Cu-Catalyzed Alkylative Carboxylation of Ynamides with Dialkylzinc Reagents and Carbon Dioxide

Article abstract of DOI:10.1002/chem.201502774

Alkylative carboxylation of ynamides with CO₂ and dialkylzinc reagents using a N-heterocyclic carbene (NHC)-copper catalyst has been developed. A variety of ynamides, both cyclic and acyclic, undergo this transformation under mild conditions to afford the corresponding α,β-unsaturated carboxylic acids, which contain the α,β-dehydroamino acid skeleton. The present alkylative carboxylation formally consists of Cu-catalyzed carbozincation of ynamides with dialkylzinc reagents with the subsequent nucleophilic carboxylation of the resulting alkenylzinc species with CO₂. Dialkylzinc reagents bearing a β-hydrogen atom such as Et₂Zn and Bu₂Zn still afford the alkylated products despite the potential for β-hydride elimination. This protocol would be a desirable method for the synthesis of highly substituted α,β- dehydroamino acid derivatives due to its high regio- and stereoselectivity, simple one-pot procedure, and its use of CO₂ as a starting material. CO₂ incorporation with alkylation: Alkylative carboxylation of ynamides with CO₂ and a dialkylzinc reagent has been achieved by using a N-heterocyclic carbene (NHC)-copper complex as the catalyst. The reactions proceeded by Cu-catalyzed carbozincation of ynamides with dialkylzinc reagents and the subsequent carboxylation of the resulting alkenylzinc species (see scheme).

Full text of DOI:10.1002/chem.201502774

DOI: 10.1002/chem.201502774
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Catalysis |Hot Paper|
Cu-Catalyzed Alkylative Carboxylation of Ynamides with
Dialkylzinc Reagents and Carbon Dioxide
Masanori Takimoto,[a, b] Sandeep Suryabhan Gholap,[a, c] and Zhaomin Hou*[a, b, c]
Abstract: Alkylative carboxylation of ynamides with CO2 and
dialkylzinc reagents using a N-heterocyclic carbene (NHC)–
copper catalyst has been developed. A variety of ynamides,
both cyclic and acyclic, undergo this transformation under
mild conditions to afford the corresponding a,b-unsaturated
carboxylic acids, which contain the a,b-dehydroamino acid
skeleton. The present alkylative carboxylation formally con-
sists of Cu-catalyzed carbozincation of ynamides with dialkyl-
zinc reagents with the subsequent nucleophilic carboxyla-
tion of the resulting alkenylzinc species with CO2. Dialkylzinc
reagents bearing a b-hydrogen atom such as Et2Zn and
Bu2Zn still afford the alkylated products despite the potential
for b-hydride elimination. This protocol would be a desirable
method for the synthesis of highly substituted a,b-
dehydroamino acid derivatives due to its high regio- and
stereoselectivity, simple one-pot procedure, and its use of
CO2 as a starting material.
Introduction
ocyclic carbene (NHC) copper complexes can serve as excellent
catalysts for the carboxylation of various organic substrates
with CO2.[5c,e,6h,7b,12,13] In this context, we have achieved the
borocarboxylation of alkynes with this substrate, CO2, and a di-
boron compound.[12] More recently, we developed the regio-
and stereoselective formal methylative carboxylation and hy-
drocarboxylation of alkynes with CO2, which afforded a variety
of a,b-unsaturated carboxylic acids with well-controlled config-
urations.[13] Despite these recent advances, the substrate scope
remains limited to relatively simple terminal- and internal
alkynes. Exploration of the catalytic carboxylation of function-
alized alkynes with CO2 is therefore of obvious interest and
importance.
Carbon dioxide (CO2) is a naturally abundant, inexpensive, and
inherently renewable feed stock of low toxicity. Accordingly, its
use as a C1 building block for the synthesis of value-added
chemicals has attracted increasing attention.[1] In particular,
transition-metal-catalyzed or -promoted carboxylation reac-
tions, which afford carboxylic acids or derivatives from CO2,
have been extensively studied in the past three decades.[1–6]
Among these reactions, the carboxylation of alkynes with CO2
is of great interest as various a,b-unsaturated carboxylic acids,
which are valuable precursors in organic synthesis, can be
synthesized efficiently. Previously, methods for the nickel-
promoted hydrocarboxylation[7] and alkylative or arylative
carboxylation[8] of alkynes as well as nickel-catalyzed [2+2+2]
Ynamides are a class of alkynes bearing an amide group
directly connected to a C–C triple bond, which have been ext-
ensively studied as functionalized alkyne derivatives in various
chemical transformations.[14] The carboxylation of ynamides
with CO2 can, in principle, provide structurally interesting nitro-
gen-substituted a,b-unsaturated carboxylic acid derivatives,
that is, a,b-dehydro-a-amino acids (DHAAs). DHAAs are an im-
portant class of components found in several biologically
active natural peptides.[15] Moreover, a,b-DHAAs and their ana-
logues can serve as useful precursors in organic synthesis, such
as in the formation of non-natural chiral a-amino acid deriva-
tives through the catalytic enantioselective hydrogenation of
a,b-DHAA esters.[15c,16,17] Therefore, much effort has been de-
voted to develop practical methods to synthesize a,b-DHAA
derivatives. In this context, various methods, such as Erlenmyer
synthesis, b-elimination from b-hydroxy-a-amino acid deriva-
tives, condensation of a-ketocarboxylic acids with amines, and
Hornor–Wadsworth–Emmons reaction of N-acyl dialkyl-
phosphorylglycine esters with aldehydes, have been
developed.[15c–g] However, procedures for the stereoselective
synthesis of b,b’-disubstituted a,b-DHAA derivatives bearing
[9]
cycloaddition of alkynes with CO2 have been developed.
More recently, Ma and co-workers reported the nickel-cata-
lyzed hydrogenative and methylative carboxylation of homo-
propargylic alcohols and related substrates.[10] In addition, Tsuji
and co-workers have reported copper-catalyzed hydrogenative
carboxylation,[11a] silacarboxylation,[11b] and double carboxyla-
tion of alkynes.[11c] Our group has recently shown that N-heter-
[a] Dr. M. Takimoto, S. S. Gholap, Prof. Dr. Z. Hou
Advanced Catalysis Research Group
RIKEN Center for Sustainable Resource Science
2-1 Hirosawa, Wako, Saitama 351-0198 (Japan)
E-mail: houz@riken.jp
[b] Dr. M. Takimoto, Prof. Dr. Z. Hou
Organometallic Chemistry Laboratory, RIKEN
2-1 Hirosawa, Wako, Saitama 351-0198 (Japan)
[c] S. S. Gholap, Prof. Dr. Z. Hou
Graduate School of Science and Engineering, Saitama University
255 Shimo-okubo, Sakura-ku, Saitama 338-8570 (Japan)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201502774.
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two different b-substituents have been very limited. Wandless
and co-workers reported a method using a stereospecific b-
elimination of cyclic sulfanamidates, which were readily pre-
pared from b-hydroxy-a-amino acid derivatives and thionyl
chloride.[18a] Although one of the b-substituents is limited to
the trifluoromethyl group, (Z)-selective condensation of isocya-
nate with trifluoromethylkentones has been achieved.[18b]
A
method involving stereoselective b-halogenetion of b-mono-
substituted DHAA derivatives along with the subsequent ste-
reospecific Suzuki–Miyaura coupling with arylboronic acids has
also been reported.[17c,18c] More recently, related methods using
a combination of stereoselective tosylation of b-keto-a-amino
acid derivatives followed by the subsequent Suzuki–Miyaura
coupling have appeared.[17e] In this paper, we report our
studies on the copper-catalyzed alkylative carboxylation of
ynamides, which provide a,b-DHAA derivatives bearing two
different b-substituents with well-controlled configuration.
Scheme 2. Methylzincation and sequential methylative carboxylation of 1a.
has a (Z)-configuration and that the methyl group is intro-
duced to the b-position of 1a (Figure 1), indicating a retention
of configuration upon carboxylation of
2a-Me.
Results and Discussion
Encouraged by these results, we next
examined the alkylative carboxylation of
ynamide 1a in a one-pot manner, that is,
by mixing the substrate, catalyst, Me2Zn,
Our initial concept is illustrated in Scheme 1. We envisioned
that alkylative carboxylation could be achieved by
a
combination of carbometalation of ynamide 1 with alkylmetal
reagents (R–M) and the subsequent nucleophilic addition of
the generated alkenylmetal species 2 to CO2. We first screened
alkylating reagents and reaction conditions suitable for the
former carbometalation process.
and CO2 together at once (Table 1). To our
Figure 1. 1H NMR
spectroscopic NOE
delight, the one-pot reaction of 1a with
Me2Zn (1.5 equiv) and CO2 (1 atm.) in the
presence of [(IPr)CuCl] (5 mol%) proceed-
ed smoothly and cleanly at room temper-
studies on 4a-Me.
ature to provide the same carboxylated product (4a-Me) in
86% yield (Table 1, entry 1). When the reaction was repeated
at 508C, the yield of 4a-Me was improved to 93% (entry 2).
The use of CuCl or [Rh(cod)(acac)] (acac=acetylacetonate;
cod=1,5-cyclooctadiene) as the precatalyst resulted in signifi-
cantly lower yields (entries 3 and 4). The [(IPr)CuCl] catalyst
Scheme 1. Carboxylation of ynamides by the carbometalation process.
Initially, we tried carbometalation of ynamide 1a by using
Me3Al as the alkylating reagent as we have previously demon-
strated for the formal methylative carboxylation of alkynes.[13]
However, such attempts failed possibly due to the high reactiv-
ity of Me3Al towards the carbonyl group of ynamide 1a provid-
ing complex reaction mixtures. In contrast, the reaction of 1a
with Me2Zn using a rhodium catalyst, which was developed by
Lam and co-workers[19] proceeded rapidly; however, the yield
of the desired product 3a-Me was not sufficient to apply to
the subsequent carboxylation process (Scheme 2, Eq. (1)). For-
tunately, [(IPr)CuCl] (IPr=1,3-bis(2,6-diisopropenyl)imidazol-2-
ylidene) serves as an excellent catalyst for this carbozincation
process under mild conditions. In the presence of [(IPr)CuCl]
(5 mol%), the reaction of ynamide 1a with Me2Zn (1.5 equiv)
in THF at room temperature occurred smoothly in six hours to
afford enamide 3a-Me in 98% yield following protonolysis of
the corresponding alkenylzinc species, 2a-Me (Scheme 2,
Eq. (2)). In addition, exposure of a crude reaction mixture con-
taining 2a-Me to CO2 (1 atm.) allowed the isolation of the car-
boxylated product 4a-Me in 95% yield after hydrolysis and
subsequent diazomethane esterification (Scheme 2, Eq. (3)).
NOE experiments on 4a-Me confirmed that the double bond
Table 1. One-pot alkylative carboxylation of 1a under various conditions.
Entry
1
Cat.
R2Zn
T [8C]
Product, 4a-R (yield [%])[a]
[(IPr)CuCl]
Me2Zn
RT
4a-Me (86%)
4a-Me (93%)
4a-Me (52%)
4a-Me (38%)
2
3
4
[(IPr)CuCl]
CuCl
[Rh(cod)(acac)]
Me2Zn
Me2Zn
Me2Zn
50
RT
RT
5
6
[(IPr)CuCl]
[(IPr)CuCl]
Et2Zn
50
50
4a-Et (92%)
4a-Bu (92%)
Bu2Zn
[a] Yield of isolated product.
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may also play a role in accelerating the nucleophilic addition
of the alkenylzinc intermediate, such as 2a-Me, toward CO2.
With the optimized reaction conditions in hand (Table 1,
entry 2), the scope of dialkylzinc reagents was examined using
ynamide 1a as the substrate (entries 5 and 6). When dialkylzinc
reagents bearing a b-hydrogen atom are used, the correspond-
ing alkylated product is still formed with no evidence of b-
hydride elimination. For example, when Et2Zn was used in the
alkylative carboxylation of 1a, the desired ethylated product
4a-Et was obtained in 92% yield (entry 5). This result contrasts
the previously reported carboxylation of alkynes using Et2Zn in
which b-hydride elimination takes place to provide only hydro-
genative carboxylation products.[10a,c] Similarly, when Bu2Zn is
used instead under similar conditions, the butylated carboxyla-
tion product 4a-Bu could be obtained in 93% yield (Table 1,
entry 6). As seen for Me2Zn, both reactions took place in a syn-
selective manner introducing the alkyl group to the b-position
of the ynamides and the carboxyl group to the a-position,
regioselectively.
Table 2. One-pot alkylative carboxylation of various cyclic ynamides.
Entry
Ynamide 1
R2Zn
T [h]
Product 4, yield[a]
1
2
3
1b
1b
1b
Me2Zn
Et2Zn
Bu2Zn
19
24
24
4b-Me (R=Me), 96%
4b-Et (R=Et), 96%
4b-Bu (R=Bu), 88%
4
1c (R’’=TBDPS)
Me2Zn
Me2Zn
Me2Zn[d]
Me2Zn[e]
Et2Zn
19
4c-Me (R=Me), 70%[b]
4c-Me, 92%
4c-Me, 74%
4c-Me, 96%
4c-Et (R=Et), 97%
4c-Bu (R=Bu), 94%
5[d]
6
1c
1c
1c
1c
1c
48[c]
48
7
8
9
48
24
30
Bu2Zn
Next, the scope of ynamide substrates was explored
(Table 2). Ynamides bearing an alkyl substituent (Table 2, en-
tries 1–9) were found to be excellent substrates in this catalytic
process. The reaction of ynamide 1b bearing a phenethyl sub-
stituent with Me2Zn and CO2 afforded 4b-Me in 96% yield
(entry 1). Both Et2Zn and Bu2Zn could also be used to give 4b-
Et (96%) and 4b-Bu (88%), respectively (entries 2 and 3). Sub-
strates bearing a tethered siloxy group (TBDPSO-, TBDPS=
tBuPh2Si) could be tolerated giving 4c-Me in 70% yield,
though 16% of 1c was also recovered (entry 4). When the
methylative carboxylation of 1c was carried out in a stepwise
manner, that is, performing the methylzincation (508C, 24 hr)
under a N2 atmosphere before the subsequent carboxylation
process (508C, 24 hr), the yield of isolated product could be
improved to 92% (entry 5). In this regard, the yield of the one-
pot procedure could be improved by increasing the number of
equivalents of the dialkylzinc reagent (entries 6 and 7). Hence,
when two equivalents of Me2Zn were used (508C, 48 h), the
yield of 4c-Me was slightly improved (74%, entry 6); however,
when the reaction was carried out with three equivalents of
Me2Zn, the desired product was obtained in 96% yield
(entry 7). In contrast, the alkylative carboxylation of 1c by
using Et2Zn and Bu2Zn proceeded smoothly when using the
one-pot method even with 1.5 equivalents of the dialkylzinc
reagents to give 4c-Et and 4c-Bu in high yields (entries 8 and
9). These results suggest that coordination of the sterically less
hindered Me2Zn to the siloxy group interferes with the methyl-
zincation process, leading to the recovery of unreacted starting
material.
10
11
12
1d
1d
1d
Me2Zn
Et2Zn
Bu2Zn
24
24
20
4d-Me (R=Me), 83%
4d-Et (R=Et), 83%
4d-Bu (R=Bu), 85%
13
14
15
1e
1e
1e
Me2Zn
Et2Zn
Bu2Zn
48[f]
48[f]
48[f]
4e-Me (R=Me), 97%
4e-Et (R=Et), 90%
4e-Bu (R=Bu), 80%
16
17
18
1 f
1 f
1 f
Me2Zn
Et2Zn
Bu2Zn
48[e]
24
4 f-Me (R=Me), 93%
4 f-Et (R=Et), 95%
4 f-Bu (R=Bu), 92%
24
[a] Yield of isolated product. [b] 16% of ynamide 1c was recovered.
[c] The reaction was carried out in a stepwise manner; the reaction of 1c
with Me2Zn (1.5 equiv) was performed at 508C for 24 h, and then the re-
sulting mixture was treated with CO2 (1 atm.) for 24 h. [d] 2 equiv of
Me2Zn was used. [e] 3 equiv of Me2Zn was used. [f] After 24 h, the flask
was refilled with CO2.
entries 13–18). However, prolonged reaction times (48 h) were
often required, possibly due to the steric hindrance imposed
by the proximal benzyl group. These products have potential
applications in asymmetric reactions due to the presence of
a chiral auxiliary moiety.[23]
Despite bearing relatively acidic protons next to the carbon-
yl group of its pyrrolidine-2-one moiety, ynamide 1d cleanly
underwent alkylative carboxylation with Me2Zn, Et2Zn, and
Bu2Zn under the standard one-pot conditions, to give 4d-Me
(83%), 4d-Et (83%), and 4d-Bu (85%), respectively (Table 2, en-
tries 10–12). Ynamides 1e and 1 f bearing Evans’ chiral oxazoli-
din-2-one moiety were also suitable substrates in this reaction;
the desired products 4e-Me, 4e-Et, and 4e-Bu, along with 4 f-
Me, 4 f-Et, and 4 f-Bu were obtained in high yields, (80–97%,
Acyclic tert-butoxycarbonyl (Boc)-protected ynamides also
undergo alkalytive carboxylation. When a substrate bearing
a benzyl group on the nitrogen atom is used, such as 1g, the
reaction is strongly dependant on the nature of the dialkylzinc
reagents. For example, when Me2Zn is used under the stan-
dard one-pot reaction conditions, the expected product was
not observed and 80% of the starting material 1g was recov-
ered. A similar result occurred when the reaction was repeated
under the sequential methylzincation/carboxylation protocol
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manner.[19–21] Transmetalation between 6 and an alkylzinc
species would provide an alkenylzinc species 2a, which could
regenerate 6 by a reversible process. Although a pathway
through direct nucleophilic carboxylation of 2a cannot be
ruled out,[3c] we currently speculate that carboxylation would
take place by CO2 insertion into the CuÀC bond in the alkenyl-
copper species 6 to afford the corresponding copper carboxyl-
ate 7. Finally, transmetalation between the copper carboxylate
7 and the dialkylzinc reagent would provide zinc carboxylate 8
regenerating alkylcopper species 5.
Table 3. Alkylative carboxylation of acyclic ynamides.
Entry
Ynamide 1
R2Zn
t [h]
Product 4, yield[a]
[b]
1
2
3
1g
1g
1g
Me2Zn
Et2Zn
Bu2Zn
48
48
24
–
4g-Et (R=Et), 76%
4g-Bu (R=Bu), 75%
Conclusion
In summary, we have developed a highly efficient NHC–Cu-
catalyzed regioselective alkylative carboxylation of ynamides
using CO2 and dialkylzinc reagents. This three-component cou-
pling reaction can be carried out easily in one pot under mild
conditions to form various nonsymmetric b-b’-disubstituted
a,b-dehydroamino acid derivatives in good to high yields. The
reaction appears to proceed by the Cu-catalyzed carbozinca-
tion of ynamides and alkenyl copper species may play an
important role in facilitating the subsequent carboxylation pro-
cess. In view of the high regio- and stereoselectivity for the for-
mations of nonsymmetrical b,b’-disubstituted a, b-dehydro-a-
amino acid derivatives with well-defined configurations,
a simple one-pot reaction operation, and the use of CO2 as
a starting material, this protocol is a practically useful and
attractive method for use in synthetic organic chemistry.
[c]
4
5
6
1h
1h
1h
Me2Zn
Et2Zn
Bu2Zn
48
30
36
–
4h-Et (R=Et), 79%
4h-Bu (R=Bu), 83%
[a] Yield of isolated product. [b] 80% of 1g was recovered. [c] 80% of 1h
was recovered.
indicating that methylzincation is not occurring under these
conditions. In contrast to these results, ethylative and butyla-
tive carboxylation of 1g proceeds smoothly under the one-pot
protocol to give the desired products 4g-Et (76%) and 4g-Bu
(75%) in good yields (Table 3, entries 2 and 3). Similarly,
ynamide 1h undergoes alkylative carboxylation under similar
conditions when Et2Zn or Bu2Zn are used to give 4h-Et (79%)
or 4h-Bu (83%) (entries 5 and 6), whilst the reaction using
Me2Zn only returned unreacted 1h (entry 4). At present, the
reason for the differing reactivity when Me2Zn is used is
unclear. However, coordination of the sterically unsaturated
Me2Zn to the Boc group may hinder methylzincation in a
similar manner as that described for 1c.
Experimental Section
Typical Procedure: Synthesis of methyl (2Z)-2-(2-oxooxazoli-
din-3-yl)-3-phenylbut-2-enoate (4a-Me) (Table 1, entry 2)
A possible reaction mechanism for the alkylative carboxyla-
tion of 1a is illustrated in Scheme 3. Transmetallation between
[(IPr)CuCl] and a dialkylzinc reagent would form an alkylcopper
species, 5. The carbonyl group on the ynamide moiety would
act as a directing group in the subsequent carbocupration pro-
cess, forming the alkenylcopper species 6 in a regioselective
In a Schlenk flask equipped with a PTFE J. Young valve and a mag-
netic stirring bar, [(IPr)CuCl] (6.5 mg, 0.013 mmol) and ynamide 1a
(50 mg, 0.27 mmol) were added and dissolved in THF (2.7 mL). A
solution of Me2Zn (2.0m in toluene, 200 mL, 0.40 mmol) was added
to this mixture at 08C. The flask was evacuated and CO2 was quick-
ly introduced. The same gas-substitution procedure was repeated
several times before the flask was sealed. After the mixture had
been stirred at 508C for 24 h, it was hydrolyzed with a 10% aque-
ous solution of HCl at 08C. The organic materials were extracted
into ethyl acetate and the resulting extract was washed with water
and brine, and then dried over anhydrous Na2SO4. After evapora-
tion of the solvents, the residue was dissolved in AcOEt (1 mL) and
treated with CH2N2 in Et2O. The reaction mixture was worked-up
according to the standard procedure. The obtained crude material
was purified by silica gel column chromatography (hexane/
EtOAc=2:1) to afford ester 4a-Me as a colorless solid (68 mg,
93%).
Spectral data for 4a-Me
IR (in CHCl3): n˜ =3040, 3030, 3020, 3013, 3017, 1725 (br), 1724,
1
1629, 1478 cmÀ1; H NMR (400 MHz, CDCl3): d=7.32–7.41 (m, 3H),
7.26–7.30 (m, 2H), 4.08 (t, J=7.8 Hz, 2H), 3.82 (s, 3H), 3.27 (t, J=
7.8 Hz, 2H), 2.49 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=164.7,
157.7, 153.4, 140.5, 128.4, 128.4, 126.4, 123.2, 62.6, 52.1, 45.7,
Scheme 3. Possible catalytic cycle.
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[M+Na]+; found: 214.0891.
Acknowledgements
This work was partly supported by a Grant-in-aid for Scientific
Research (S) (No. 26220802, to H.Z.) and (C) (No. 26460029, to
M.T.) from the Ministry of Education, Culture, Sports, Science
and Technology of Japan. We are grateful to A. Karube for
HRMS analysis.
Keywords: carbon dioxide
ynamides · zinc
·
carboxylation
·
copper
·
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Full Paper
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Received: July 15, 2015
Published online on September 8, 2015
Chem. Eur. J. 2015, 21, 15218 – 15223
www.chemeurj.org
15223
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim