Trialkyl Methanetricarboxylate as Dialkyl Malonate Surrogate in Copper-Catalyzed Enantioselective Propargylic Substitution

Article abstract of DOI:10.1021/acs.orglett.5b02463

The first copper-catalyzed enantioselective propargylation of trialkyl methantricarboxylate with propargylic alcohol derivatives was developed. The tricarboxylate unit in the obtained adducts could be easily transformed into a malonate moiety by treating with in situ generated NaOEt in excellent yield without racemization.

Full text of DOI:10.1021/acs.orglett.5b02463

Letter
pubs.acs.org/OrgLett
Trialkyl Methanetricarboxylate as Dialkyl Malonate Surrogate in
Copper-Catalyzed Enantioselective Propargylic Substitution
Guanxin Huang, Cang Cheng, Luo Ge, Beibei Guo, Long Zhao, and Xiaoyu Wu*
Department of Chemistry, College of Sciences, Shanghai University 99 Shangda Road, Shanghai 200444, China
S
* Supporting Information
ABSTRACT: The first copper-catalyzed enantioselective
propargylation of trialkyl methantricarboxylate with prop-
argylic alcohol derivatives was developed. The tricarboxylate
unit in the obtained adducts could be easily transformed into a
malonate moiety by treating with in situ generated NaOEt in
excellent yield without racemization.
wing to the broad spectrum of reactivity of the alkyne
functionality, addition of various nucleophiles to
Scheme 1. Previous Examples of Propargylation of
Meldrum’s Acid
O
propargylic alcohols or their derivatives has long been pursued
by quite a number of research groups.1 Early studies in this area
included the Nicholas reaction via the activation of propargylic
alcohol by formation of a cobalt−alkyne complex with a
stoichiometric amount of Co2(CO)8.2 In 1994, the catalytic
version of this process was first implemented by Murahashi and
co-workers, wherein aminations of propargyl phosphates and
acetates were promoted by a copper complex.3 Since then, a
variety of methodologies have been successfully developed for
catalyzed propargylic substitution of propargylic alcohols and
their derivatives.1 Meanwhile, asymmetric versions of this
catalytic process have been developed by several research
groups employing terminal alkyne propargylic alcohols or their
derivatives as reaction partners.4−8 In particular, since 2000
Nishbayashi and coauthors reported a series of findings on
propargylation reactions catalyzed by a thiolate-bridged
diruthenium complex.1c,f These reactions were rendered
asymmetric when chiral disulfides were employed to generate
ruthenium complexes.4 Meanwhile, some other groups, e.g.
Marrsaveen’s group,5 Hou’s group,6 and Hu’s group,7 employed
combinations of copper salts and chiral ligands as catalysts for
reactions between various nucleophiles and propargylic alcohol
derivatives.
Despite these achievements, to our knowledge, a successful
example of catalyzed enantioselective addition of dialkyl
malonate to propargylic alcohol derivatives, bearing either an
internal or a terminal alkyne moiety, remains unknown. Since
such propargylic substitution can provide access to synthetically
useful γ,δ-alkynyl malonates, alternative methods have been
highly sought after. The most related successful example was
reported by Hu et al., employing methyl substituted Meldrum’s
acid as a nucleophile catalyzed by a Cu−N,N,P-ligand complex
leading to the desired propargylic substituted product in
moderate yield and excellent ee (Scheme 1, eq 1).7c The same
reaction was also conducted by Maarseveen et al., employing a
Cu−Pybox complex as the catalyst affording the desired
product in moderate yield and low ee (eq 2).5b Unsubstituted
Meldrum’s acid led to the double propargylation product, when
an achiral Ru-complex was recruited as the catalyst (eq 3).9
Replacing Meldrum’s acid with dimethyl malonate in this
catalysis system gave only a mixture of unidentified products
with complete consumption of the starting propargylic alcohol.
Based on these observations, dialkyl malonate or Meldrum’s
acid might be unfit for Ru- or Cu-catalyzed addition to
progargylic alcohols or their derivatives. In the search for a
suitable malonate surrogate for this type of reaction, we
envisioned that trialkyl methanetricarboxylate, the pKa of which
approximately equals that of Meldrum’s acid (ca. 7.3),10 might
provide a good opportunity. Trialkyl methanetricarboxylates,
which can be generally prepared from dialkyl malonates via
deprotonation and subsequent addition to alkyl chloroformate,
have long been employed as masked malonates.11 Therefore,
we considered the possibility of performing an alternative and
unprecedented propargylation reaction with trialkyl methane-
tricarboxylate, the propargylated products of which could be
Received: August 26, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02463
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Letter
readily converted to malonate derivatives after appropriate
elaboration. Herein, we report the successful implementation of
this asymmetric catalytic process leading to the propargylated
products in excellent yields and good to excellent ee’s.
results slightly inferior to those of 1a (entry 6 vs entry 5).
Increasing the steric encumbrance around the nucleophilic
carbon by replacing the methyl or ethyl group with bulky tert-
butyl or benzyl group did not help to improve the chiral
induction (entries 7−9). Similar to the results reported by
Nishibayashi et al.,9 no formation of the desired product was
observed when using diethyl or dimethyl malonates as reaction
components in the current catalytic system. The absolute
stereochemistry of 3ac was determined by correlation after its
conversion to 3-phenylpentanoic acid (see Supporting
Information for details). The stereochemistry of other
propargylated products could be assigned by analogy.
Recently, copper−Pybox complexes were frequently re-
cruited by several research groups for enantioselective
propargylic substitution employing terminal alkyne propargylic
alcohol derivatives as reaction components, via formation of
copper allenylidene complexes as key intermediates.12 Two
very recent examples are etherification of propargylic esters
with alcohols or phenols reported by Nishibayashi et al.,12b and
propargylation of 3-substituted indoles at indolic C3 position
reported by You et al.8 Given the success of this catalytic
system in propargylation, we anticipated that it could be
extended to the reaction between a trialkyl methanetricarbox-
ylate and a propargylic alcohol derivative.
Substrates 1a and 2c were selected as model substrates to
explore the effects of copper salts and the ligands on the
performance of the propargylation reaction (Table 2), as the
To this end, we first examined the reaction between
triethylmethanetricarboxylate (TEMT, 1a) and 1-phenylprop-
2-ynyl acetate (2a) promoted by a copper complex in situ
generated from CuBr (10 mol %) and (S)-sec-butyl-Pybox
(Ligand A, 12 mol %) at room temperature with methanol as
solvent and DIPEA as base (Table 1, entry 1). As expected, the
Table 2. Survey of Copper Salts and Ligands for Propargylic
Substitution of 1a with 2c
a
Table 1. Initial Screening of Reaction Conditions for
Propargylic Substitution of Trialkyl Methanetricarboxylate
a
b
c
entry
copper salt
CuBr
ligand time (h) yield (%)
ee (%)
1
2
3
4
5
6
A
A
A
A
A
A
A
A
A
B
C
D
E
F
20
20
20
20
20
20
48
48
48
20
40
40
5
91
90
89
90
92
96
−
83
83
73
86
82
90
−
CuCl
CuI
b
c
Cu(CH3CN)4PF6
Cu(CH3CN)4ClO4
Cu(CH3CN)4BF4
Cu(OTf)2
entry
1
2
3
temp (°C) time (h) yield (%)
ee (%)
1
1a
1a
1a
1a
1a
1b
1c
1d
1e
2a
2a
2a
2b
2c
2c
2c
2c
2c
3ac
3ac
3ac
3ac
3ac
3bc
3cc
3dc
3ec
20
0
3
10
24
24
20
20
20
20
20
80
83
80
83
91
87
87
86
85
31
68
76
74
83
75
81
71
79
2
d
7
3
−20
−20
−20
−20
−20
−20
−20
d
8
Cu(acac)2
−
−
−
−
4
d
9
Cu(OAc)2
5
10
11
12
13
14
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
92
32
57
90
89
−
76
60
42
75
86
−
6
7
8d
9e
7
a
General conditions: 1 (0.2 mmol), 2 (0.24 mmol), CuBr (10 mol %),
ligand A (12 mol %), and DIPEA (2 equiv) in methanol (1.5 mL).
d
15
G
A
48
20
e
16
95
90
b
c
Yield referred to isolated pure 3. Enantiomeric excess of 3 was
a
General conditions: 1a (0.2 mmol), 2c (0.24 mmol), Copper salt (10
mol %), ligand (12 mol %), and DIPEA (2 equiv) in methanol (1.5
determined by chiral HPLC analysis.
b
c
mL). Yield referred to isolated pure 3ac. Enantiomeric excess of 3ac
was determined by chiral HPLC analysis. No formation of 3ac as
determined by TLC. General conditions, except that Cu-
(CH3CN)4BF4 (5 mol %) and ligand (6 mol %) in methanol (1 mL).
reaction proceeded smoothly to afford the desired product 3ac
in 80% yield after 3 h, albeit in a rather low ee of 30%. When
the temperature was lowered from room temperature to 0 °C,
the enantioselectivity was increased substantially from 31% ee
to 68% ee (entry 2). The ee of 3ac was further improved to
76%, when the reaction was performed at −20 °C (entry 3).
While a longer reaction time (24 h) was required to secure a
high conversion rate of the starting materials. Replacing 2a with
tert-butyl 1-phenylprop-2-ynyl carbonate (2b) under similar
reaction conditions led to the formation of 3ac with results
comparable to those of 2a (entry 4). While the use of 1-phenyl-
2-ynyl pivalate (2c) as a propargylic component resulted in a
higher enantioselectivity of 83% ee (entry 5). Using less
sterically crowded trimethylmethanetricarboxylate (1b) as a
nucleophile did not enhance the reaction rate and provided
d
e
combination of these two substrates (Table 1, entry 5)
delivered more promising results than others. First, various
copper salts were examined. All the copper(I) salts worked well
to afford 3ac in excellent yields and good to excellent ee’s
(entries 1−6), and Cu(CH3CN)4BF4 proved to be the best in
terms of both yield and ee (entry 6). In sharp contrast, when
copper(II) salts were employed as catalyst precursors, no
formation of the desired product was observed even after a
much longer reaction time (entries 7−9). According to the
previous reports and our own observations in copper-complex
B
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Letter
catalyzed propargylation, typically both copper(I) and copper-
(II) salts were suitable catalyst precursors.6,7,12 The reason why
copper(II) salts failed in this study remains unclear at present
and needs to be explored.
2−7). Substrates bearing a methoxymethoxyl (MOMO) group
at the ortho-, meta-, or para-site of benzene ring were also
examined (entries 8−10). The position of the substituents
seemed to have a strong effect on the enantioselectivity of the
reaction, as 2j bearing the MOMO group at the ortho-position
led to 3aj with 72% ee, while meta-substituted 2k and para-
substituted 2l delivered propargylation products with higher
enantioselectivities, 91% ee and 90% ee, respectively. Replacing
the MOMO group with a benzyloxy group at the para-site of
the benzene ring led to a propargylated product with
performance comparable to that of 2l (entry 11 vs entry 10).
Naphthyl substituted substrate 2n was also fit in the current
system (entry 12). According to the previous reports on
asymmetric propargylation, typically an aliphatic-substituted
propargylic substrate was less reactive than an aromatic one,
and its propargylation reaction usually led to a low yield.4−9 It
was notable, in the current system, the reaction between
aliphatic-substituted propargylic substrate 2o and 1a proceeded
smoothly to afford 3ao in 84% yield, albeit in rather modest
47% ee (entry 13). More advanced substrates, such as 2p, 2q,
and 2r (entries 14−16), all performed very well to afford
propargylated products in excellent yields and high ee’s.
Notably, 3ap and 3aq were potentially useful in elaborating
into AMG 837, which is a GPR40 agonist,13 while 3ar
possessed the structural framework of a tumor necrosis factor
inhibitor.14
Next, other tridentate ligands B−G were examined for the
propargylation reaction (entries 10−15). Ligand B (isopropyl-
Pybox) derived from (S)-valine with less bulky groups as
compared with ligand A (sec-butyl-Pybox) derived from (S)-
isoleucine provided a comparable yield, albeit in a lower ee
(entry 10). Ligand C (tert-butyl-Pybox) and ligand D (benzyl-
Pybox) turned out to be less effective as compared with ligand
A and ligand B, affording inferior results even after longer
reaction time (entries 11, 12). Significant acceleration of the
reaction rate was observed when ligand E (phenyl-Pybox) or
ligand F (iso-butyl-Pybox) was employed, as the reaction time
was shortened to 5 or 7 h respectively for complete
consumption of 1a, while the ee’s in both cases were inferior
to that of ligand A (entries 13, 14). Ligand G (indenyl-Pybox)
was completely ineffective in this reaction (entry 15). To our
delight, the loading of the Cu(CH3CN)4BF4 and ligand A could
be lowered to 5 and 6 mol % respectively when the reaction
was performed at higher concentrations (entry 16). Attempts to
further improve the outcome of this reaction by changing the
base or the solvent were unsuccessful, as no better results were
obtained (not shown; see Supporting Information for details).
With the optimized reaction conditions in hand (Table 2,
entry 16), we set out to investigate the scope of the reaction
concerning different substituents at the propargylic position
(Table 3). To our pleasure, phenyl-substituted propargylic
substrates with either electron-donating groups, such as the
methyl and methoxyl group, or electron-withdrawing groups,
such as the fluoro, chloro, bromo, and trifluoromethyl group, at
the para-site of the benzene ring all performed well to afford
the propargylated products in excellent yields and ee’s (entries
With an effective protocol for eantioselective propargylic
substitution of TEMT (1a) developed, transformation of the
triester moiety of propargylation products into a malonate
moiety was next explored (Table 4). We found that treating
a
Table 4. Decarboxylation of Triester 3
a
Table 3. Substrate Scope of Propargylic Pivalates
a
General conditions: 3 (0.1 mmol), NaH (0.2 mmol), ethanol (0.2
b
mmol), in THF (2 mL) at 0 °C. Yield referred to isolated pure 4.
c
Enantiomeric excess of 4 was determined by chiral HPLC analysis.
triesters 3 with NaOEt in situ generated from NaH and EtOH
with THF as solvent at 0 °C provided malonates 4 in excellent
yields and with excellent conservation of chiral enrichment.
Thus, the present work shows that TEMT (1a) can act as an
efficient carbon-centered nucleophile in Cu−Pybox catalyzed
propargylic substitution, therefore representing a suitable
surrogate for diethyl malonate.
In summary, asymmetric propargylic substitution of TEMT
with various propargylic pivalates bearing a terminal alkyne
moiety has been developed by employing the copper−Pybox
a
b
See footnote e in Table 2. Yield referred to isolated pure 3.
c
Enantiomeric excess of 3 was determined by chiral HPLC analysis.
d
Ligand E was employed.
C
DOI: 10.1021/acs.orglett.5b02463
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(d) Zhu, F. L.; Wang, Y. H.; Zhang, D. Y.; Hu, X. H.; Chen, S.; Hou,
C. J.; Xu, J.; Hu, X. P. Adv. Synth. Catal. 2014, 356, 3231. (e) Zhu, F.
L.; Wang, Y. H.; Zhang, D. Y.; Xu, J.; Hu, X. P. Angew. Chem., Int. Ed.
2014, 53, 10223. (f) Zhang, D. Y.; Zhu, F. L.; Wang, Y. H.; Hu, X. H.;
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(9) Nishibayashi, Y.; Yoshikawa, M.; Inada, Y.; Hidai, M.; Uemura, S.
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(10) For pKa of TEMT, see: (a) Guthrie, J. P. Can. J. Chem. 1979, 57,
1177. For pKa of Meldrum’s acid, see: (b) Arnett, E. M.; Harrelson, J.
A. J. Am. Chem. Soc. 1987, 109, 809.
complex as the catalyst, with excellent yields and high ee’s
achieved. This is the first example utilizing TEMT as the
nucleophile in asymmetric catalysis. The present work shows
that TEMT can act as a suitable surrogate for diethyl malonate
in asymmetric propargylic substitution, as one of three ester
groups in the propargylation product could be easily removed
by treating with NaOEt without loss of enantiomeric
enrichment. Further extension of this method to a broader
range of substrates and its application in the synthesis of
biologically active molecules is currently underway in our
laboratory.
(11) For a review about the chemistry of methanetricarboxylic esters:
Newkome, G. R.; Baker, G. R. Org. Prep. Proced. Int. 1986, 18, 117.
(12) For examples of copper-Pybox catalyzed propargylic sub-
stitution: (a) Shibata, M.; Nakajima, K.; Nishibayashi, Y. Chem.
Commun. 2014, 50, 7874. (b) Nakajima, K.; Shibata, M.; Nishibayashi,
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B. B.; Xu, L. J.; Chen, J.; Cao, W. G.; Zhao, G.; Wu, X. Y. Org. Lett.
2014, 16, 5584. Also see refs 5 and 8.
(13) (a) Akerman, M.; Houze, J.; Lin, D. C. H.; Liu, J.; Luo, J.;
Medina, J. C.; Qiu, W.; Reagan, J. D.; Sharma, R.; Shuttleworth, S. J.;
Sun, Y.; Zhang, J.; Zhu, L. Int. Appl. PCT, WO 2005086661, 2005.
(b) Houze, J. B.; Zhu, L.; Sun, Y.; Akerman, M.; Qiu, W.; Zhang, A. J.;
Sharma, R.; Schmitt, M.; Wang, Y.; Liu, J.; Liu, J.; Medina, J. C.;
Reagan, J. D.; Luo, J.; Tonn, G.; Zhang, J.; Lu, J. Y.-L.; Chen, M.;
Lopez, E.; Nguyen, K.; Yang, L.; Tang, L.; Tian, H.; Shuttleworth, S. J.;
Lin, D. C.-H. Bioorg. Med. Chem. Lett. 2012, 22, 1267.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02463.
■
S
General experimental conditions, NMR spectra, and
HPLC analysis of the products (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: wuxy@shu.edu.cn.
Notes
The authors declare no competing financial interest.
(14) Christensen, S. B., IV; Karpinski, J. M.; Frazee, J. S. Int. Appl.
PCT, WO 9703945, 1997.
ACKNOWLEDGMENTS
■
We acknowledge research support from the National Natural
Science Foundation of China (Nos. 21272150 and 21072125).
Dr. Hanwei Hu at Topharman is also gratefully acknowledged
for helpful discussions.
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