Highly diastereo-/enantioselective Cu-catalyzed propargylic alkylations of propargyl acetates with cyclic enamines

Article abstract of DOI:10.1039/c5ra25627e

Highly diastereo- and enantioselective copper-catalyzed propargylic alkylations of propargylic acetates with morpholine-derived cyclic enamines for the construction of vicinal tertiary stereocenters have been developed. By the employment of a less sterically hindered chiral tridentate P,N,N-ligand, good to excellent diastereo- (up to >98 : 2 dr) and enantioselectivity (up to 99% ee) could be achieved for a wide range of substrates.

Full text of DOI:10.1039/c5ra25627e

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Highly diastereo-/enantioselective Cu-catalyzed
propargylic alkylations of propargyl acetates with
cyclic enamines†
Cite this: RSC Adv., 2016, 6, 14763
c
b
b
Cheng Zhang,ab Yun-Ze Hui, De-Yang Zhang and Xiang-Ping Hu
Received 2nd December 2015
Accepted 26th January 2016
*
DOI: 10.1039/c5ra25627e
www.rsc.org/advances
Highly diastereo- and enantioselective copper-catalyzed propargylic with the virtual absence of successful reports describing the
alkylations of propargylic acetates with morpholine-derived cyclic application of this transformation to cyclic enamines7 encour-
enamines for the construction of vicinal tertiary stereocenters have aged our further exploration of copper catalysts in the domain
been developed. By the employment of a less sterically hindered chiral of this substrate class. In fact, our previous studies have dis-
tridentate P,N,N-ligand, good to excellent diastereo- (up to >98 : 2 dr) closed that a highly diastereo- and enantioselective [3 + 3]
and enantioselectivity (up to 99% ee) could be achieved for a wide cycloaddition instead of propargylic alkylation preferentially
range of substrates.
took place for the reaction between propargylic esters and cyclic
enamines although this cycloaddition is believed to proceed via
the propargylic alkylation as the key step (Scheme 1B).8 It's
therefore anticipated that an enantioselective propargylic
alkylation of propargylic esters with cyclic enamines could be
realized if the last cyclization step can be efficiently inhibited.
Herein we report a highly diastereo- and enantioselective
Transition-metal-catalyzed propargylic substitutions represent
an important class of reactions due to their ability to introduce
an electron-rich triple bond that is a versatile entity for further
chemical transformations.1 In 2008, van Maarseveen2 and
Nishibayashi3 independently reported the rst copper-catalyzed
asymmetric propargylic amination. Since then, a variety of
nitrogen, oxygen, and carbon nucleophiles have proved to be
suitable reagents for the copper-catalyzed asymmetric prop-
argylic substitution.4 However, the methods for Cu-catalyzed
propargylic substitution that employ prochiral nucleophiles to
build two vicinal stereocenters and display high diastereo- and
enantioselectivity remain elusive.5
Recently, our group have demonstrated the power of copper
catalysis in accessing vicinal tertiary stereocenters with our
report on the diastereo- and enantioselective asymmetric
propargylic alkylation of acyclic enamines (Scheme 1A).6
However, the use of cyclic enamines was less successful, leading
to poor chemoselectivity. The success of this protocol combined
aDepartment of Drug Discovery and Biomedical Sciences, South Carolina College of
Pharmacy, Medical University of South Carolina, 280 Calhoun Street MSC140
QF307, Charleston, South Carolina 29425, USA
bDalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023,
China. E-mail: xiangping@dicp.ac.cn; xiangping1974@163.com
cFaculty of Engineering and Built Environment, University of Newcastle, Callaghan,
NSW 2308, Australia
† Electronic supplementary information (ESI) available: Experimental details,
characterization data and copies of NMR spectra for all products, and
Crystallographic Information Framework (CIF) le of compound (S,R)-3r. CCDC
1439964. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c5ra25627e
Scheme 1 Copper-catalyzed asymmetric reaction between prop-
argylic esters with enamines.
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copper-catalyzed propargylic alkylation of propargylic acetates diastereo-/enantioselectivity in the Cu-catalyzed asymmetric
with morpholine-derived cyclic enamines by the employment of propargylic alkylation of acyclic enamines,6 however, was
a less sterically hindered chiral tridentate P,N,N-ligand to build disappointed. Only poor chemoselectivity (3a : 4 ¼ 61 : 39) was
up two vicinal tertiary stereocenters, in which >98 : 2 dr and up obtained although the enantioselectivity for syn-3a was high
to 99% ee for syn-diastereoisomers have been achieved (entry 1). This should be high reactivity of copper/L1 complex
(Scheme 1C).
that couldn't efficiently suppress the last cyclization step. We
Considering the signicant inuence of the amino moiety of therefore envisioned that ligand having lower reactivity
enamine substrates on the outcomes in the copper-catalyzed should be more suitable to this reaction. A less sterically
[3 + 3] cycloaddition,8 our initial attempt focused on probing hindered P,N,N-ligand L3 was therefore employed in the reac-
the effect of enamines on the reaction. As shown in Table 1, the tion, and as expected, gave the similar result to that with L2
amino moiety of enamines displayed the crucial role in the (entry 3). Excellent chemo- and diasteroselectivity was observed
chemoselectivity of the reaction. When N,N-diethylamino with (S,S)-Ph-pybox L4 as ligand, however, enantioselectivity for
substituted enamine 2a was used as the reaction partner, only syn-3a was low (entry 4). With (S)-SegPhos L5, high chemo-
[3 + 3] cycloadduct was obtained and no alkylation product was selectivity but low diasteteo- and enantioselectivity was ach-
detected (entry 1). By the introduction of cyclic amino group ieved (entry 5). Following investigation of copper salts didn't
into enamines, the formation of the alkylation product 3a was improve the reaction outcome (entries 6–8). Lowering the
observed (entries 2–4). In particular, the use of enamine 2d reaction temperature to 0 ꢀC could signicantly improve the
bearing a morpholine structure as the nucleophile predomi- chemoselectivity, exclusively giving the alkylation product 3a in
nantly gave rise to the alkylation product 3a in 80% yield good diastereoselectivity, regardless of the use of L2 or L3
(entry 4).
(entries 9–10). Especially, ligand L3 led to the alkylation product
Having established an efficient copper-catalyzed propargylic 3a in 82% yield, and with 94/6 dr and an ee-value of up to 94%
alkylation of cyclic enamine 2d, we next investigated the effects for the major syn-diastereoisomer (entry 10).
of different ligands, copper salts, reaction temperature on the
Having identied the optimal set of reaction conditions, we
efficiency and selectivity of the reaction. 1-Phenyl-2-propynyl then investigated the scope of this reaction with respect to
acetate 1a and 4-(cyclohex-1-en-1-yl)morpholine 2d were propargylic acetates, and the results are shown in Table 3.
chosen as standard reaction partners, and some selected results We found that the reaction proceeded smoothly for all 1-aryl-2-
of these experiments are summarized in Table 2. Initially, the propynyl acetates. In all cases, only alkylation products,
effect of the ligand was investigated (Fig. 1). As we have dis- predominately syn-diastereoisomers, were obtained and no
closed, the use of chiral ferrocenyl P,N,N-ligand L2 led to the [3 + 3] cycloadduct was detected. The position of the substituent
predominant formation of the alkylation products 3a with syn- on the phenyl ring had less inuence on the reaction. Thus, all
3a as the major diastereoisomer in 91% ee (entry 2). An attempt three substrates bearing a Cl-group at the different position on
to improve the reaction outcome by the use of structurally rigid the phenyl ring gave the similarly good results (entries 2–4). The
and bulky ketimine P,N,N-ligand L1, which displayed excellent electronic properties of the substituent at the para-position
showed little effect on the diastereo-/enantioselectivity. Prop-
argylic acetates bearing either electron-donating or electron-
Table 1 Screening the reaction between propargylic acetate 1a and
withdrawing substituents on the phenyl ring fared very well in
enamines 2a
the reaction, delivering the alkylation products in high yield,
diastereo-, and enantioselectivity (entries 5–8). 2-Naphthyl
substrate 1i also worked well, gave the alkylation product 3i in
88% yield, 94 : 6 dr and 92% ee for syn-diastereoisomer
(entry 9). We were pleased to discover that the use of heteroaryl-
substituted propargylic acetates (substrates 1j and 1k) resulted
in smooth reactions and delivered the alkylation products 3j
and 3k with high yield and diastereoselectivity and with good to
excellent enantioselectivity (entries 10–11).
To further evaluate this asymmetric protocol, we next
examined the diversity of cyclic enamines permitted in the
reaction, and the results are listed in Table 4. In all cases, the
reaction proceeded smoothly to afford the alkylation products
as the only outcome with syn-diastereoisomers as the major
products. In comparison to 4-(cyclohex-1-en-1-yl)morpholine
2d, ve-membered cyclic enamines gave the similar yield and
diastereoselectivity, but a slightly decreased enantioselectivity.
Entry
Enamine (2)
3a (syn/anti) : 4b
Yield of 3ac (%)
1
2
3
4
2a
2b
2c
2d
<2 (—) : >98
22 (71/29) : 78
36 (78/22) : 64
94 (91/9) : 6
—
16
27
80
a
Reaction conditions: Cu(OAc)2$H2O (0.015 mmol), (Rc,Sp)-L2 (0.0165 The substituents in cyclohexenyl ring were well tolerated,
mmol), 1a (0.3 mmol), 2 (0.36 mmol), iPr2NEt (0.36 mmol) were
delivering the corresponding alkylation products in high yield
and with excellent diastereo- and enantioselectivity. Impor-
stirred in 2 mL of MeOH at rt for 12 h. Determined by 1H NMR.
b
c
Isolated yield aer column chromatography.
tantly, aliphatic acyclic ketone enamine also served well as the
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Table 2 Optimization of reaction parametersa
Entry
[Cu]
L*
syn-3a : anti-3a : 4b
Yield of 3ac (%)
ee of syn-3ad (%)
1
2
3
4
5
6
7
8
Cu(OAc)2$H2O
Cu(OAc)2$H2O
Cu(OAc)2$H2O
Cu(OAc)2$H2O
Cu(OAc)2$H2O
CuI
CuOTf$(C6H6)1/2
Cu(OTf)2
Cu(OAc)2$H2O
Cu(OAc)2$H2O
L1
L2
L3
L4
L5
L3
L3
L3
L2
L3
55 : 6 : 39
86 : 8 : 6
84 : 8 : 8
97 : 3 : 0
55 : 45 : 0
80 : 20 : 0
89 : 7 : 4
88 : 7 : 5
90 : 10 : 0
94 : 6 : 0
51
80
76
88
63
74
72
72
67
82
94
91
92
42
52 (51)f
76 (56)f
92
90
92
94
9e
10e
a
i
Reaction conditions: copper salt (0.015 mmol), L* (0.0165 mmol), 1a (0.3 mmol), 2d (0.36 mmol), Pr2NEt (0.36 mmol) were stirred in 2 mL of
MeOH at rt for 12 h unless otherwise specied. Determined by GC or 1H NMR. Isolated yield of syn-3a and anti-3a in total. Determined by
b
c
d
HPLC on chiral column. e The reaction was performed at 0 ꢀC for 10 h. The ee-values of anti-3a in parentheses.
f
rst step, a copper complex forms the p-complex A with prop-
argylic acetate 1a. Deprotonation of A with a base then gives
a
Cu–acetylide complex B, which would explain why
Table 3 Scope of propargylic esters 1a
Fig. 1 Ligand evaluated in the Cu-catalyzed asymmetric propargylic
alkylation.
Yield of
ee of
Entry
1 (R)
3
3b (%)
drc
syn-3d (%)
reaction partner although the use of (S)-L1 instead of (R)-L3 was
required. In this case, (S)-L1 showed better performance than
(R)-L3 presumably due to the steric effect, giving the alkylation
product 3q in moderate yield and diastereoselectivity but with
perfect ee of 99%.
1
2
3
4
5
6
7
8
1a: R ¼ Ph
3a
3b
3c
3d
3e
3f
3g
3h
3i
82
80
85
88
88
90
84
92
88
90
86
94 : 6
93 : 7
>98 : 2
>98 : 2
97 : 3
94 : 6
94 : 6
92 : 8
94 : 6
94 : 6
91 : 9
94
95
97
95
92
95
95
91
92
80
95
1b: R ¼ 4-ClC6H4
1c: R ¼ 3-ClC6H4
1d: R ¼ 2-ClC6H4
1e: R ¼ 4-FC6H4
1f: R ¼ 4-BrC6H4
1g: R ¼ 4-CF3C6H4
1h: R ¼ 4-MeC6H4
1i: R ¼ 2-naphthyl
1j: R ¼ 2-furyl
The absolute conguration of the propargylic alkylation
product was unambiguously determined by X-ray structure
analysis of 3r,9 which was prepared by the reaction of 1-(4-
bromophenyl)prop-2-yn-1-yl acetate 1f with 4-(1,4-dioxaspiro
[4.5]dec-7-en-8-yl)morpholine in the catalysis of Cu(OAc)2$H2O
and (S)-L3. A (S,R)-absolute conguration was assigned as
shown in Scheme 2, which is corresponding to syn-
diastereoisomer.
9
10
11
3j
3k
1k: R ¼ 3-pyridyl
a
Reaction conditions: Cu(OAc)2$H2O (0.015 mmol), L3 (0.0165 mmol), 1
(0.3 mmol), 2d (0.36 mmol), iPr2NEt (0.36 mmol) were stirred in 2 mL of
b
MeOH at 0 ꢀC for 10 h. Isolated yield of syn-3a and anti-3a in total.
Based on the experimental results and previous reports,4b,7b
a reaction pathway is proposed as shown in Scheme 3. In the
c
d
Determined by GC or 1H NMR. Determined by HPLC on chiral
column.
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Table 4 Scope of morpholine-derived cyclic enaminesa
a
Reaction conditions: Cu(OAc)2$H2O (0.015 mmol), L3 (0.0165 mmol),
1a (0.3 mmol), 2d–j (0.36 mmol), iPr2NEt (0.36 mmol) were stirred in 2
b
mL of MeOH at 0 ꢀC for 10 h. Isolated yield of syn-3a and anti-3a in
total. Determined by GC or 1H NMR. Determined by HPLC on
c
d
chiral column. e (S)-L1 was used instead of (R)-L3.
Scheme 3 Proposed mechanism.
a propargylic acetate bearing an internal alkyne moiety such as
1,3-diphenyl-2-propynyl acetate 5 did not react at all. Elimina-
tion of an acetoxyl moiety from B affords the copper–allenyli-
dene complex C or its resonance structure, the copper–acetylide
complex D bearing a cationic g-carbon. The nucleophilic attack
of b-carbon atom of enamine 2d to the Cg-atom of the copper–
allenylidene complex (C) gives the corresponding copper–ace-
tylide complex (E), which should be the key step for the ster-
eoselection. The intramolecular shi of H atom generates the
copper p-alkyne complex F. The starting complex A is then re-
generated from F by liberating the propargylic alkylation
product G by the ligand exchange with another propargylic
acetate 1a.
A transition state of Cu–allenylidene complex with chiral
P,N,N-ligand is also proposed to explain the observed stereo-
chemistry as shown in Scheme 4. The edge-to-face aromatic
interaction4b and the steric hinderance make the attack of
Scheme 2 Synthesis of (S,R)-3r and its absolute configuration deter-
mined by X-ray analysis.
Scheme 4 Proposed model for the diastereo-/enantioselectivities.
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enamine Cb-nucleophile at the propargylic cation favourably
from the Re face via M-2 mode to generate (R,S)-3a.
H. Matsuzawa, Y. Tanabe, Y. Miyake and Y. Nishibayashi, J.
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5 For successful examples in the construction of vicinal
stereocenters in terms of diastereo- and enantioselectivity,
see: (a) L. Zhao, G.-X. Huang, B.-B. Guo, L.-J. Xu, J. Chen,
W.-G. Cao, G. Zhao and X.-Y. Wu, Org. Lett., 2014, 16, 5584;
(b) W. Shao, H. Li, C. Liu, C.-J. Liu and S.-L. You, Angew.
Chem., Int. Ed., 2015, 54, 7684.
6 D.-Y. Zhang, F.-L. Zhu, Y.-H. Wang, X.-H. Hu, S. Chen,
C.-J. Hou and X.-P. Hu, Chem. Commun., 2014, 50, 14459.
7 For a singular example of a copper-catalyzed propargylic
alkylation of N,N-diethyl-1-cyclohexen-1-amine with 1-
phenyl-2-propynyl benzoate in 33% yield and with 10/1 dr
and 72% ee, see: (a) P. Fang and X.-L. Hou, Org. Lett., 2009,
11, 4612; for a singular example of a copper-catalyzed
decarboxylative propargylic alkylation of 1-phenylprop-2-yn-
1-yl 2-oxocyclohexanecarboxylate in 88% yield with 7/1 dr
and 86% ee, see: (b) F.-L. Zhu, Y. Zou, D.-Y. Zhang,
Y.-H. Wang, X.-H. Hu, S. Chen, J. Xu and X.-P. Hu, Angew.
Chem., Int. Ed., 2014, 53, 1410.
Conclusions
In conclusion, we have developed a highly diastereo- and
enantioselective copper-catalyzed propargylic alkylation of
propargylic acetates with morpholine-derived cyclic enamines
for the construction of two vicinal tertiary stereocenters. The
reaction was preferential to the formation of syn-diastereoiso-
mers of the propargylic alkylation products in the complete
chemoselectivity. By the employment of
a
chiral 1-
phenylethylamine-derived tridentate P,N,N-ligand, good to
excellent diastereoselectivity (>98 : 2) and enantioselectivity (up
to 99% ee) have been achieved for a wide range of substrates. In
comparison with the reaction of acyclic enamines, less sterically
hindered P,N,N-ligand showed better performance in the
propargylic alkylation of cyclic enamines in term of chemo-
selectivity, suggesting that its lower reactivity efficiently
supressed the last cyclization step. Further development and
application of this reaction are underway.
Acknowledgements
This work was nancially supported by the National Natural
Science Foundation of China (21572226, 21262011) and the
Dalian Institute of Chemical Physics.
Notes and references
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9 CCDC 1439964 for (S,R)-3r †.
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