Silver-Catalyzed Cross-Olefination of Donor and Acceptor Diazo Compounds: Use of N-Nosylhydrazones as Diazo Surrogate

Article abstract of DOI:10.1002/ejoc.201601610

The cross-olefination reaction of donor and acceptor diazo compounds was explored. The use of N-nosylhydrazones as diazo surrogates and the dependence on silver catalysis were crucial for the reaction development. A variety of (hetero)aryl N-nosylhydrazones and α-diazo esters, amides, and phosphonates were compatible, and the functionalized alkene products were afforded in good to high yields with moderate (Z)/(E) selectivities. The experimental and DFT calculation results suggest that the cross-selectivity is due to selective activation of the silver catalyst for donor diazo compounds.

Full text of DOI:10.1002/ejoc.201601610

A Journal of
Accepted Article
Title: Silver-Catalyzed Cross-Olefination of Donor and Acceptor Diazo
Compounds: Use of N-Nosylhydrazones as Diazo Surrogate
Authors: Xihe Bi, Zhaohong Liu, Binbin Liu, Xue-Feng Zhao, and Yan-
Bo Wu
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201601610
Link to VoR: http://dx.doi.org/10.1002/ejoc.201601610
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European Journal of Organic Chemistry
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Silver-Catalyzed Cross-Olefination of Donor and Acceptor Diazo
Compounds: Use of N-Nosylhydrazones as Diazo Surrogate
Zhaohong Liu,[a] Binbin Liu,[a] Xue-Feng Zhao,[c] Yan-Bo Wu,*[c] Xihe Bi*[a][b]
Dedication ((optional))
Abstract: The cross-olefination reaction of donor and acceptor diazo
compounds is reported. The use of N-nosylhydrazones as the diazo
surrogates and the dependence on silver catalysis are crucial for the
reaction development. A variety of (hetero)aryl N-nosylhydrazones
and α-diazo esters, amides, and phosphonates were compatible,
affording functionalized alkenes in good-to-high yields with moderate
Z/E selectivity. Experimental and DFT calculation results suggest the
cross-selectivity is due to the selective activation of silver catalyst for
donor diazo compounds.
the diazo olefination reaction more synthetically useful, but the
coupling components remain restricted to acceptor diazo
compounds.[6-10] To our knowledge, the highly reactive donor
diazo compounds have not been exploited in the diazo cross-
olefination reaction.[11] Here, we wish to report the first cross-
coupling between donor and acceptor diazo compounds, by
combining the use of N-nosylhydrazones as diazo surrogates
and the silver catalysis (Figure 1b). This provides a convenient
approach to β-aryl α,β-unsaturated carbonyl that is a key unit in
many pharmaceutically relevant compounds such as Lacidipine,
Tranilast, Rescinnamine, and Fexaramine.[12]
.
Introduction
The convergent formation of alkenes occupies a central position
in organic synthesis. Wittig-type reaction and olefin metathesis
play a dominant role in this field.[1,2] As an alternative approach,
a carbenoid-induced coupling of two diazo compounds has been
emerging as
a synthetically valuable olefination reaction.
However, the coupling of two fragments always derives from the
same diazo reagent[3] or proceeds by an intramolecular
process.[4] The intermolecular diazo cross-coupling remains less
developed, mainly owing to the competitive diazo homo-coupling
process.[5] Pioneering efforts have been devoted to exploring
such an olefin synthesis in an intermolecular way (Figure 1a).
The groups of Del Zotto[6] and Hodgson[7] successively studied
the cross-coupling of two different acceptor diazo compounds by
ruthenium catalysis, leading to unsymmetrical olefines in more
than statistical yields. But it was not until in 2011 that Davies and
co-workers described an efficient cross-coupling of two distinct
donor/acceptor and acceptor diazo compounds with a rhodium-
based catalytic system.[8] Pérez and coworkers subsequently
revisited this reaction using their silver-complex catalyst.[9] More
recently, the Sun group successfully expanded the repertoire of
diazo cross-olefination to two donor/acceptor diazo components
by gold or copper catalysis, thus allowing for the synthesis of
tetrasubstituted alkenes.[10] These contributions have promoted
Figure 1. Cross-Olefination of Diazo Compounds.
[a]
Z. Liu, B. Liu and Prof. X. Bi
Jilin Province Key Laboratory of Organic Functional Molecular
Design & Synthesis, Department of Chemistry
Northeast Normal University, Changchun 130024, China
E-mail: bixh507@nenu.edu.cn
Results and Discussion
Homepage: http://www.bigroup.com.cn/
To develop donor-acceptor diazo cross-olefination, two key
problems must be solved: (1) the easy homo-coupling of donor
diazo compounds; (2) requiring a metal catalyst preferably
promoting the cross-coupling. N-sulfonylhydrazones as donor
diazo precursor have been widely exploited in organic
synthesis.[13] We recently discovered the low-temperature
decomposable property of N-nosylhydrazones, and thus
overcame the inherent drawback of N-tosylhydrazones that
require high dissociation temperature (> 70 °C).[14] The slow
release of donor diazo species from N-nosylhydrazones and the
[b]
[c]
Prof. X. Bi
State Key Laboratory of Elemento-Organic Chemistry
Nankai University, Tianjin 300071, China
X.-F. Zhao and Prof. Y.-B. Wu
Key Laboratory of Materials for Energy Conversion and Storage of
Shanxi Province
Institute of Molecular Science
Shanxi University, Taiyuan 030006, China
E-mail: wyb@sxu.edu.cn
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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low reaction temperature could reduce the diazo homo-coupling
event to the maximum extent. Consequently, N-nosylhydrazones
could be the ideal diazo surrogate in the study of donor diazo
cross-coupling. After gold rush and traditional copper catalysis,
silver catalysis has been emerging as an active area in organic
synthesis.[15] The application of silver salt as the catalyst for
decomposition of diazo compounds is traditionally associated
with Wolff rearrangement.[16] In recent years, silver-catalyzed
reactions of diazo compounds have moved beyond this classical
chemistry. A number of groups such as Dias and Lovely,[17]
Pérez,[9,18] Davies,[19] and Wang[20] have made leading
contributions in this field. Importantly, silver catalysts commonly
displayed unique and excellent catalytic selectivity in these
reactions. As our continued interest in silver chemistry,[21] we
carried out the studies on the reactivity of silver carbenoids
derived from N-nosylhydrazones, and discovered the silver-
catalyzed cyclopropenation of alkynes.[14] In this paper, we will
describe the silver-catalyzed donor-acceptor diazo cross-
olefination.
ruthenium catalysts all dominantly produced dimer 3a, along
with small amount of cross-coupling product 3a. Note that high
yields of diethyl fumarate generated from the homo-coupling of
2a were obtained under gold-, copper, ruthenium-, and rhodium-
catalyzed conditions, in line with previous reports (see Table
S1).[5-7] In contrast to copper and gold that were nearly inactive,
silver salts preferably promoted the cross-coupling reaction.
Most of silver salts were capable of selectively affording very
high ratio of the desired product 3a. The counter anions were
found to play a critical role. Among the examined silver salts,
AgOTf and AgOTFA gave the best results with 74% and 78%
yields of 3a, respectively, without homo-coupling product 3a.
Intriguingly, no diethyl fumarate form the homo-coupling of 2a
was detected under silver catalysis. Eventually, dilution of the
reaction to 0.05 M led to an optimal condition, resulting in 3a in
90% NMR yield and 86% isolated yield with a moderate Z/E ratio
of 56:44. It is worth mentioning that the handling N-
nosylhydrazones is easy and safe.
With the optimal conditions in hand, we set out to explore the
reaction scope with respect to N-nosylhydrazones (Scheme 1).
The reaction scope was broad, as a variety of aryl- and
heteroaryl-substituted substrates could be applied to the silver-
catalyzed cross-coupling reaction with ethyl diazoacetate 2a,
affording diverse β-(hetero)aryl acrylates (3a-3o) in moderate to
high yields. The steric and electronic effect of substituents on
the aromatic ring showed a little influence on the reaction
outcome. For instance, the strong electron-withdrawing nitro
group was tolerable leading to 50% yield of product yield 3k. In
addition, fused aryl and heteroaryl groups, such as naphthyl,
furyl, thienyl, and indolyl, proved to be compatible, affording the
corresponding products 3l-3o in 50-60% yields.
Figure 2. Optimization of the Reaction Conditions. Reaction conditions: 1a
(0.3 mmol), NaH (0.45 mmol, 2a (0.45 mmol) and catalyst in DCM (3 mL, 0.1
M) at 40 °C under argon atmosphere for 20 h. Catalyst: IPrAuNTf (5 mol%),
NaBArF (5 mol%); CuBr2 (10 mol%), Phen (10 mol%); GRUBBS II (1 mol%);
Rh2(OOct)4 (5 mol%); Silver salts (20 mol%). NMR yields were determined by
1H NMR analysis using CH2Br2 as an internal standard. [a] DCM (6 mL, 0.05
M) was used and isolated yield was 86%.
Scheme 1. Substrate Scope of N-Nosylhydrazones. Z/E ratios were in a
range of 1:1 ~ 3:2 which were determined by 1H-NMR analysis.
The substrate scope of acceptor diazo compounds was also
examined in the reaction with 4-chlorophenyl N-nosylhydrazone
1a as the coupling partner (Scheme 2). Wide variation of the O-
substituents of α-diazoesters demonstrated the excellent
functional group tolerance. For example, in addition to alkyl, aryl,
and heteroaryl groups (4a-4f, 50-90%), unsaturated functional
We commenced the study with the reaction of 4-chlorophenyl
N-nosylhydrazone 1a and ethyl diazoacetate 2a as the model.
Some data regarding the catalytic effect of transition metals
were shown in Figure 2. Except for the rhodium catalyst that
resulted in equal amount of cross-coupling product 3a (32%)
and homo-coupling product 3a (30%), gold, copper, and
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groups including terminal and internal alkenes (4g, 4h) as well
as internal alkyne (4i) were tolerable, without formation of
cyclopropane or cyclopropene products. Other functional groups
such as ether, TMS, Br, ester, and amide groups were also
compatible under silver-catalyzed conditions, affording the
corresponding functionalized acrylates 4j-4n in 54-74% yields. In
addition to diazoacetates, other kinds of α-diazo carbonyl
compounds such as α-diazo amide, ketone, and phosphonate
were examined. Similarly, these diazo compounds all efficiently
reacted with 1a to produce alkenes 4o-4q in 45-84% yields.
Encouraged by these results, we turned our attention to the
donor/acceptor diazo compounds that were successful in the
reports by Davies[8] and Sun.[10] To our delight, α-aryl
diazoacetates efficiently reacted with 1a to give trisubstituted α-
aryl acrylates 4r-4t in moderate yields. Notably, although the Z/E
selectivity was in a range of 1:1~3:2, the Z- and E-isomers could
be separated simply by column chromatography, thus providing
a preparative entry to Z-olefins, which are difficult to access by
Heck reaction.
Next, more complex substrates were investigated. Delightfully,
several acceptor diazo-derived complex natural products
succeeded in the cross-coupling with N-nosylhydrazone 1a
using our method. For instance, the transformation of steroid
derivatives such as Cholesterol-, Pregnenolone-, and Estrone-
derived acceptor diazo compounds afforded the cross-coupling
products 5a-5c in 62-72% yields. A derivative of the natural
perfume Eugenol provided the corresponding product 5d in 54%
yield. Note that the alkene functionality was intact under the
silver-catalyzed conditions.
Scheme 3. Late-Stage Diversification of Natural Products.
Treatment of ethyl diazoacetate 2a with silver catalyst alone,
in the absence of N-nosylhydrazones, led to 53% yield of C–Cl
insertion product 6,[17,19c] along with 32% recovery of 2a (Eq. 1).
Note that no homo-coupling product diethyl fumarate was
formed. This result clearly demonstrates the activation ability of
Ag toward acceptor diazo compounds is weaker than Cu, Ru,
and Rh.
To better understand the excellent chemoselectivity between
donor and acceptor diazo compounds, the density functional
theory (DFT) calculations were performed at m06/6-31G(d)[sdd
for Ag] level[22] on the model reaction of phenyl diazomethane (A)
and ethyl diazoacetate (B) using AgOTf as the catalyst. In line
with the general theory, the DFT results suggest that the cross-
olefination reaction may have two elementary steps. In the first
step, AgOTf catalyst could lead to the decomposition of diazo
compounds and form the corresponding silver carbenoids. As
shown in Figure 3, the formation of silver carbenoid A-AgOTf is
an exothermic process, with energy barrier of 9.9 kcal/mol and
reaction energy of –15.1 kcal/mol. In contrast, the generation of
carbenoid B-AgOTf has much higher energy barrier (17.1), and
is endothermic (6.7 kcal/mol). Furthermore, structural checking
revealed a hydrogen bond between phenyl ring and OTf in both
silver carbenoid A-AgOTf and corresponding transition state TSA.
Scheme 2. Scope of Acceptor Diazo Compounds. Z/E ratios were in a
range of 1:1 ~ 3:2 which were determined by 1H-NMR analysis.
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The formation of such a hydrogen bond could lower the energies
and promote the generation of A-AgOTf. In the second step, the
silver carbenoid A-AgOTf will couple with another diazo
component to form the olefins. As drawn in Figure 3 and Figure
S1, the energy barriers for the cross-coupling between A-AgOTf
and phenyl diazomethane A or ethyl diazoacetate B to form
Another question is regarding the Z-/E-selectivity of olefin. As
shown in the latter part of Figure 3, the energies released by the
coupling to form E-A-B and Z-A-B are –82.2 and –76.2 kcal/mol,
respectively, suggesting the irreversible conversion in both
pathways. Thus, the Z/E selectivity should be determined by the
energy barriers rather than the reaction energies. According to
olefins Z-/E-A-A or Z-/E-A-B are 9.3/10.7 and 11.0/10.7 kcal/mol, our calculations, the energy barriers are 11.0 kcal/mol (Z-TSA-B
)
respectively. The formation of self-coupling product A-A seems
to be favoured, but the A-A coupling event can be excluded,
because of the extremely low concentration of phenyl
diazomethane A in the reaction solution. Consequently, the in-
situ generated silver carbenoid A-AgOTf is able to react with
ethyl diazoacetate B to produce the corresponding cross-
coupling product A-B.
and 10.7 kcal/mol (E-TSA-B), respectively. The energy barrier
difference (ΔΔG) of 0.3 kcal/mol is negligible, which could not
result in significant Z/E selectivity. The small energy difference
of the transition states probably accounts for the lack of
stereoselectivity. Such a prediction is consistent with our
experimental observation of 1:1~3:2 Z/E ratios.
Figure 3. The Energy Profile for the Donor-Acceptor Cross Olefination Reaction.
This work was supported by the NSFC (21522202, 21502017,
21372038, 21273140), the Ministry of Education of the People’s
Republic of China (NCET-13-0714), the Jilin Provincial
Research Foundation for Basic Research (20140519008JH),
Fundamental Research Funds for Central Universities
(2412015BJ005, 2412015KJ013, 2412016KJ040), the Special
Program for Applied Research on Super Computation of the
NSFC-Guangdong Joint Fund (the second phase), the Program
for the Outstanding Innovative Teams of Higher Learning
Institutions of Shanxi, and the HPC Center of Shanxi University.
Conclusions
In summary, the cross-olefination reaction between donor and
acceptor diazo compounds has been developed using N-
nosylhydrazones as the diazo surrogate under silver-catalyzed
conditions. This method enables the cross-coupling of a variety
of diazo substrates, affording a variety of functionalized alkenes
in good-to-high yields. This work has for the first time expanded
the repertoire of diazo cross-coupling to highly reactive donor
diazo compounds, and thus opened a new avenue to explore
the diazo cross-olefination methodology.
Keywords: N-nosylhydrazone • diazo compound • silver-
catalyzed • cross-coupling • alkene
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COMMUNICATION
The cross-olefination of donor and
acceptor diazo compounds was
developed by using N-
Key Topic*
Author(s), Corresponding Author(s)*
nosylhydrazones as diazo surrogate
under silver catalysis. This work for
the first time expands the repertoire of
diazo cross-olefination to highly
reactive donor diazo compounds.
Page No. – Page No.
Title
*Diazo Coupling
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