Stereoselective Synthesis of Tetrasubstituted Furylalkenes via Gold-Catalyzed Cross-Coupling of Enynones with Diazo Compounds

Article abstract of DOI:10.1021/acs.orglett.7b01467

A stereoselective, gold-catalyzed, cross-coupling reaction of enynones with diazo compounds has been developed, affording 2-alkenylfurans in moderate to good yields with excellent E-stereoselectivity. Upon using diazo compounds as nucleophiles to trap the in situ formed gold furyl carbene, this protocol provides a novel path toward the formation of unsymmetrical tetrasubstituted alkenes.

Full text of DOI:10.1021/acs.orglett.7b01467

Letter
pubs.acs.org/OrgLett
Stereoselective Synthesis of Tetrasubstituted Furylalkenes via Gold-
Catalyzed Cross-Coupling of Enynones with Diazo Compounds
Pei Liu and Jiangtao Sun*
Jiangsu Key Laboratory of Advanced Catalytic Materials & Technology, School of Petrochemical Engineering, Changzhou University,
Changzhou 213164, P. R. China
S
* Supporting Information
ABSTRACT: A stereoselective, gold-catalyzed, cross-coupling
reaction of enynones with diazo compounds has been
developed, affording 2-alkenylfurans in moderate to good
yields with excellent E-stereoselectivity. Upon using diazo
compounds as nucleophiles to trap the in situ formed gold
furyl carbene, this protocol provides a novel path toward the
formation of unsymmetrical tetrasubstituted alkenes.
decades, the cross-coupling reactions between acceptor-H/
acceptor-H, acceptor-H/donor-H, acceptor-H/acceptor−
donor, and acceptor−donor/acceptor−donor diazo compounds
have been well investigated, providing an interesting way to
access di-, tri-, and tetrasubstituted alkenes.1,2 However, some
unavoidable limitations still exist with respect to reaction
stereoselectivity as well as scope of diazo compounds (Scheme
1a). Nevertheless, the competition between cross-coupling
versus homocoupling processes often leads to low efficiency. A
breakthrough was made by Davies and co-workers,3 who
reported an elegant rhodium-catalyzed cross-coupling reaction
of diazo compounds to prepare trisubstituted alkenes. Later, our
group successfully developed a gold-catalyzed protocol to
synthesize unsymmetrical tetrasubstituted alkenes.4a Alterna-
tively, using diazo compounds as the key partners, chemists
developed useful methodologies to prepare functionalized
alkenes by coupling with other readily available substrates.5
Despite these advances, the chemoselective and stereoselective
synthesis of tetrasubstituted alkenes still remains under-
developed.
ransition-metal-catalyzed cross-coupling reaction of two
Tdiazo moieties represents an important protocol in
constructing carbon−carbon double bonds.1,2 Typically, this
reaction involves the initial generation of electrophilic metal−
carbene species followed by nucleophilic attack by another diazo
reagent to give the bond formation (Scheme 1a). In the past
Scheme 1. Olefin Formation Involving Metal−Carbene
Species: Previous Reports and Our Strategy
́
Recently, Lopez and Vicente reported ZnCl2-catalyzed cross-
coupling reactions of enynones with diazoacetates/vinyl
diazoacetates to generate 2-alkenylfurans containing trisubsti-
tuted olefin moieties in moderate to good stereoselectivities
(Scheme 1b).6 However, they mentioned that this approach was
not applicable for phenyl diazoacetates.6a Namely, the synthesis
of tetrasubstituted alkenes cannot be accomplished via their
protocol. In connection with our research interest in olefin
formation through metal-catalyzed diazo cross-coupling reac-
tions,4 we conceived that gold-catalyzed cross-coupling of
enynones with donor/acceptor diazo compounds would
probably result in the formation of tetrasubstituted alkenes
(Scheme 1c). If possible, this reaction would significantly expand
the scope of such carbene involved olefin formation.
Received: May 15, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01467
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Organic Letters
Letter
a
Table 1. Optimization of the Reaction Conditions
b
entry
cat.
additive (mol %)
solvent
yield (%) 3aa/1a′/2a′
1
Ph3PAuCl
AgSbF6(5)
AgSbF6(5)
AgSbF6(5)
AgSbF6(5)
AgSbF6(10)
AgSbF6(5)
AgSbF6(5)
AgOTf(10)
AgNTf2(10)
AgBF4(10)
NaBArF(10)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DCE
10/−/−
34/8/0
2
JohnPhosAuCl
3
XPhosAuCl
tBuXPhosAuCl
38/15/<5
30/11/<5
68/6/<5
7/−/−
51/21/6
56/12/<5
68/13/<5
75/6/<5
66/7/<5
5/−/−
4
5
XantPhos(AuCl)2
(2,4-tBu2C6H3O)3PAuCl
IPrAuCl
6
7
8
XantPhos(AuCl)2
Xantphos(AuCl)2
XantPhos(AuCl)2
XantPhos(AuCl)2
XantPhos(AuCl)2
9
10
11
12
13
14
15
16
17
18
19
20
21
22
AgBF4(10)
AgBF4(10)
AgBF4(10)
AgBF4(10)
AgBF4(10)
XantPhos(AuCl)2
XantPhos(AuCl)2
XantPhos(AuCl)2
XantPhos(AuCl)2
CuBr
70/14/10
61/12/6
THF
toluene
dioxane
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
68/13/11
55/12/13
33/16/<5
25/18/0
CuCl
Rh2(OAc)4
Rh2(Oct)4
Rh2(esp)2
a
The reactions were carried out with 1a (0.2 mmol), 2a (0.22 mmol), catalyst (5 mol %), and additive (5 or 10 mol %) in solvent (5 mL) at rt for 1
b
h. Isolated yields.
Recently, metal−carbenes generated in situ from enynones
have been widely employed in various transformations.7 Inspired
by the former reports, at the outset, we utilized enynone 1a and
phenyl diazoacetate 2a as model substrates to investigate the
optimal reaction conditions (Table 1). The reactions were
initially performed in dichloromethane at room temperature.
First, utilization of Ph3PAuCl/AgSbF6 (5 mol %) furnished
cross-coupling product 3aa in 10% yield (entry 1). Replacing
did not improve the reaction (entries 8 and 9). To our delight,
the addition of AgBF4 furnished 3aa in 75% yield with E-
configuration associated with trace amount of homocoupling
products 1a′ and 2a′ (entry 10). The combination of
XantPhos(AuCl)2 with NaBArF gave 3aa in 66% yield (entry
11). Both gold complex and silver salt played crucial role in the
reaction (entries 12 and 13). Moreover, other solvents such as
1,2-dichloroethane (DCE), tetrahydrofuran (THF), toluene and
dioxane are not suitable to the reaction (entries 14−17).
Furthermore, the use of copper catalysts led to very low yield
(entries 18 and 19), whereas rhodium catalysts were totally inert
in this reaction (entries 20−22).
With the optimal conditions in hand, we next explored the
scope of diazo compounds (Scheme 2). First, the reaction of
enynone 1a with an array of aryl diazoacetates was examined.
Both electron-rich and electron-deficient aryl diazo compounds
were tolerated, providing the corresponding products in
moderate to good yields, although o-methyl phenyl diazoacetate
t
gold catalyst with JohnPhosAuCl, XPhosAuCl, and BuXPho-
sAuCl slightly improved the reaction (entries 2−4). The
homocoupling product 1a′ was isolated in nearly 10% yield.
Gratifyingly, when XantPhos(AuCl)2 was used, 68% yield of 3aa
was isolated associated with 6% yield of 1a′ (entry 5). However,
more electron-deficient phosphinate gold catalyst was inert to
this reaction (entry 6). Next, the use of IPrAuCl/AgSbF6
delivered 3aa in 51% yield together with 21% yield of 1a′
(entry 7). By using XantPhos(AuCl)2 as the gold catalyst, the
silver salts were then screened. The use of AgOTf and AgNTf2
B
DOI: 10.1021/acs.orglett.7b01467
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Organic Letters
Letter
a−
c
a−c
Scheme 2. Substrate Scope for Diazo Compounds
Scheme 3. Substrate Scope for Enynones
a
All reactions were performed with 1a (0.2 mmol), 2 (0.22 mmol),
XantPhos(AuCl)2 (5 mol %), and AgBF4 (10 mol %) in CH2Cl2 (5
b
c
mL) at rt for 1 h. Isolated yields. The products were isolated in
single isomer.
reaction of enynones 1e and 1f with 2a also proceeded smoothly
to produce the final products in moderate yields.
Our previous work disclosed that the metal-catalyzed coupling
of donor/donor diazo compounds did not yield alkenes but
symmetrical azines.9 When donor/donor diazo compounds 4a
and 4b were subjected to this gold-catalyzed protocol, the
expected 2-alkenylfurans were not obtained. Instead, unsym-
metrical azines 5aa and 5ab were isolated in moderate yields
(Scheme 4), which provided an interesting approach toward
unsymmetrical azines.
a
All reactions were performed with 1a (0.2 mmol), 2 (0.22 mmol),
XantPhos(AuCl)2 (5 mol %), and AgBF4 (10 mol %) in CH2Cl2 (5
mL) at rt for 1 h. Isolated yields. The products were isolated in
single isomer.
Scheme 4. Reaction of Enynone with Donor/Donor Diazo
Compounds
b
c
gave 3ac only in 31% yield. The use of thiophene diazoacetate
produced 3ah in 63% yield. Gratifyingly, alkyl diazoacetates were
also suitable substrates, and the desired 2-alkenylfurans were
obtained in 64% yield (3ai) and 51% yield (3aj), respectively. In
contrast, alkyl diazoacetates are not appropriate in metal-
catalyzed diazo cross-coupling reactions.1−4 Furthermore,
benzoyl diazo compound was also applicable in this reaction,
and the desired product 3ak was isolated in 48% yield. Notably,
the reaction of 1a with phenyl vinyl diazoacetate delivered diene
3al in 64% yield. The double bonds formed in the α-position
rather than γ-position to the carboxylic ester, which was quite
different with the zinc-catalyzed reaction of vinyl diazoacetate
with enynones.6a It also should be noted that the reaction is
stereoselective. All of the alkene moieties were obtained in
excellent E-configuration. The structures of 3ae, 3ak, and 3al
were confirmed by X-ray analysis.8
Different reaction mechanisms for the formation of 2-
alkenylfurans and azines have been proposed (Scheme 5). The
reaction of enynone 1a with gold catalyst generates gold−
carbene species I,7c,h which undergoes carbon nucleophilic attack
by 2a to give gold intermediate II with a newly formed C−C
bond. Subsequent extrusion of N2 and deauration provides the
final product 3aa with tetrasubstituted olefins. In contrast, the
nitrogen nucleophilic attack of 4a to gold−carbene delivers gold
intermediate III with C−N bond formation, which followed by
deauration to give rise to azine 5aa. Moreover, for the high
stereoselectivity of olefins, a possible explanation is transition
state-I (TS-I) might be the most stable one than TS-II and TS-
III, which led to the preferential formation of E-configuration.
Next, the reaction of various enynones with phenyl
diazoacetate 2a was carried out (Scheme 3). The use of
enynones substituted with alkyl groups (1b and 1c) furnished 2-
alkenylfurans 3ba and 3ca in 69% and 70% yield, respectively.
Enynone 1d bearing terminal alkyne was tolerated and the
corresponding product 3da was isolated in 52% yield. The
C
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Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
C.; Prieto, F.; Perez, P. J. Organometallics 1999, 18, 2601. (g) Barluenga,
Scheme 5. Proposed Reaction Mechanisms
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In summary, we have developed a novel gold-catalyzed cross-
coupling reaction of enynones and diazo compounds. The
corresponding 2-alkenylfurans bearing tetrasubstituted alkenes
were obtained in moderate to good yields with excellent
stereoselectivity. Typically, these unsymmetrical tetrasubstituted
alkenes cannot be easily accomplished by other approaches.
ASSOCIATED CONTENT
* Supporting Information
■
(6) (a) Gonzal
8536. (b) Mata, S.; Gonzal
R. Chem. - Eur. J. 2017, 23, 1013.
́
ez, J.; Lop
́
ez, L. A.; Vicente, R. Chem. Commun. 2014, 50,
S
́
ez, M. J.; Gonzalez, J.; Lopez, L. A.; Vicente,
́
́
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b01467.
(7) Selected examples of metal furyl carbenes, see: (a) Miki, K.;
Nishino, F.; Ohe, K.; Uemura, S. J. Am. Chem. Soc. 2002, 124, 5260.
Experimental procedures, characterization data, and NMR
spectra (PDF)
́ ́
(b) Barluenga, J.; Riesgo, L.; Vicente, R.; Lopez, L. A.; Tomas, M. J. Am.
Chem. Soc. 2008, 130, 13528. (c) Wang, T.; Zhang, J. Dalton. Trans.
2010, 39, 4270. (d) Xia, Y.; Qu, S.; Xiao, Q.; Wang, Z.-X.; Qu, P.; Chen,
L.; Liu, Z.; Tian, L.; Huang, Z.; Zhang, Y.; Wang, J. J. Am. Chem. Soc.
AUTHOR INFORMATION
Corresponding Author
■
2013, 135, 13502. (e) Vicente, R.; Gonzal
Lopez, L. A. Angew. Chem., Int. Ed. 2012, 51, 8063. (f) Gonzal
Gonzalez, J.; Perez-Calleja, C.; Lop
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Lett. 2014, 16, 5780. (h) Ma, J.; Jiang, H.; Zhu, S. Org. Lett. 2014, 16,
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ez, J.; Riesgo, L.; Gonzal
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ez, J.;
́
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ez, J.;
*E-mail: jtsun08@gmail.com, jtsun@cczu.edu.cn.
ORCID
́
́
́
ez, L. A.; Vicente, R. Angew. Chem.,
ez, L. A.; Vicente, R. Org.
́
́
Jiangtao Sun: 0000-0003-2516-3466
Notes
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8998. (j) Hu, F.; Xia, Y.; Ma, C.; Zhang, Y.; Wang, J. Org. Lett. 2014, 16,
4082. (k) Xia, Y.; Ge, R.; Chen, L.; Liu, Z.; Xiao, Q.; Zhang, Y.; Wang, J.
J. Org. Chem. 2015, 80, 7856. (l) Yu, Y.; Yi, S.; Zhu, C.; Hu, W.; Gao, B.;
Chen, Y.; Wu, W.; Jiang, H. Org. Lett. 2016, 18, 400. (m) Luo, H.; Chen,
K.; Jiang, H.; Zhu, S. Org. Lett. 2016, 18, 5208. (n) Yang, J.-M.; Li, Z.-Q.;
Li, M.-L.; He, Q.; Zhu, S.-F.; Zhou, Q.-L. J. Am. Chem. Soc. 2017, 139,
3784. (o) Xia, Y.; Chen, L.; Qu, P.; Ji, G.; Feng, S.; Xiao, Q.; Zhang, Y.;
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(8) CCDC 1549809 (3ae), 1549810 (3ak), 1549811 (3al), and
1549812 (5aa).
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(No. 21572024), Natural Science Foundation of Jiangsu
Province (BK20151184), and Jiangsu Key Laboratory of
Advanced Catalytic Materials & Technology (BM2012110) for
financial support.
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