Highly enantioselective Copper-Catalyzed Propargylic substitution of Propargylic Acetates with 1,3-Dicarbonyl compounds

Article abstract of DOI:10.1021/ol403469m

A chiral tridentate ketimine P,N,N-ligand has been successfully applied in the copper-catalyzed enantioselective propargylic substitution of propargylic acetates with a variety of β-dicarbonyl compounds, in which excellent enantioselectivities (up to >99% ee) and high yields have been obtained.

Full text of DOI:10.1021/ol403469m

Letter
pubs.acs.org/OrgLett
Highly Enantioselective Copper-Catalyzed Propargylic Substitution
of Propargylic Acetates with 1,3-Dicarbonyl Compounds
Fu-Zhong Han,†,‡ Fu-Lin Zhu,‡ Ya-Hui Wang,‡ Yuan Zou,‡ Xin-Hu Hu,‡ Song Chen,‡
and Xiang-Ping Hu*,‡
†College of Chemistry and Chemical Engineering, Qiqihar University, Qiqihar 161006, China
‡Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023, China
S
* Supporting Information
ABSTRACT: A chiral tridentate ketimine P,N,N-ligand has been
successfully applied in the copper-catalyzed enantioselective propargylic
substitution of propargylic acetates with a variety of β-dicarbonyl
compounds, in which excellent enantioselectivities (up to >99% ee) and
high yields have been obtained.
Recent progress on the catalytic asymmetric propargylic
substitution has demonstrated that high enantioselectivity could
be obtained by the direct attack of a nucleophile at the Cγ atom
of the metal−allenylidene complex bearing a chiral ligand.5−9
We therefore believe that β-dicarbonyl compounds should be
also a suitable nucleophile kind for the “direct” catalytic
asymmetric propargylic substitution. As a result, herein we
describe the first highly enantioselective copper-catalyzed
propargylic alkylation of propargylic acetates with various β-
diketones using a tridentate ketimine P,N,N-ligand, in which
excellent enantioselectivities (up to >99% ee) were achieved.
Importantly, the present catalytic system showed broad
generality with regard to β-dicarbonyl nucleophiles, in which
cyclic β-ketoesters and malonate derivatives also proved to be
suitable nucleophiles.
We started our investigation by looking at the catalytic
asymmetric propargylic alkylation of 1-phenyl-2-propynyl
acetate (1a) with 2-methyl-1,3-cyclohexanedione (2a), and
the results are summarized in Table 1. Initially, ligands such as
BINAP (L1), diPh-pybox (L2), and ferrocenyl P,N,N-ligand
(Rc,Sp)-L3, which have proved to be efficient in the Cu-
catalyzed asymmetric propargylic substitution, were inves-
tigated. However, all of these ligands led to disappointingly
low conversion and/or enantioselectivity (entries 1−3).
Interestingly, ligand (R)-L4, a phenyl analogue of (Rc,Sp)-L3
developed in our group,9b showed a promising enantiomeric
excess of 53% ee and a yield of 85% (entry 4). We therefore
evaluated the effect that modifications to the ligand structure of
(R)-L4 had on the reaction outcome. The results in Table 1
atalytic allylic alkylation of allylic alcohol derivatives with
Cthe stabilized “soft” carbanions, such as β-diketones and
β-ketoesters, represents one of the most reliable methods in
organic synthesis.1 In sharp contrast, few examples have been
realized for the catalytic propargylic alkylation of propargylic
alcohol derivatives with β-dicarbonyl compounds, although the
transition-metal-catalyzed propargylic substitution has made
considerable progress in the past decades.2 The development of
catalytic propargylic substitution with β-dicarbonyl compounds
as nucleophiles, especially in an asymmetric catalytic version,
remains a great challenge.
In 2011, van Maarseveen3 attempted the first copper-
catalyzed asymmetric propargylic substitution of 1-phenyl-2-
propynyl acetate with 2,2,5-trimethyl-1,3-dioxane-4,6-dione, a
cyclic derivative of malonate. However, only low enantiose-
lectivity (6% ee) was obtained. Quite recently, Nishibayashi and
co-workers4 have reported a cooperative ruthenium- and
copper-catalyzed propargylic alkylation of propargylic alcohols
with β-ketoesters, in which up to 95% ee was achieved by the
enantioselective attack of an enolate generated in situ from a
chiral copper complex and a β-ketoester at the electrophilic Cγ
atom in an achiral ruthenium allenylidene intermediate.
Although the reaction scope was limited to acyclic β-ketoesters,
this “indirect” strategy represents the first successful application
of β-dicarbonyl compounds to asymmetric propargylic
substitutions. In addition to these two examples, however, the
use of other β-dicarbonyl compounds, in particular β-diketones
as nucleophiles, has not been explored. The development of a
catalytic system that could catalyze the asymmetric propargylic
substitution in broad substrate spectrum with regard to β-
dicarbonyl compounds is therefore highly desirable.
Received: November 29, 2013
Published: December 27, 2013
© 2013 American Chemical Society
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Table 1. Optimization of Cu-Catalyzed Asymmetric
Table 2. Cu-Catalyzed Asymmetric Propargylic Alkylation
with 2-Methyl-1,3-cyclohexanedione (2a) as Nucleophile:
Scope of Propargylic Acetates
Propargylic Alkylation of 1-Phenyl-2-propynyl Acetate (1a)
a
a
with 2-Methyl-1,3-cyclohexanedione (2a)
b
c
entry
1: R
1a: R = Ph
3
yield (%)
ee (%)
1
3aa
3ba
3ca
3da
3ea
3fa
95
87
90
90
88
93
85
95
92
91
94
90
65
63
98
99
99
99
98
99
>99
98
94
98
98
96
97
98
2
1b: R = 2-ClC6H4
1c: R = 3-ClC6H4
1d: R = 4-ClC6H4
1e: R = 4-FC6H4
1f: R = 4-BrC6H4
1g: R = 4-CF3C6H4
1h: R = 4-MeC6H4
1i: R = 4-MeOC6H4
1j: R = 3-MeOC6H4
1k: R = 2-naphthyl
1l: R = 2-thienyl
1m: R = Me
3
4
5
6
7
3ga
3ha
3ia
8
9
10
11
12
3ja
b
c
entry
[Cu]
L*
base
Et3N
yield (%) ee (%)
3ka
3la
d
1
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
L1
L2
L3
L4
L5
L6
L6
L6
L6
L6
L6
L6
−
10
d
2
Et3N
90
13
3ma
3na
d
d
3
Et3N
−
53
14
1n: R = Bn
4
Et3N
85
82
85
a
The reaction was carried out with 1a−n (0.6 mmol), 2a (0.5 mmol),
5
Et3N
92
[Cu(MeCN)4]BF4 (5 mol %), (R)-L6 (7.5 mol %), and i-Pr2NEt (1.2
b
6
Et3N
94
mmol) in 4 mL of MeOH at 0 °C for 12 h. Yield of isolated product.
d
c
7
DBU
−
The ee values were determined by HPLC analysis using a chiral
d
8
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
89
87
95
95
92
95
97
96
98
91
stationary phase. The reaction was performed at rt under a catalyst
loading of 10 mol %.
9
Cu(OTf)2
10
11
12
Cu(OAc)2.H2O
[Cu(CH3CN)4]BF4
[Cu(CH3CN)4]ClO4
a
The reaction was carried out with 2a (0.5 mmol), 1a (0.6 mmol),
[Cu] (5 mol %), L* (7.5 mol %), and base (1.2 mmol) in 4 mL of
b
c
MeOH at 0 °C for 12 h. Yield of isolated product. ee values were
d
determined by HPLC analysis using a chiral stationary phase. Not
determined due to low conversions.
disclosed that both of (R)-L5 and (R)-L6 bearing a ketimine
moiety were suitable ligands for the model reaction, with (R)-
L6 derived from 2-benzopyridine being optimal in terms of the
yield and enantioselectivity (entries 5 and 6). Subsequent
optimization of reaction conditions with ligand (R)-L6 was
then carried out. The results disclosed that the base showed a
significant effect on the reaction. Thus, no desired product was
separated in the presence of DBU as the base (entry 7), while
the use of i-Pr2NEt provided better results than that of Et3N
(entry 8). Investigation of copper precursors showed that all of
the copper salts tested displayed excellent to perfect perform-
ance, although some influence on the reaction was observed.
Among these copper salts, [Cu(MeCN)4]BF4 proved to be the
best choice, which gave the corresponding alkylation product in
95% yield with an ee value of 98% (entry 11).
Utilizing the optimized conditions, we investigated the scope
of propargylic acetates, and the results are summarized in Table
2. The reaction worked efficiently for all 1-aryl-substituted
substrates tested, with the desired products being obtained in
high yields and with excellent to perfect enantioselectivities (up
to >99% ee). It appeared that the position of the substituent on
the phenyl ring had little effect on the reactivity and
enantioselectivity. Thus, all of three substrates with a Cl
group at the different positions of the phenyl ring gave similar
results (entries 2−4). However, the electronic properties of the
substituent at the para-position of the phenyl ring showed
some influence on the enantioselectivity. Thus, a p-methoxy
substituent led to slightly decreased enantioselectivity (94% ee)
(entry 9). In addition, 2-naphthyl-substituted substrate
presented a suitable substrate for the reaction (entry 11).
Heteroaromatic propargylic acetate 1l turned out to serve well
as the substrate for our methodology (entry 12). Furthermore,
aliphatic substrates 1m,n worked well, leading to the desired
propargylic products in excellent enantioselectivity. However,
an elevated catalyst loading (10 mol %) and higher reaction
temperature were required for achieving a reasonable
conversion in these cases (entries 13 and 14). The absolute
configuration of chiral propargylic products was unambiguously
determined by X-ray crystal structure analysis of 3fa, which is
assigned as (S).10
Furthermore, the scope of β-dicarbonyl nucleophiles was
investigated (Table 3). The reaction demonstrated a broad
generality for β-dicarbonyl compounds, in which various cyclic
and acyclic diketones, β-ketoesters, and malonate derivatives
were found to be suitable substrates. For both 1,3-cyclo-
hexanediones (2b,c) with a tertiary carbon as the nucleophilic
atom, the reaction proceeded with excellent performance
(entries 1 and 2). In comparison with its six-membered
analogues, 2-methyl-1,3-cyclopetanedione 2d showed slightly
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Letter
partners, giving the corresponding substitution products with
good results (entries 6 and 7). Cyclic β-ketoesters were also
investigated, and the reaction was performed at room
temperature. In all cases, the reaction resulted in the alkylation
product in high yield as a mixture of two diastereoisomers with
perfect enantioselectivities for major diastereomer (entries 8
and 9). 2,2,5-Trimethyl-1,3-dioxane-4,6-dione, an inefficient
nucleophile in van Maarseveen’s catalytic system, also proved to
be a suitable nucleophile, with the corresponding propargylic
alkylation product being obtained in excellent enantioselectivity
(97% ee) (entry 10).
Table 3. Cu-Catalyzed Asymmetric Propargylic Alkylation of
1-Phenyl-2-propynyl Acetate (1a): Scope of β-Dicarbonyl
a
Compounds
Based upon our experimental results and other data, we
proposed the plausible mechanism for the formation of 3aa as
shown in Scheme 1. Initially, the Cu complex forms a π-
Scheme 1. Proposed Reaction Pathway
complex A with the propargylic acetate.11 Deprotonation with
N,N-diisopropylethylamine gives Cu−acetylide complex B,
which explains why 1,3-diphenyl-2-propynyl acetate, an internal
alkyne, did not react at all in this reaction. Loss of an acetyl
group from B forms Cu−allenylidene complex C, where the
copper−acetylide complex D bearing a cationic γ-carbon exists
as a resonance structure.7f,12 Nucleophilic attack of 2-methyl-
1,3-cyclohexanedione 2a at the Cγ atom of C, followed by a
hydrogen atom shift, gives a Cu−π-alkyne complex E. Further
investigations to elucidate the reaction mechanism are
underway and will be reported in due course.
a
In conclusion, we have documented the first copper-
catalyzed propargylic alkylation of propargylic acetates with β-
diketones as nucleophiles by employing a chiral tridentate
ketimine P,N,N-ligand derived from 2-benzopyridine, in which
excellent enantioselectivities (up to >99% ee) were achieved.
The result disclosed that the ligand structure has a great impact
on the efficiency and selectivity of the reaction, and the
presence of a ketimine moiety in P,N,N-ligand structure
appears to be necessary for achieving good performance. The
present catalytic system was also efficient for cyclic β-ketoesters
and cyclic malonate derivatives. Studies on mechanistic
investigations as well as the extension of the protocol to
other carbon nucleophiles are in progress.
Reaction conditions: 1a (0.6 mmol), 2b−k (0.5 mmol), [Cu-
(MeCN)4]BF4 (5 mol %), (R)-L6 (7.5 mol %), and i-Pr2NEt (1.2
mmol) in 4 mL of MeOH at 0 °C for 12 h. Yield of isolated product
was provided, and ee values were determined by HPLC analysis using
b
c
a chiral stationary phase. Reactions were performed at room
temperature. The ratio of anti/syn was determined by 1H NMR.
d
The reaction was performed at −20 °C.
lower enantioselectivity in 91% ee (entry 3). For 2H-indene-
1,3-dione substrate 2e, excellent performance (94% yield, and
98% ee) was achieved (entry 4). Acyclic diketone, 3-methyl-2,4-
pentanedione (2f), also worked well, leading to the desired
product in good yield and with perfect enantioselectivity (>99%
ee) (entry 5). Interestingly, 1,3-diketones without an additional
substituent on the nucleophilic atom were also suitable reaction
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Miyake, Y.; Nishibayashi, Y. Org. Lett. 2011, 13, 592. (c) Ikeda, M.;
Miyake, Y.; Nishibayashi, Y. Organometallics 2012, 31, 3810.
(9) For examples on the cycloaddition via catalytic asymmetric
propargylic substitution, see: (a) Kanao, K.; Miyake, Y.; Nishibayashi,
Y. Organometallics 2010, 29, 2126. (b) Zhang, C.; Hu, X.-H.; Wang, Y.-
H.; Zheng, Z.; Xu, J.; Hu, X.-P. J. Am. Chem. Soc. 2012, 134, 9585.
(10) For details of the X-ray analysis of 3fa, see the Supporting
Information.
(11) Himo, F.; Lovell, T.; Hilgraf, R.; Rostovtsev, V. V.; Noodleman,
L.; Sharpless, K. B.; Fokin, V. V. J. Am. Chem. Soc. 2005, 127, 210.
(12) Imada, Y.; Yuasa, M.; Nakamura, I.; Murahashi, S.-I. J. Org.
Chem. 1994, 59, 2282.
ASSOCIATED CONTENT
■
S
* Supporting Information
Procedures, characterization, and X-ray data (CIF). This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: xiangping@dicp.ac.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the Dalian Institute of Chemical Physics
(CAS) is gratefully acknowledged. We also thank Prof.
Hongchao Guo for providing several chiral ligands (synthesized
in the National Key Technologies R&D Program of China,
2012BAK25B03, CAU) for screening reaction conditions.
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