Development of an enantioselective amine-silver co-catalyzed Conia-ene reaction

Article abstract of DOI:10.1039/c7cc01807j

The development of a novel cooperative catalytic system for an amine-silver co-catalyzed Conia-ene reaction of alkyne-tethered C-H-acidic compounds is reported. By using a cost-effective silver salt and a small diamine for the 5-exo-dig-cyclization the cy

Full text of DOI:10.1039/c7cc01807j

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Development of an Enantioselective Amine-Silver Co-Catalyzed
Conia-Ene Reaction
Received 00th January 20xx,
Accepted 00th January 20xx
M. Blümel, D. Hack, L. Ronkartz, C. Vermeeren, and D. Enders*
DOI: 10.1039/x0xx00000x
www.rsc.org/
The development of a novel cooperative catalytic system for an
amine-silver co-catalyzed Conia-ene reaction of alkyne-tethered C-
H-acidic compounds is reported. By using a cost-effective silver
salt and
a small diamine for the 5-exo-dig-cyclization the
cyclopentane products are obtained in very good yields. The
enantioselectivity of the reaction could be controlled by
exchanging the diamine co-catalyst with a cinchona-derived
primary amine.
Since its development by Conia and Le Perchec in 1973, the Fig. 1 Comparison of known approaches and our work for an enantioselective
Conia-ene reaction, a variation of the classic ene-reaction, has Conia-ene reactions. (L = ligand, Mh = hard metal, Ms = soft metal)
attracted much interest and was not only further developed,
but also employed in the synthesis of complex molecules.1,2 In chiral additives were employed. Following
a different
the beginning strong acids and bases were used to promote approach, carrying out Conia-ene reactions in the presence of
the cyclization reaction, but were soon replaced by metal- a copper catalyst and a chiral urea12 or an iron-salene
based Lewis acids activating the nucleophile, the alkyne, or complex13, Dixon et al. and White et al. obtained excellent
both.
results (Figure 1, b).Combining both general approaches, we
Especially pure alkyne activation is very common, because envisioned that the cooperative combination of a primary
it allows for remarkably mild reaction conditions. The first amine for the enamine activation of the ketone and especially
Conia-ene reaction relying on this activation mode was cost-efficient silver catalysts for the electrophilic activation of
described by Toste and co-workers in 2004, who used the alkyne would provide the ideal properties for the Conia-
PPh3AuCl and AgOTf to in situ generate the active [PPh3Au]OTf ene reaction of alkyne-tethered β-ketoesters and related
catalyst.3 The development of the improved catalyst compounds without the need of a second metal co-catalyst
[PPh3Au]NTf2 by Gagosz et al.4 and sterically less hindered (Figure 1, c). Furthermore, readily available, chiral amines
phosphine ligands for larger ring synthesis by Sawamura et al.5 could be used to easily control the stereoselectivity of the
further promoted this field.
cyclization process. To the best of our knowledge there is no
Despite the large number of non-enantioselective precedence in the literature of a silver-catalyzed addition of an
protocols using a broad range of metals, including not only enamine to an alkyne.
gold, but for example also In,6 Zn,7 or Co8, asymmetric
The initial study towards the Conia-ene reaction of β-
methods remain scarce and usually rely on the cooperative ketoester 1a showed that no cyclization occurred in the
activation with a complex heterobimetallic catalyst system and presence of tert-butylamine when silver carbonate and TFA
a chiral ligand (Figure 1, a). Toste et al. were the first to report were used as co-catalysts. Interestingly, the reaction
an asymmetric version using a Pd(DTBMSegPhos) complex and proceeded smoothly when the bifunctional primary amine
A
Yb(OTf)3 as co-catalyst.9 Later catalyst systems consisting of was used instead. Possibly the second amine group allows for
La(OiPr)3/AgOAc10 or Zn(OAc)2/Yb(OTf)311 in combination with
an interaction with the silver; thus, fixing the substrate in a
reactive conformation. In the screening of several silver
sources (Table 1, entries 1-3)14 soluble and insoluble species
proved to be effective and AgNTf2∙MeCN was identified as the
best silver source. Especially the use of CHCl3 as solvent had a
further beneficial effect on the outcome of the cyclization
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074
Aachen, Germany. E-mail: enders@rwth-aachen.de
Electronic
Supplementary
Information
(ESI)
available:
See
DOI: 10.1039/x0xx00000x
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Table 1 Optimization of the amine silver co-catalyzed Conia-ene reactiona
Table 2 Screening of different metal sources for an enantioselective Conia-ene
reactiona
Entry
[M]
[PPh3Au]NTf2
In(OTf)3
AgNTf2∙MeCN
AgOTf
t [h]
24
48
20
44
42
42
65
72
48
Yieldb [%]
eec [%]
0
1
75
72
74
74
67
62
43
1
2
3
4
5
6
7
8
9
94
78
63
45
35
38
45
24
84
Entry
1
2
3
4
5
6
7
8
[Ag]b
Ag2O
A [mol%] Acid (mol%) Solvent
Yieldc [%]
81
20
20
20
20
20
20
20
20
20
20
10
TFA (20)
TFA (20)
TFA (20)
TFA (20)
TFA (20)
TFA (20)
TFA (20)
B (20)
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
AgSbF6
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
80
84
84
74
78
78
86
86
AgSbF6
AgBF4
AgF
Ag2SO4
CCl4
1,2-DCE
toluene
CHCl3
CHCl3
CHCl3
Ag2CO3
a
9
10
11
C (20)
D (20)
B (10)
The reactions were carried out with β-ketoester 1a (0.25 mmol), [M] (10
mol%), 9-epi-quinidine amine E (20 mol%), and TFA (20 mol%) in 0.25 mL CH2Cl2
86
89
b
c
(c = 1 M) at ambient temperature. Yield of the isolated product 2a.
CHCl3
Determined by HPLC with a chiral stationary phase.
a
The reactions were carried out with β-ketoester 1a (0.25 mmol), [Ag] (10
mol%), amine A, and acid in 0.25 mL of the given solvent (c = 1 M) at ambient
quinine- and cinchonidine-based catalysts gave good yields,
but lower ee values. Hydrogenation of the vinyl group at the
quinuclidine ring can strongly influence the catalyst folding and
thus effect the selectivity. Indeed, we observed an increased
enantioselectivity of 78% ee and a comparable yield of 61%
when using the hydrogenated quinidine amine J. Furthermore,
only low reaction efficiency or enantioselectivity was achieved
when bifunctional amines with a secondary amine or thiourea
b
temperature. In the case of AgNTf2, the acetonitrile complex AgNTf2∙MeCN
was used as the silver source. c Yield of the isolated product 2a.
reaction leading to the cyclopentane 2a in 84% yield (entry 4).
Using different acid co-catalysts marginally effected the
reaction efficiency and similar yields were obtained for all
tested acids (entries 8-10). Finally, the catalyst loading of the
amine
A and acid B could be decreased to 10 mol%,
moiety were employed. Subsequently, amine
investigate the effect of different acidic co-catalysts.
J was used to
respectively, even giving a slightly increased yield of 89%
(entry 11). Further decreasing the catalyst loading of the
amine, the acid, and the silver salt negatively influenced the
catalytic activity.
Encouraged by the results of the non-asymmetric version
of the amine-silver co-catalyzed Conia-ene reaction, we set our
focus on the enantioselective variation of the protocol. We
envisaged that the use of a chiral amine should provide the
necessary face discrimination in the transition state of the
Conia-ene reaction. Our first choice were cinchona-derived
amines naturally incorporating the primary-tertiary amine
motif in a chiral environment. Using quinidine amine
E we
started the investigation towards an asymmetric Conia-ene
reaction by screening various metal species as carbophilic
Lewis acids (Table 2).14 The use of [Ph3PAu]NTf2 catalyst
introduced by Gagosz and co-workers4 and In(OTf)3 as part of
the catalyst system lead to the cyclized product; albeit no
enantioselectivity was observed (entries 1, 2). Only silver salts
could convert the β-ketoester 1a in good yields in an
enantioselective fashion. Insoluble silver sources, e.g. Ag2CO3,
usually gave slightly higher yields; whereas the reaction with
silver salts containing weakly coordinating counterions, e.g.
AgSbF6, proceeded with higher stereocontrol (entries 3-9).
With 63% yield and 75% ee AgNTf2∙MeCN was identified as the
most effective silver salt.
Scheme
1 Screening of various chiral amines and acidic additives for an
enantioselective Conia-ene reaction. The first set of reactions was carried out
with β-ketoester 1a (0.25 mmol), AgNTf2∙MeCN (10 mol%), amine, and TFA (20
mol%) in 0.25 mL CH2Cl2 (c = 1 M) at ambient temperature. The screening of the
For the next set of variations, we first screened various
diamine and acid co-catalysts (Scheme 1) and found that
acids was analogous carried out with amine J.
2 | J. Name., 2012, 00, 1-3
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Table 3 Optimization of the enantioselective Conia-ene reactiona
Table 4 Substrate scope of the novel amine-silver co-catalyzed Conia-ene reaction
Entry
1
2
3
4
5
6
7
8
Solvent
CHCl3
CCl4
[Ag] [mol%]
T [°C]
rt
rt
rt
rt
rt
rt
rt
40
0
Yieldb [%]
69
eec [%]
48
69
60
80
86
80
90
90
“Racemic” Methoda Asymmetric Methodb
2
R1
R2
Yieldc [%]
Yieldc [%]
eed [%]
95
93
93
87
93
91
88
11
27
51
0
10
10
10
10
10
10
10
10
10
10
2.5
35
45
57
63
14
76
85
82
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
Me
Me
Me
Me
Me
Me
Me
Et
Et
Pr
iPr
Ph
COOEt
COOMe
COOBu
COOallyl
COOiPr
COOtBu
COOBn
COOMe
COOEt
COOEt
COOEt
COOEt
COMe
89
77
86
77
75
89
97
95e
78
46e
54f
54f
67
90e
93f
39f
89
97
91
94
92
97
93
93e
97e
32e
20g
55e
-
86e
-
46g
1,2-DCE
EtOAc
DMF
toluene
MeOH
MeOH
MeOH
MeOH
MeOH
9
10
11
91
89
95
−20
0
28
86
a
The reactions were carried out with β-ketoester 1a (0.25 mmol),
AgNTf2∙MeCN (10 mol%), 9-epi-quinidine amine E (20 mol%), and TFA (20
mol%) in 0.25 mL CH2Cl2 (c = 1 M) at ambient temperature. Yield of the
isolated product 2a. c Determined by HPLC with a chiral stationary phase.
65
-
70
-
Me
Me
Me
Me
b
COPh
SO2Me
SO2Ph
Independent from the acidity the use of N-Boc-protected
amino acids and pTSA resulted in lower enantioselectivities
and TFA was used for the further optimization of the reaction
conditions (Table 3).14 The nature of the solvent tremendously
influenced the efficiency of the reaction with respect to yield
as well as stereoselectivity. Usually more polar solvents were
better suitable for the cyclization reaction leading to the cyclo-
pen-tanes with up to 86% ee (entry 5). To our surprise,
methanol as protic solvent further increased the
enantioselectivity to 90% and the yield to 76% (entry 7). We
then continued to vary the temperature, which only had a
small effect on the selectivity; albeit decreased yields were
observed for the reaction at −20 °C (entries 8-10). Finally, the
loading of the silver source could be reduced to 2.5 mol%,
which increased the yield to 86% and the enantioselectivity to
95% ee (entry 11).
11
a
The reactions were carried out with β-ketoester
1
(0.25 mmol),
AgNTf2∙MeCN (10 mol%), A (20 mol%), B (20 mol%) in 0.25 mL CHCl3 (c = 1 M)
at ambient temperature. The reactions were carried out with β-ketoester 1
b
(0.25 mmol), AgNTf2∙MeCN (2.5 mol%), dihydro-9-epi-quinidine amine J (20
c
mol%), and TFA (20 mol%) in 0.25 mL MeOH (c = 1 M) at 0 °C. Yield of the
d
e
isolated product 2. Determined by HPLC with a chiral stationary phase.
Synthesized at 40 °C. f Synthesized in toluene at 80 °C. g Synthesized at 60 °C.
Thereafter, we demonstrated the synthetic utility by
converting the β-ketoester 1a on a gram-scale to cyclopentane
2a with the same level of yield and stereoselectivity (Scheme
2). Additionally, the germinal diacylated exo-methylene
cyclopentane 2a could be transformed to the corresponding
epoxide 3, as well as the alcohols
4 and 5 in high yields by
standard procedures.
We propose that the first step of the mechanism is the
With the optimized reaction conditions at hand we set out
to extend the scope of the novel cooperative amine-silver co-
catalyzed Conia-ene reaction (Table 4). A series of β-ketoesters
1
could be converted into the corresponding cyclopentanes
with high yields of up to 97% and high enantioselectivity of up
to 95% (entries ). In contrast to the bulkiness of the ester
2
a-g
group, the steric hindrance of the keto group prevented an
efficient reaction and higher temperatures had to be
employed (entries h-l); unfortunately, lower enantioselectiviti-
es resulted in these cases. In addition, β-diketones and β-
ketosulfones were also suitable substrates for the amine-silver
co-catalyzed Conia-ene reaction (entries
m-p). Depending on
the steric hindrance of the substrates elevated temperatures
were also necessary. The cyclic diketones and sulfones were
obtained in moderate to good yields and up to a moderate
level of enantioselectivity.15 Substrates with a tBu-keto group,
an alkyne-tethered β-ketoamide, and internal alkynes were no
suitable substrates for this catalyst system.16
Scheme
2 Gram-scale transformation of β-ketoester 1a and subsequent
epoxidation as well as reduction of cyclopentane 2a
.
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condensation of the primary amine with the keto group in the primary amine and underlines the potential of the newly
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DOI: 10.1039/C7CC01807J
developed catalytic system. Currently the application of this
presence of the acidic co-catalyst leading to enamine
6
(Scheme 3). The failure of the reaction in the case of internal catalytic system to other transformations and the
alkynes suggests the formation of the silver acetylide that development of other cooperative organo-metal co-catalyzed
results after the coordination of a silver cation to the alkyne transformations are investigated.
) and the loss of a proton from intermediate . The
9
(7
8
subsequent attack of the enamine nucleophile to the acetylide
is energetically unfavourable, because the intermediate anion
10 lacks electronic stabilization; however, protonation, proto-
deargentation, and hydrolysis of the iminium ion 12 leads to
Notes and references
1
2
J. M. Conia and P. Le Perchec, Synthesis, 1975, 1.
For a recent review on Conia-ene and related reactions see:
D. Hack, M. Blümel, P. Chauhan, A. R. Philipps and D. Enders,
Chem. Soc. Rev., 2015, 44, 6059.
the cyclopentane
silver acetylide
2
. A second pathway is possible when the
9
is activated by the coordination of a second
3
(a) J. J. Kennedy-Smith, S. T. Staben and F. D. Toste, J. Am.
Chem. Soc., 2004, 126, 4526; (b) S. T. Staben, J. J. Kennedy-
Smith and F. D. Toste, Angew. Chem. Int. Ed., 2004, 43, 5350.
N. Mézailles, L. Ricard and F. Gagosz, Org. Lett., 2005, 7,
4133.
(a) A. Ochida, H. Ito and M. Sawamura, J. Am. Chem. Soc.,
2006, 128, 16486; (b) H. Ito, Y. Makida, A. Ochida, H. Ohmiya
and M. Sawamura, Org. Lett., 2008, 10, 5051.
silver cation. In this case the 5-exo-dig-cyclization leads to the
potentially more stabilized disilver species 14 that after double
protodeargentation and imine hydrolysis yields the cyclic
4
5
product
2. To gain deeper insight in the mechanism we
conducted a deuterium-labelling experiment with a substrate
bearing deuterium on the alkyne; interestingly, no deuterium
was incorporated in the product suggesting the formation of
6
7
For examples on indium-catalyzed Conia-ene reactions, see:
(a) Y. Itoh, H. Tsuji, K. Yamagata, K. Endo, I. Tanaka, M.
Nakamura and E. Nakamura, J. Am. Chem. Soc., 2008, 130,
17161; (b) K. Takahashi, M. Midori, K. Kawano, J. Ishihara
and S. Hatakeyama, Angew. Chem. Int. Ed., 2008, 47, 6244;
(c) L. Liu, L. Wei, Y. Lu and J. Zhang, Chem. – Eur. J., 2010, 16,
11813; (d) S. Morikawa, S. Yamazaki, Y. Furusaki, N. Amano,
K. Zenke and K. Kakiuchi, J. Org. Chem., 2006, 71, 3540.
For examples on zinc-catalyzed Conia-ene reactions, see: (a)
M. Nakamura, C. Liang and E. Nakamura, Org. Lett., 2004, 6,
2015; (b) C.-L. Deng, R.-J. Song, Y.-L. Liu and J.-H. Li, Adv.
Synth. Catal., 2009, 351, 3096; (c) W. Hess and J.W. Burton,
Adv. Synth. Catal., 2011, 353, 2966; (d) T. P. Lebold, A. B.
Leduc and M. A. Kerr, Org. Lett., 2009, 11, 3770; (e) S.
Morikawa, S. Yamazaki, M. Tsukada, S. Izuhara, T. Morimoto
and K. Kakiuchi, J. Org. Chem., 2007, 72, 6459; (f) S.
Yamazaki, S. Morikawa, K. Miyazaki, M. Takebayashi, Y.
Yamamoto, T. Morimoto, K. Kakiuchi and Y. Mikata, Org.
Lett., 2009, 11, 2796.
an acetylide intermediate (e.g.
9
).17 However, when the
reaction was carried out in deuterated methanol mainly a
cyclopentane was formed that contained deuterium at both
olefinic positions. Unfortunately, with that result we were not
able to conclude, whether the reaction proceeds in a cis- or
trans-fashion and which pathway is preferred.
In conclusion, we have developed a novel cooperative
catalytic system consisting of a silver salt and a diamine for the
amine-silver co-catalyzed Conia-ene reaction of alkyne-
tethered β-ketoesters, β-diketones, and β-ketosulfones. The
enantioselectivity of the cyclization reaction could easily be
controlled by replacing the diamine with a cinchona-derived
8
9
For examples on cobalt-catalyzed Conia-ene reactions, see:
(a) P. Cruciani, C. Aubert and M. Malacria, Tetrahedron Lett.,
1994, 6677; (b) J.-L. Renaud, C. Aubert and M. Malacria,
Tetrahedron, 1999, 55, 5113.
B. K. Corkey and F. D. Toste, J. Am. Chem. Soc., 2005, 127,
17168.
10 A. Matsuzawa, T. Mashiko, N. Kumagai and M. Shibasaki,
Angew. Chem. Int. Ed., 2011, 50, 7616.
11 S. Suzuki, E. Tokunaga, D. S. Reddy, T. Matsumoto, M. Shiro
and N. Shibata, Angew. Chem. Int. Ed., 2012, 51, 4131.
12 T. Yang, A. Ferrali, F. Sladojevich, L. Campbell and D. J. Dixon,
J. Am. Chem. Soc., 2009, 131, 9140.
13 S. Shaw and J. D. White, J. Am. Chem. Soc., 2014, 136, 13578.
14 The complete tables of the optimizations can be found in the
ESI.
15 The cyclic sulfone 2o underwent a subsequent Mislow-
Evans-type rearrangement. This process was accelerated in
protic solvents; consequently, no Conia-ene product was
observed for the enantioselective version.
16 A complete list of unsuitable substrates can be found in the
ESI.
17 The results of the deuterium-labelling experiments and a
model for the enantioselectivity are provided in the ESI.
Scheme 3 Proposed mechanism of the novel amine-silver co-catalyzed Conia-ene
reaction.
4 | J. Name., 2012, 00, 1-3
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