons and
thus sensitive to basic conditions were also competent substrates
in this reaction (Entry 17-20). It was noteworthy that several
vinylogous products (5c, 5d, 5f, 5g and 5p) were obtained in >99%
ee, which significantly facilitate its application in organic synthe-
sis without enantiomeric enrichment in the subsequent trans-
formation. A gram scale reaction of 3b and 2a in the presence of
1 mol % copper(I) catalyst and 1 mol % Et3N afforded the con-
R
R
P
Ph
Ph
(R,R)-Ph-BPE
Me
O
Ar = Ph,
(R)-BINAP;
Ar = Tol,
(R)-TOL-
BINAP
(R,R)-QUINOXP*
(R)-QUINAP
R = H, Ar = Ph, (R)-SEGPHOS;
(R,Rp)-TANIAPHOS
R = F, Ar = Ph, (R)-DIFLUORPHOS;
R = H, Ar = 3,5-tBu2-4-OMe-Ph,
(R)-DTBM-SEGPHOS
The reaction between 3a and 2a was studied as a model sys-
tem(Table 1). In the presence of 5 mol % copper(I)-(R)-BINAP
complex and 5 mol % DIPEA, the vinylogous Mannich-type reac-
tion afforded a mixture of α-adduct and γ-adduct with a ratio of
1:0.6, favoring the α-addition as observed in the literature.7
Moreover, enantioselectivity was poor. Using (R)-TOL-BINAP
instead of (R)-BINAP, the regioselectivity was slightly improved,
as well as enantioselectivity. (R)-SEGPHOS, (R)-DIFLUORPHOS,
(R,R)-QUINOXP*, (R,R)-Ph-BPE and (R)-QUINAP were not
suitable ligands for this reaction, as no notably superior results
were observed. Ferrocene-embedded (R,Rp)-TANIAPHOS was
beneficial to give 89% yield and 10/1 regioselectivity, favoring the
γ-addition. However, the enantioselectivity was still poor. Finally,
as we envisioned, the bulky (R)-DTBM-SEGPHOS was identified
as the best ligand in terms of both regioselectivity and enanti-
oselectivity. The vinylogous product was obtained in 88% yield
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stant results (entry 1), which highlights the robustness of this
mation of 8a to a reported compound in several steps (For de-
1
2
3
4
5
6
7
8
methodology. The absolute configuration of 5a was determined
to be R by transformation of 5a to a known compound in several
steps (For details, see SI). The configurations of other vinylogous
products were assigned by analogy.
tails, see SI). The configurations of other bisvinylogous products
were assigned tentatively.
Scheme 2. Direct Catalytic Asymmetric Vinylogous Man-
nich-Type Reactions with Substituted β,γ-Unsaturated N-
Acylpyrazoles.
Table 3. Substrate Scope of the Direct Catalytic Asymmetric
Bisvinylogous Mannich-Type Reaction of 6b and N-Boc
Imines 2a
Cu(CH3CN)4PF6 (1 mol%)
(R)-DTBM-SEGPHOS (1 mol%)
O
NHBoc
R
O
NBoc
H
TEA (1 mol%)
R
+
X
0.2 M, THF, -40 oC, 8 h
Ph
X
Ph
9
9a-9d
X = 3,5-Ph2-pyrazole
2a
10a-10d
10
11
12
13
14
15
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R = Me, 92%,
Et, 98%,
nPr, 97%,
iPr, 97%,
/
/
/
/
= >20/1, >20/1 dr, >99% ee
= >20/1, >20/1 dr, >99% ee
= >20/1, >20/1 dr, >99% ee
= >20/1, >20/1 dr, >99% ee
Cu(CH3CN)4PF6 (5 mol%)
(R)-DTBM-SEGPHOS (5 mol%)
TEA (5 mol%)
O
BocHN
Ph
O
NBoc
+
X
0.2 M, THF, 0 oC, 24 h
X
Ph
H
11
12
2a
X = 3,5-Ph2-pyrazole
94%,
/ = >20/1, 81% ee
The vinylogous reaction conditions were successfully extended
to the substituted β,γ-unsaturated N-acylpyrazoles (Scheme 2).
An array of aliphatic substituents, including methyl, ethyl, pro-
pyl and isopropyl, was well tolerated at the γ-position. It is par-
ticularly noteworthy that products 10a-10d were isolated in >99%
ee. As for the β-methyl substrate 11, higher reaction temperature,
more catalyst loading and longer reaction time were required to
compensate for its relatively lower reactivity. The product 12 was
obtained in excellent yield and regioselectivity, but the enanti-
oselectivity was moderate.
Scheme 3. Transformation of Vinylogous Mannich-Type
Product 5a.
In the following bisvinylogous reaction, (R,Rp)-TANIAPHOS
outperformed as the best ligand in terms of yield, regioselectivity
and enantioselectivity (For the details, see Table S1 in SI). Fur-
ther optimization of reaction conditions identified Cy2NMe as
the choice of the base, ̶
60 oC as the choice of reaction tempera-
The α,β-unsaturated N-acylpyrazole in vinylogous Mannich-
type product was a versatile functional group.17 N-acylpyrazole
served as a useful ester equivalent (Scheme 3).13 For example,
typical aminolysis proceeded smoothly to afford amide 13 in 71%
yield. The alcoholysis occurred easily to generate the ester 14 in
89% yield. The hydrolysis of 5a gave the free α,β-unsaturated
acid 15 in 91% yield. An exhaustive reduction of 5a gave the 1,5-
amino-alcohol 16 in 81% yield. Moreover, the α,β-unsaturated
double bond was a transformative functional group, which was
converted to vicinal diol 17 and 18 in good yield and acceptable
diastereoselectivity under the conditions of Sharpless asymmet-
ric dihydroxylation.18
ture and 6b as the choice of substrate. The bisvinylogous reac-
tion was more challenging as 5 mol % copper(I) complex and
Cy2NMe were required for the study of substrate scope (Table 3).
Aromatic imines with both electron-donating and electron-
withdrawing substituents were suitable substrates (entry 1-13).
However, in the cases of entry 6 and entry 13, the bisvinylogous
Mannich-type reactions proceeded with decreased regioselectivi-
ty (ε/α = 9/1 and ε/α = 12/1), which led to the relatively lower
yield of ε-adduct. Furthermore, the enantioselectivity of bisvi-
nylogous product 8k was eroded slightly by introducing a para-F
substituent on the phenyl ring. The hetero-aromatic imines, as
well as 1-naphthyl imine, served also as appropriate substrates.
The labile aliphatic imines were well tolerated under the current
basic system without significantly eroded yield, but lower tem-
perature and longer reaction time were necessary for high enan-
tioselectivity and high yield. The bisvinylogous products 8q, 8r,
8s and 8t were isolated in good to excellent yield and enantiose-
lectivity, together with excellent regioselectivity. The absolute
configuration of 8a was determined to be R through transfor-
In summary, a highly stereo- and regioseletive catalytic
asymmetric vinylogous Mannich-type reaction was developed.
The methodology has a broad substrate scope, mild reaction
conditions, low catalyst loading and leads to products that are
readily transformed. The key to control the regioselectivity was
the combination of a bulky pyrazole and a bulky phosphine lig-
and. Moreover, by simply switching the chiral phosphine ligand,
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L.; Ji, J.; Xie, M.; Liu, X.; Feng, X. Org. Lett. 2011, 13, 3056-3059.
the vinylogous catalytic system was easily extended to the bisvi-
nylogous Mannich-type reaction with excellent yield, regio- and
enantioselectivity. The expansion of current catalytic system to
other types of vinylogous reactions and application to natural
product synthesis are underway.
(d) Guo, Y.-L.; Bai, J.-F.; Peng, L.; Wang, L.-L.; Jia, L.-N.; Luo,
X.-Y.; Tian, F.; Xu, X.-Y.; Wang, L.-X. J. Org. Chem. 2012, 77,
8338-8343. (e) Yin, L.; Takada, H.; Kumagai, N.; Shibasaki, M.
Angew. Chem. Int. Ed. 2013, 52, 7310-7313. (f) Nakamura, S.;
Yamaji, R.; Hayashi, M. Chem. Eur. J. 2015, 21, 9615-9618.
(5) For recent examples of catalytic asymmetric Mukaiyama vi-
nylogous Mannich reactions with linear dienolsilanes, see: (a)
Itoh, J.; Fuchibe, K.; Akiyama, T. Angew. Chem. Int. Ed. 2006, 45,
4796-4798. (b) Sickert, M; Schneider, C. Angew. Chem. Int. Ed.
2008, 47, 3631-3634. (c) Giera, D. S.; Sickert, M.; Schneider, C.
Org. Lett. 2008, 10, 4259-4262. (d) González, A. S.; Arrayás, R.
G.; Rivero, M. R.; Carretero, J. C. Org. Lett. 2008, 10, 4335-4337.
(e) Giera, D. S.; Sickert, M.; Schneider, C. Synthesis 2009, 3797-
3802. (f) Sickert, M.; Abels, F.; Lang, M.; Sieler, J.; Birkemeyer,
C.; Schneider, C. Chem. Eur. J. 2010, 16, 2806-2818. (g) Zhang, Q.;
Hui, Y.; Zhou, X.; Lin, L.; Liu, X.; Feng, X. Adv. Synth. Catal.
2010, 352, 976-980.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
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Experimental procedures and characterization of new
compounds. (PDF)
1H , 13C and 19F NMR spectra of new compounds. (PDF)
AUTHOR INFORMATION
Corresponding Author
(6) For discussions of the regioselectivity of dienolates formation
and reactivity, see: (a) Denmark, S. E.; Jr. Heemstra, J. R.; Beut-
ner, G. L. Angew. Chem. Int. Ed. 2005, 44, 4682-4698. (b) Ratjen,
L.; García-García, P.; Lay, F.; Beck, M. E.; List, B. Angew. Chem.
Int. Ed. 2011, 50, 754-758. (c) Kalesse, M.; Cordes, M.; Symken-
berg, G.; Lu, H.-H. Nat. Prod. Rep. 2014, 31, 563-594.
liangyin@sioc.ac.cn
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
(7) (a) Yamaguchi, A.; Aoyama, N.; Matsunaga, S.; Shibasaki, M.
Org. Lett. 2007, 9, 3387-3390. (b) Yazaki, R.; Nitabaru, T.;
Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc. 2008, 130, 14477-
14479.
(8) For two recent reviews on vinylogous Mukaiyama additions, see:
(a) Pansare, S. V.; Paul, E. K. Chem. Eur. J. 2011, 17, 8770-8779.
(b) Bisai, V. Synthesis 2012, 44, 1453-1463.
(9) (a) Trost, B. M. Science 1991, 254, 1471-1477. (b) Handbook of
Green Chemistry-Green Catalysis (Eds: Anasta, P. T.; Crabtree, R.
H.), Wiley-VCH, Weinheim, 2009. (c) Newhouse, T.; Baran, P.
S.; Hoffmann, R. W. Chem. Soc. Rev. 2009, 38, 3010-3021.
(10) Bazán-Tejeda, B.; Bluet, G.; Broustal, G.; Campagne, J.-M. Chem.
Eur. J. 2006, 12, 8358-8366.
We gratefully acknowledge the financial support from the
“Thousand Youth Talents Plan”, the National Natural Sciences
Foundation of China (No. 21672235), the Strategic Priority Re-
search Program of the Chinese Academy of Sciences (No.
XDB20000000), the “Shanghai Rising-Star Plan” (No.
15QA1404600), CAS Key Laboratory of Synthetic Chemistry of
Natural Substances and Shanghai Institute of Organic Chemistry.
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