Copper-Catalyzed 1,2-Methoxy Methoxycarbonylation of Alkenes with Methyl Formate

Article abstract of DOI:10.1002/anie.201904263

Reported here is a copper-catalyzed 1,2-methoxy methoxycarbonylation of alkenes by an unprecedented use of methyl formate as a source of both the methoxy and the methoxycarbonyl groups. This reaction transforms styrene and its derivatives into value-added β-methoxy alkanoates and cinnamates, as well as medicinally important five-membered heterocycles, such as functionalized tetrahydrofurans, γ-lactones, and pyrrolidines. A ternary β-diketiminato-Cu^I-styrene complex, fully characterized by NMR spectroscopy and X-ray crystallographic analysis, is capable of catalyzing the same transformation. These findings suggest that pre-coordination of electron-rich alkenes to copper might play an important role in accelerating the addition of nucleophilic radicals to electron-rich alkenes, and could have general implications in the design of novel radical-based transformations.

Full text of DOI:10.1002/anie.201904263

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Accepted Article
Title: Copper-Catalyzed 1,2-Methoxy Methoxycarbonylation of Alkenes
with Methyl Formate
Authors: Balázs Budai, Alexandre Leclair, Qian Wang, and Jieping Zhu
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201904263
Angew. Chem. 10.1002/ange.201904263
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10.1002/anie.201904263
Angewandte Chemie International Edition
COMMUNICATION
Copper-Catalyzed 1,2-Methoxy Methoxycarbonylation of Alkenes
with Methyl Formate
Balázs Budai, Alexandre Leclair, Qian Wang, Jieping Zhu*
precursor of methoxycarbonyl radical A from the viewpoint of
synthetic efficiency and sustainability. From the bond
dissociation energy (BDE) of MeOC(O)-H (95.4 kcal/mol)[15] and
tBuO-H (105.5 kcal/mol, Scheme 1), it is reasonable to expect
that t-butoxy radical would be able to abstract the hydrogen from
methyl formate to generate A. Indeed, Urry et al. in their seminal
work demonstrated that heating a mixture of methyl formate with
di-t-butylperoxide in an autoclave (130 °C, ethylene, 340-440
p.s.i.) afforded a mixture of homologated alkanoates (Scheme
1c).[16] The result indicated that both t-BuO∙ and the alkyl radical
RCH2∙ are capable of abstracting a hydrogen from methyl
formate. However, the competing oligomerization processes
rendered this chain process synthetically insignificant.
Abstract: Here we report a copper-catalyzed 1,2-methoxy
methoxycarbonylation of alkenes by an unprecedented use of
methyl formate as a source of both the methoxy and the
methoxycarbonyl groups. This reaction transforms styrene and
its derivatives to value-added b-methoxy alkanoates,
cinnamates as well as medicinally important five-membered
heterocycles such as functionalized tetrahydrofurans, g-
lactones and pyrrolidines.
A ternary b-diketiminato-Cu(I)-
styrene complex, fully characterized by NMR spectroscopy and
X-ray crystallographic analysis, is capable of catalyzing the
same transformation. Our finding suggests that pre-
coordination of electron-rich alkenes to copper might play an
important role in accelerating the addition of nucleophilic
radicals to electron-rich alkenes and could have general
implications in the design of novel radical-based
transformations.
a) Taniguchi’s work on carbazates under iron-catalyzed conditions.
O
R2
R1
O
R2
OH
Fe(Pc) (0.1 equiv)
THF, air, 65 °C
NH2
+
MeO
N
H
MeO
R1
A
COOMe
b) Overman’s work on methyl N-phthalimidoyl oxalate under photoredox conditions.
Intramolecular addition of alkoxycarbonyl radicals,
generated in situ by reduction of carbonic acid derivatives
(ROCOX, X = Cl, SePh, TePh), onto tethered alkenes is known
for years[1] and has been successfully used in the total synthesis
of complex natural products.[2] Intermolecular Minisci-type
alkoxycarbonylation of electron-poor heteroaromatics has also
been developed.[3] On the other hand, examples on the
difunctionalization of alkenes initiated by intermolecular addition
of alkoxycarbonyl radicals remained rare. In this regard,
Taniguchi and coworkers reported the first examples of iron-
catalyzed oxidative 1,2-hydroxy methoxycarbonylation of
electron-rich alkenes using carbazates as precursors of
methoxycarbonyl radical A (Scheme 1a).[4] Overman and
Slutskyy demonstrated that A, generated from methyl N-
phthalimidoyl oxalate under visible light photoredox conditions,
reacted only with electron-poor Michael acceptors to afford 1,4-
dicarbonyl compounds and defined A as nucleophilic,[5] rather
than ambiphilic radical proposed previously based on
computational studies (Scheme 1b).[6-9] Other potentially
explosive, toxic and corrosive chemicals[3,10-14] have also been
developed for the generation of methoxycarbonyl radical A.
However, these earlier investigations focused primarily on the
generation, rather than the synthetic application of A.
O
O
EWG
[Ru(bpy)3](PF6)2 (0.015 equiv)
Hantzsch ester (2.0 equiv)
O
EWG
+
MeO
N
H
O
COOMe
Blue LEDs, CH2Cl2, 23 °C
O
c) Urry’s work on the methoxycarbonylation of ethylene by a radical chain mechanism.
O
tBuOOtBu, 130 °C
COOMe
n
+
H2C CH2
MeO
H
340-440 p.s.i.
n = 1, 3, 5, 7, 9, 11
H-COOMe
95.4
H-OtBu
105.5
BDE (kcal/mol):
d) This work: Cu-catalyzed difunctionalization of electron-rich alkenes.
O
RO
O
MeO
H
MeO
R2
R1
R2 Mn+1
COOMe
FG
FG
A
COOMe
R1
R2
R2
Mn
M
D
C
R1
R1
B
1
COOMe
R1
COOMe
R1
COOMe
R2
R2
OMe
COOMe
COOMe
R1
R1
R1
O
N
Ts
O
O
2
3
4
5
6
Scheme 1. Methoxycarbonyl radical: Generation and synthetic application.
As an abundant commodity chemical produced over
770,000 metric tons a year, methyl formate would be an ideal
To address the aforementioned challenges, we sought to
develop a non-chain difunctionalization process combining the
radical addition reaction with the metal-catalyzed transformation.
Assuming that the presence of iron salt in Taniguchi’s protocol
might be responsible for the apparent contradictory results of
Taniguchi and Overman regarding the electronic properties of
radical A, a working hypothesis was advanced as shown in
Scheme 1d. Coordination of electron-rich alkenes to a metal
would afford metal-p complex B with decreased LUMO energy
of the double bond,[17] facilitating therefore the addition of
nucleophilic methoxycarbonyl radical A.[18] Functionalization of
the carbon-metal bond would then furnish the b-functionalized
[*]
B. Budai, A. Leclair, Dr. Q. Wang, Prof. Dr. J. Zhu
Laboratory of Synthesis and Natural Products
Institute of Chemical Sciences and Engineering
Ecole Polytechnique Fédérale de Lausanne
EPFL-SB-ISIC-LSPN, BCH 5304, 1015 Lausanne (Switzerland)
E-mail: jieping.zhu@epfl.ch
Homepage: http://lspn.epfl.ch
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/anie.201904263
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COMMUNICATION
alkanoate D with concurrent regeneration of the catalytic
species. We report herein the realization of this unprecedented
transformation that converts unactivated alkenes 1 to b-
methoxy alkanoates 2 (FG = OMe) under copper catalysis.[19]
The versatility of the process is illustrated by the ready access
to other important structural motifs such as cinnamates 3,
tetrahydrofurans 4, g-lactones 5 and pyrrolidines 6 by slightly
modifying the work-up procedure and the nature of the
substituents of the starting materials 1.
other Cu-catalyzed carboetherification of alkenes developed
previously in this laboratory.[20]
The scope of this transformation was next explored
(Scheme 2). The terminal alkenes bearing an alkyl and an aryl
substituent were converted to the corresponding b-methoxy
alkanoates (2a-2h) regardless of the steric and stereoelectronic
effect of the substituents. The 1,1-diaryl substituted ethylenes
participated in the reaction without event (2i-2t). More
importantly, styrenes, known to be highly prone to
polymerization in radical processes, were transformed to 3-
methoxy-3-arylpropanoates 2u-2aa in good yields. The
presence of strong electron-donating group (OMe) and strong
electron-withdrawing group (NO2) were tolerated in this
transformation. A broad range of functional groups such as
halides (F, Cl, Br), ester, sulfonamide and cyano were
compatible with the reaction conditions, providing therefore
handles for further functionalization. Simple aliphatic alkenes
were however not suitable substrates for this transformation,
probably due to the competitive H-abstraction of the allylic CH
(BDE of allylic CH in propene: 88 kcal/mol). Ethoxy
ethoxycarbonylation of 1a under standard conditions afforded
the desired product in low yield. Finally, the scalability of the
reaction was also examined with three classes of substrates. To
our delight, compounds 2a, 2i, 2u were all formed in
comparable yields in gram-scale experiments.
Cu(OTf)2 (0.1 equiv)[a]
L1 (0.1 equiv)
Cl
Cl
R2
R2
R1
O
OMe
COOMe
NH
N
R1
Cl
Me
H
OMe
Cl
Me
TBPA (4.0 equiv)
65-75 °C
1
2
L1
Me OMe
COOMe
R
OMe
COOMe
OMe
COOMe
R
R
2a R = H, 77%, (72%)[b]
2b R = 4-Me, 79%
2c R = 3-Me, 76%
2d R = 4-F, 73%
2e R = Et, 70%
2f R = i-Pr, 58%
2g R = cyclohexyl, 59%
2h R = CH2NHTs, 59%
2i R = H, 70%, (72%)[b]
2j R = 4-NO2, 69%[c]
2k R = 4-F, 83%
OMe
2l R = 4-Br, 67%
COOMe
2m R = 4-CO2Et, 63%[c]
2n R = 4-CN, 68%[c]
2o R = 4-CF3, 57%
2p R = 3-CF3, 62%
2q R = 3-Me, 44%
R
R2
OMe
COOMe
2u R = H, 58%, (53%)[b]
2v R = 4-Me, 66%
2w R = 4-MeO, 60%
2x R = 3,4-di-MeO, 63%
2y R = 4-F, 54%
R1
2r R1 = R2 = 4-F, 67%
2s R1 = R2 = 4-Cl, 54%
(75%)[d]
Cu(OTf)2 (0.1 equiv)[a], L1 (0.1 equiv)
TBPA (4.0 equiv), 75 °C
R2
R2
O
2z R = 4-Cl, 45%
2aa R = 4-Br, 53%
2t R1 = 3-Cl, R2 = H, 60%
COOMe
R1
R1
H
OMe
then TfOH (2.0 equiv), 75 °C
1
3
Scheme 2. Cu-catalyzed reaction of electron-rich alkenes with methyl
formate: Synthesis of b-methoxy alkanoates. [a] Reaction was performed at
0.25 mmol scale in methyl formate (c 0.1 M). [b] Gram-scale experiment. [c]
The reaction was performed at 85 °C. [d] Yield based on conversion.
Me
R
COOMe
COOMe
R
R
COOMe
R
3a R = H, 62% (E/Z > 20:1)
3b R = 4-F, 58% (E/Z > 20:1)
3c R = 4-MeO, 64% (E/Z > 20:1)
3d R = H, 74% (E/Z > 20:1)
3h R = H, 76%
3i R = 4-F, 64%
3j R = 4-Me, 57%
3e R = 4-F, 69% (E/Z > 20:1)
3f R = 4-MeO, 51% (E/Z > 20:1)
3g R = 4-Me, 79% (E/Z > 20:1)
a-Methyl styrene (1a, R1 = Ph, R2 = Me, Scheme 2) was
chosen as a test substrate. In our initial experiments, the b-
methoxy alkanoate 2a was indeed isolated, albeit with a very
low yield. Efforts were therefore dedicated to optimize this novel
1,2-methoxy methoxycarbonylation process by varying
systematically the copper salts, the ligands, the peroxide and
the reaction temperature (see SI for details). The key
observation was summarized as follows: a) Cu(OTf)2 turned out
to be the catalyst of choice and tert-butyl peroxyacetate (TBPA)
was the best source of the alkoxy radical; b) diketimines stood
out as a ligand of choice from those screened (phenanthrolines,
bisquinolines, bipyridines, Pybox, bisoxazolines, salens) and L1
derived from pentane-2,4-dione and 2,6-dichloroaniline
outperformed other differently substituted diketimines; c) the
reaction outcome was very sensitive to the reaction temperature.
At the optimum temperature of 75 °C, the reaction proceeded
quickly and the product 2a remained stable for hours under the
reaction conditions. At higher temperatures (85 °C), partial
degradation of 2a occurred as the reaction proceeded. Overall,
performing the reaction of 1a in methyl formate (c 0.1 M) in the
presence of tert-butyl peroxyacetate (TBPA), a catalytic amount
of Cu(OTf)2 and ligand L1 (0.1 equiv) at 75 °C under nitrogen
atmosphere afforded 2a in 77% isolated yield. Of mechanistic
importance, the efficiency of this transformation decreased
significantly when MeOH was used as co-solvent
(HCOOMe/MeOH = 2:1, 22% NMR yield), in sharp contrast to
Scheme 3. Conversion of styrenes to cinnamate derivatives. [a] Reaction
was performed at 0.25 mmol scale in methyl formate (c 0.1 M).
Conversion of terminal alkenes to a,b-unsaturated esters
is a transformation of high importance in the synthesis of
complex bioactive compounds. The cross-metathesis and a
more classic two-step sequence involving ozonolysis of the
double bond followed by the Wittig reaction of the resulting
carbonyl compound are two of the most frequently used
reactions for this purpose. We therefore set out to investigate
the one-pot conversion of terminal alkenes 1 to a,b-unsaturated
esters 3 taking advantage of the intermediacy of compound 2.[21]
A wide range of bases, Lewis and Brønsted acids were
examined in order to promote the in situ b-elimination of the b-
methoxy alkanoates and triflic acid (TfOH) stood out from this
screening (See SI for details). Under optimized conditions, the
a,b-unsaturated ester 3a was isolated in good yield with
excellent E/Z selectivity (Scheme 3). a-Methyl styrene and its
derivatives with different electronic properties were converted to
the corresponding b,b-disubstituted a,b-unsaturated esters (3d-
3g) with high synthetic efficiency. 1,1-Diaryl substituted
ethylenes were similarly transformed to the homologated esters
(3h-3j).
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10.1002/anie.201904263
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To further extend the application scope of this protocol,
methoxycarbonylative cycloetherification, lactonization and
cycloamination were examined (Scheme 4). Gratifyingly,
heating a methyl formate solution of 4-phenylpent-4-en-1-ol (7a)
under standard conditions provided the 2,2-disubstituted
tetrahydrofuran 4a together with a small amount of ester 10.
However, adding a catalytic amount of sulfuric acid (0.1 equiv)
before aqueous work-up afforded cleanly 4a in 72% yield. The
methyl 4-phenylpent-4-enoate (8a, X = COOMe) and N-(4-
phenylpent-4-en-1-yl)tolylsulfonamide (9a, X = CH2NHTs) were
transformed into the corresponding lactone 5a and pyrrolidine
6a, respectively, in similar yields. As it is illustrated in Scheme
3, substrates with different electronic properties were converted
to the corresponding heterocycles. However, the presence of
OMe group led in general to the corresponding products with
reduced yields due mainly to the instability of the resulting
heterocycles.
afforded homoallylic alcohol 15 in 27% yield (Scheme 5b).
Should the radical intermediate E be involved, the formation of
1,2-dihydronaphthalene 16 would be expected. The fact that 16
was not detected suggested that the reaction might proceed
through an organometallic species F rather than the radical
intermediate E. Although intermediate F could in principle
undergo homolytic cleavage to afford homoallylic radical E and
Cu(II) species,[22] the reductive elimination of F was apparently
kinetically faster to provide methyl ether 15 instead.
a) Experiments probing the source of methoxy group
Me OMe
Standard
Me OCD3
COOMe
COOMe
+
conditions[a]
CD3OD
+
+
NMR yield
73-81%
HCOOCH3
1a
2a
10
11
ratio
ratio
1
Standard
Me OMe
Me OCD3
conditions[a]
CH3OH
COOCD3
+
COOCD3
NMR yield
66-68%%
HCOOCD3
1a
12
13
1
10
Cu(OTf)2 (0.1 equiv)[a]
L1 (0.1 equiv)
b) Radical clock experiment
COOMe
COOMe
COOMe
X
Standard
O
O
conditions[a]
+
TBPA (4.0 equiv), 65-75 °C
R
Y
R
H
OMe
Z
H
OMe
OMe
15 27%, ratio 5:1
then aqueous H2SO4 (0.1 equiv)
75 °C
7 X = CH2OH
8 X = COOMe
4 Y = O, Z = H, H
5 Y = Z = O
14
16 0%
COOMe
COOMe
9 X = CH2NHTs
6 Y = NTs, Z = H, H
X = CH2NHTs[d]
X = COOMe[c]
X = CH2OH[b]
COOMe
CuIIIOMe
COOMe
COOMe
F
E
O
O
N
Ts
R
R
R
O
c) Synthesis and X-ray structure of LCu(I)-styrene complex 18
5a R = H, 75%
4a R = H, 75%
Me
Cl
Me
Cl
5b R = 4-Me, 70%
5c R = 4-F, 70%
5d R = 4-CN, 69%
5e R = 4-OMe, 44%
5f R = 3-Me, 47%
5g R = 3-Cl, 68%
6a R = H, 69%
4b R = 4-Me, 58%
4c R = 4-F, 77%
4d R = 4-CN, 62%
4e R = 4-OMe, 47%
4f R = 3-Me, 57%
6b R = 4-Me, 51%
6c R = 4-F, 42%
6d R = 3-Me, 55%
6e R = 3-Cl, 45%
Me
Cl
Me
Cl
N
N
Styrene
Pentane
Cu
N
N
Cl
Cl
Cu
H
Cl
Cl
H
H
17
18
MeOOC
OMe
OH
Scheme 5. Control experiments and X-ray structure of LCu(I)-styrene
complex 18. [a] 1a or 14 (0.25 mmol), in HCOOCH3 or HCOOCD3 (c 0.1 M),
Cu(OTf)2 (0.1 equiv), L1 (0.1 equiv), TBPA (4.0 equiv), 75 °C.
10
Scheme 4. Cu-catalyzed reaction of methyl formate with alkenes bearing an
internal nucleophile. [a] Reaction was performed at 0.25 mmol scale in methyl
formate (c 0.1 M). [b] Synthesis of tetrahydrofurans; [c] Synthesis of g-
lactones; [d] Synthesis of pyrrolidines.
Since fragmentation of the cyclopropyl methyl radical was a
kinetically fast process, the aforementioned results implied that
the alkene-Cu complex might be formed before radical addition.
Gratifyingly, stirring a pentane solution of styrene and the b-
diketiminato Cu(I) (µ-benzene) complex 17, synthesized
according to Warren,[23] afforded a new complex 18 whose
structure was fully established by spectroscopic and X-ray
single crystal structure analysis (Scheme 5c).[24,25] In the
presence of an equal amount of Cu(OTf)2 or TfOH, both 17 and
To gain insight into the reaction mechanism, a series of
control experiments were carried out. As it would be expected,
the reaction did not proceed in the absence of copper catalyst.
Performing the methoxy methoxycarbonylation of 1a in the
presence of CD3OD (2.0 equiv) under otherwise standard
conditions afforded compounds 2a and 11 in a 10 to 1 ratio.
Conversely, performing the same reaction in HCOOCD3 in the
presence of MeOH (2.0 equiv) afforded 12 and 13 in a ratio of 1
to 10 (Scheme 5a). The results of these two crossover
experiments suggested that both methoxycarbonyl and
methoxy groups came from methyl formate and that the
formation of C-O bond did not go through a cationic intermediate.
In addition, reaction of 2a with HCOOCD3 under standard
conditions led also to the formation of a small amount of 11 via
most probably the ionization of 2a to carbocation followed by
nucleophilic trapping. We hypothesized that this pathway could
also account for the formation of the minor products 11 and 12
18
were
competent
catalysts
for
the
methoxy
methoxycarbonylation of 1a under otherwise standard
conditions.
On the basis of the results of these control experiments, a
possible reaction pathway is depicted in Scheme 6. Reduction
of tert-butyl peroxyacetate (TBPA) by Cu(I) would generate the
tert-butoxy radical which would abstract hydrogen from methyl
formate to afford the nucleophilic methoxycarbonyl radical A. [26]
On the other hand, coordination of LCu(I) to electron-rich
alkenes 1 would afford Cu(I)-p complex B that would react with
A to furnish C. Radical rebound of adduct C with A would
produce the Cu(III) intermediate D which might be in equilibrium
with methoxy complex G. Reductive elimination of the latter
in
the
crossover
experiments.
Submitting
1-(1-
cyclopropylvinyl)benzene (14) to the standard conditions
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10.1002/anie.201904263
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COMMUNICATION
would then furnish the b-methoxy alkanoate 2 with concurrent
regeneration of the Cu(I) species.[27] In line with this mechanistic
hypothesis, the yield of 2a was reduced to 28% when the
reaction was performed under CO atmosphere under otherwise
identical conditions. An experimental protocol was designed
that allowed us to detect the generated CO under the reaction
conditions (See SI).
Keywords: Alkene difunctionalization; methoxycarbonyl
radical; homogeneous catalysis; heterocycle; methyl formate
[1]
[2]
a) M. D. Bachi, E. Bosch, Tetrahedron Lett. 1986, 27, 641-644; b) M.
D. Bachi, E. Bosch, J. Org. Chem. 1992, 57, 4696-4705; c) C. Plessis,
S. Derrrer, Tetrahedron Lett. 2001, 42, 6519-6522.
a) A. K. Singh, R. K. Bakshi, E. J. Corey, J. Am. Chem. Soc. 1987,
109, 6187-6189; b) B. M. Trost, J. Waser, A. Meyer, J. Am. Chem. Soc.
2008, 130, 16424-16434; c) J. E. Forbes, R. N. Saicic, S. Z. Zard,
Tetrahedron 1999, 55, 3791-3802; d) S. Takahashi, T. Nakata, J. Org.
Chem. 2002, 67, 5739-5752.
CuII
R2
R2
R1
OMe
COOMe
O
CuIL
R1
R2
MeO
H
2
1
MeO
R2 CuIII
tBuO
tBuOH
[3]
[4]
R. Bernardi, T. Caronna, R. Galli, F. Minisci, M. Perchinunno,
Tetrahedron Lett. 1973, 14, 645-648; b) F. Coppa, F. Fontana, E.
Lazzarini, F. Minisci, G. Pianese, L. Zhao, Tetrahedron Lett. 1992, 33,
3057-3060.
L
CuIL
R1
R1
O
COOMe
B
G
MeO
CO
A
a) T. Taniguchi, Y. Sugiura, H. Zaimoku, H. Ishibashi, Angew. Chem.
Int. Ed. 2010, 49, 10154-10157; Angew. Chem. 2010, 122, 10352-
10355. Contribution from other groups, see: b) Y.-H. Su, Z. Wu, S.-K.
Tian, Chem. Commun. 2013, 49, 6528-6530; c) X. Xu, Y. Tang, X. Li,
G. Hong, M. Fang, X. Du, J. Org. Chem. 2014, 79, 446-451; d) R. Ding,
Q.-C. Zhang, Y.-H. Xu, T.-P. Loh, Chem. Commun. 2014, 50, 11661-
11664; e) G. Wang, S. Wang, J. Wang, S.-Y. Chen, X.-Q. Yu,
Tetrahedron 2014, 70, 3466-3470; f) Z. Zong, S. Lu, W. Wang, Z. Li,
Tetrahedron Lett. 2015, 56, 6719-6721; For addition to isocyanide,
see: g) X. Li, M. Fang, P. Hu, G. Hong, Y. Tang, X. Xu, Adv. Synth.
Catal. 2014, 356, 2103-2106; h) C. Pan, J. Han, H. Zhang, C. Zhu, J.
Org. Chem. 2014, 79, 5374-5378.
OMe
O
R2 CuIIL
R2 CuIII
L
R1
R1
COOMe
C
COOMe
O
D
MeO
A
Scheme 6. Possible reaction pathway.
We have also carried out kinetic studies on the initial rate of
the methoxy methoxycarbonylation of styrene and its 4-
substituted derivatives (4-Cl, 4-F, 4-Me, 4-OMe) and found that
the rate of formation followed the following order: 2w (R =
OMe) >> 2v (R = 4-Me) ∼ 2u ( R = H) > 2z (R = 4-Cl) > 2y (R =
4-F, see SI). Considering that the radical A is nucleophilic, this
observation could be tentatively accounted for by the fact that
the electron rich alkene 1v (R = 4-Me) is more prone to form the
alkene-Cu complex B, accelerating therefore the subsequent
radical addition reaction.
[5]
[6]
Y. Slutskyy, L. E. Overman, Org. Lett. 2016, 18, 2564-2567.
S. H. Kyne, C. H. Schiesser, H. Matsubara, Org. Biomol. Chem. 2007,
5, 3938-3943.
[7]
Acyl radical is also nucleophilic and reacts preferentially with electron-
poor double bond, see: a) V. Chudasama, R. J. Fitzmaurice, S.
Caddick, Nat. Chem. 2010, 2, 592-596; b) T. Wu, H. Zhang, G. Liu,
Tetrahedron 2012, 68, 5229-5233; c) M.-B. Zhou, R.-J. Song, X.-H.
Ouyang, Y. Liu, W.-T. Wei, G.-B. Deng, J.-H. Li, Chem. Sci. 2013, 4,
2690-2694; d) F. Jia, K. Liu, H. Xi, S. Lu, Z. Li, Tetrahedron. Lett. 2013,
54, 6337-6340; e) H. Wang, L.-N. Guo, X.-H. Duan, Adv. Synth. Catal.
2013, 355, 2222-2226; f) L. Zhang, H. Huang, C. Yang, W. Xia, Org.
Lett. 2015, 17, 1034-1037.
In summary, methyl formate was successfully exploited for
[8]
[9]
a) For iron-catalyzed peroxidation-carbamoylation of alkenes using
formamides as precursors of aminoacyl radicals, see: J.-K. Cheng, L.
Shen, L.-H. Wu, X.-H. Hu, T.-P. Loh, Chem. Commun. 2017, 53,
12830-12833; b) For iron-catalyzed carbo-carbamoylation of electron-
poor akenes, see: V. G. Correia, J. C. Abreu, C. A. E. Barata, L. H.
Andrade, Org. Lett. 2017, 19, 1060-1063.
the first time in
a
synthetically useful Cu-catalyzed
difunctionalization of alkenes. Acting as a donor of both
methoxycarbonyl and methoxy groups,[28] methyl formate
transforms styrene and its derivatives to value-added b-
methoxy alkanoates, cinnamates as well as medicinally
important five-membered heterocycles. It was believed that “the
reaction of alkyl radicals is synthetically significant only when
the olefinic double bond is conjugated with electron-withdrawing
groups owing to the nucleophilic character of the alkyl
radical”.[29] While the statement is correct in absolute sense, the
landscape is changing and the transition metal-catalyzed
difunctionalization of electron-rich alkenes involving addition of
nucleophilic alkyl radical is seen in the recent literature.[30] We
surmised that pre-coordination of electron rich double bond to
metal might play an important role and it could have general
implications in designing novel radical-based transformations.
For an account on the reactivity of acyl radical, see: d) C. H. Schiesser,
U. Wille, H. Matsubara, I. Ryu, Acc. Chem. Res. 2007, 40, 303-313.
[10] K. Bartel, A. Goosen, A. Scheffer, J. Chem. Soc. (C) 1971, 3766-3769.
[11] D. E. Zabel, W. S. Trahanovsky, J. Org. Chem. 1972, 37, 2413-2418.
[12] M. Fiorentino, L. Testaferri, M. Tiecco, L. Troisi, J. Org. Chem. 1976,
41, 173-175.
[13] P. A. Simakov, F. N. Martinez, J. H. Horner, M. Newcomb, J. Org.
Chem. 1998, 63, 1226-1232.
[14] M. A. Lucas, C. H. Schiesser, J. Org. Chem. 1996, 61, 5754-5761.
[15] J. L. Holmes, F. P. Lossing, P. M. Mayer, J. Am. Chem. Soc. 1991,
113, 9723-9728.
[16] W. H. Urry, E. S. Huyser, J. Am. Chem. Soc. 1953, 75, 4876-4877.
[17] A. H. C. Horn, T. Clark, J. Am. Chem. Soc. 2003, 125, 2809-2816.
[18] B. P. Roberts, Chem. Soc. Rev. 1999, 28, 25-35.
Acknowledgements
[19] a) X. Zhu, S. Chiba, Chem. Soc. Rev. 2016, 45, 4504-4523; b) Y.
Shimizu, M. Kanai, Tetrahedron Lett. 2014, 55, 3727-3737; c) S. R.
Chemler, P. H. Fuller, Chem. Soc. Rev. 2007, 36, 1153-1169.
[20] a) C. Chatalova-Sazepin, Q. Wang, G. M. Sammis, J. Zhu, Angew.
Chem. Int. Ed. 2015, 54, 5443-5446; Angew. Chem. 2015, 127, 5533-
5536; b) T. M. Ha, C. Chatalova-Sazepin, Q. Wang, J. Zhu, Angew.
Chem. Int. Ed. 2016, 55, 9249-9252; Angew. Chem. 2016, 128, 9395-
9398; c) A. Bunescu, T. M. Ha, Q. Wang, J. Zhu, Angew. Chem. Int.
Ed. 2017, 56, 10555-105558; Angew. Chem. 2017, 129, 10691-10694.
This research was supported by the Swiss National Science
Foundation (SNSF, N° 200021-178846/1) and EPFL
(Switzerland). We thank Dr. F.-T. Farzaneh and Dr. R. Scopelliti
for X-ray crystallographic analysis of copper complex 18.
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[21] Synthesis of a,b-unsaturated ketones/aldehydes from alkenes, see: a)
J. Wang, C. Liu, J. Yuan, A. Lei, Angew. Chem. Int. Ed. 2013, 53, 2256-
2259; Angew. Chem. 2013, 125, 2312-2315; b) Y. Bao, G.-Y. Wang,
Y.-X. Zhang, K.-J. Bian, X.-S. Wang, Chem. Sci. 2018, 9, 2986-2990.
[22] Y. Miller, L. Miao, A. S. Hosseini, S. R. Chemler, J. Am. Chem. Soc.
2012, 134, 12149-12156.
suggestion. For carbocupration of alkynes, see: a) J.-F. Normant, M.
Bourgain, Tetrahedron Lett. 1971, 2583-2586; For carbocupration of
strained cyclopropenes, see: b) E. Nakamura, M. Isaka, S. Matsuzawa,
J. Am. Chem. Soc. 1998, 110, 1297-1298; For intramolecular
carbocupration of alkenes, see: c) K. K. Toh, Y.-F. Wang, E. P. J. Ng,
S. Chiba, J. Am. Chem. Soc. 2011, 133, 13942-13945; d) W. You, M.
K. Brown, J. Am. Chem. Soc. 2014, 136, 14730-14733. For a
comprehensive mechanistic discussion, see ref 19b.
[23] R. T. Gephart, C. L. McMullin, N. G. Sapiezynski, E. S. Jang, M. J. B.
Aguila, T. R. Cundari, T. H. Warren, J. Am. Chem. Soc. 2012, 134,
17350-17353.
[28] PhI(OAc)2 acting as a donor of both methyl and acetoxy group, see: Y.
Wang, L. Zhang, Y. Yang, P. Zhang, Z. Du, C. Wang, J. Am. Chem.
Soc. 2013, 135, 18048-18051.
[24] CCDC 1900564 (18) contains the supplementary crystallographic data
for this paper. These data are provided free of charge by The
Cambridge Crystallographic Data Centre.
[29] F. Minisci, Acc. Chem. Res. 1975, 8, 165-171.
[25] For related Cu(I)-styrene complex, see: R. W. Quan, Z. Li, E. N.
[30] Nucleophilic alkyl radical: a) W. Jian, L. Ge, Y. Jiao, B. Qian, H. Bao,
Angew. Chem. Int. Ed. 2017, 56, 3650-3654; Angew. Chem. 2017,
129, 3704-3708; b) B. Qian, S. Chen, T. Wang, X. Zhang, H. Bao, J.
Am. Chem. Soc. 2017, 139, 13076-13082; c) W.-Y. Li, C.-S. Wu, Z.
Wang, Y. Luo, Chem. Commun. 2018, 54, 11013-11016; d) X. Bao, T.
Yokoe, T. M. Ha, Q. Wang, J. Zhu, Nat. Commun. 2018, 9, 3725,
Nucleophilic acyl radical: e) W. Liu, Y. Li, K. Liu, Z. Li, J. Am. Chem.
Soc. 2011, 133, 10756-10759.
Jacobsen, J. Am. Chem. Soc. 1996, 118, 8156-8157.
•
[26] Reduction of TBPA by Cu(I)X would generate tBuO and (AcO)Cu(II)X.
The latter could be rapidly reduced to Cu(I) again as in the Kharasch-
Sosnovsky reaction, see: a) M. S. Kharasch, G. Sosnovsky, N. C.
Yang, J. Am. Chem. Soc. 1959, 81, 5819-5824; b) C. L. Jenkins, J. K.
Kochi, J. Am. Chem. Soc. 1972, 94, 843-855.
[27] Carbocupration of alkene by in situ generated Cu(II)COOMe species
could be an alternative reaction pathway. We thank the referee for this
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Entry for the Table of Contents (Please choose one layout)
Layout 1:
Synthetic Method
R2
Me
Cl
Me
Cl
Cu(OTf)2 (0.1 equiv)
L1 (0.1 equiv)
Balázs Budai, Alexandre Leclair, Qian
Wang, and Jieping Zhu*__________ Page
– Page
R2
R1
R1
H
OMe
COOMe
N
HN
Cl
O
TBPA (4.0 equiv)
65-75 °C
Cl
L1
OMe
1
Copper-Catalyzed 1,2-Methoxy
Methoxycarbonylation of Alkenes with
Methyl Formate
Generous donor. Methyl formate acts as a donor of both methoxycarbonyl and methoxy groups in the
above Cu-catalyzed alkene difunctionalization process. Formation of diketiminato-Cu(I)-styrene ternary
complex 1, fully characterized, was proposed to accelerate the addition of nucleophilic methoxycarbonyl
radical.
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