Silver-Catalyzed Cyclopropanation of Alkenes Using N-Nosylhydrazones as Diazo Surrogates

Article abstract of DOI:10.1021/acs.orglett.7b03374

An efficient silver-catalyzed [2 + 1] cyclopropanation of sterically hindered internal alkenes with diazo compounds in which room-temperature-decomposable N-nosylhydrazones are used as diazo surrogates is reported. The unexpected unique catalytic activity of silver was ascribed to its dual role as a Lewis acid activating alkene substrates and as a transition metal forming silver carbenoids. A wide range of internal alkenes, including challenging diarylethenes, were suitable for this protocol, thereby affording a variety of cyclopropanes with high efficiency in a stereoselective manner under mild conditions.

Full text of DOI:10.1021/acs.orglett.7b03374

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Silver-Catalyzed Cyclopropanation of Alkenes Using
N‑Nosylhydrazones as Diazo Surrogates
Zhaohong Liu,† Xinyu Zhang,† Giuseppe Zanoni,§ and Xihe Bi*,†,‡
†Jilin Province Key Laboratory of Organic Functional Molecular Design & Synthesis, Department of Chemistry, Northeast Normal
University, Changchun 130024, China
‡State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China
§Department of Chemistry, University of Pavia, Viale Taramelli 12, 27100 Pavia, Italy
S
* Supporting Information
ABSTRACT: An efficient silver-catalyzed [2 + 1] cyclopropanation of
sterically hindered internal alkenes with diazo compounds in which room-
temperature-decomposable N-nosylhydrazones are used as diazo surro-
gates is reported. The unexpected unique catalytic activity of silver was
ascribed to its dual role as a Lewis acid activating alkene substrates and as a
transition metal forming silver carbenoids. A wide range of internal
alkenes, including challenging diarylethenes, were suitable for this
protocol, thereby affording a variety of cyclopropanes with high efficiency in a stereoselective manner under mild conditions.
intrinsic explosive property of diazo compounds prevent their
use for large-scale manufacturing. Recent advances in the
activation of aryldiazoacetates by silver catalysis resulted in
preparatively useful yields while requiring a large stoichiometric
excess for internal olefins as substrates (5−10 equiv).7d Other
non-diazo starting materials, such as benzylidene iron carbene
complex (path b)8 and toxic α-[(alkoxycarbonyl)oxy]stannanes
(path c),9 were also explored for the cyclopropanation reaction,
but they required stoichiometric amounts of preformed metal
carbenes. Echavarren and co-workers employed cyclohepta-
trienes as a safe alternative to diazo compounds to generate
gold(I) carbenoids via a retro-Buchner reaction under catalytic
conditions, affording a range of 1,2,3-trisubstituted cyclo-
propanes in moderate to excellent yields (path d).10 In
addition, zinc vinyl carbenoids generated from cyclopropenes
with diarylethenes afforded vinylcyclopropanes in medium
yields (path e).11 Nevertheless, the development of novel and
efficient methods enabling the cyclopropanation of sterically
hindered internal alkenes is constantly in demand. As part of
our continued interest in the low-temperature decomposition
of N-nosylhydrazones and their synthetic applications with
silver catalysis,12 we herein report an efficient silver-catalyzed
cyclopropanation of 1,2-diarylalkenes with N-nosylhydrazones
(path f). As further disclosed herein, this protocol could be
extended to other internal and terminal alkenes.
he cyclopropane moiety, itself a synthon in organic
1
Tsynthesis, can be found in bioactive natural products and
pharmaceuticals.2 Consequently, the construction of the
cyclopropane ring, especially with easily available starting
materials, has attracted considerable attention.3 In this context,
the [2 + 1] cyclopropanation of alkenes plays a dominating
role.3,4 However, this method remains problematic because
most alkene substrates are restricted to terminal, activated, or
aliphatic internal olefins.5 The application to unactivated 1,2-
disubstituted alkenes, especially the more sterically hindered
diarylethenes, is still a challenging task.6
To date, very few synthetically useful methods for the
cyclopropanation of diarylalkenes have been described (Figure
1). For instance, metal carbenoids generated by the
decomposition of diazo compounds such as diazo esters can
be cyclized with diarylalkenes to form cyclopropanes;
unfortunately, disappointing yields (below 50%) are often
observed (path a).7 Moreover, the inherent toxicity and
Initially, optimization of the reaction conditions was
performed using the reaction of benzaldehyde N-nosylhydra-
zone (1a) with (E)-1,2-diphenylethene (2a) as a model
reaction. Selected results on the effect of transition metal
salts as catalysts are summarized in Scheme 1. Unexpectedly,
commonly used carbene transfer catalysts, such as rhodium,
Figure 1. Strategies for the [2 + 1] cyclopropanation of 1,2-
diarylalkenes.
Received: October 30, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03374
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a b
,
Scheme 1. Screening of Transition Metal Catalysts
Scheme 2. Scope of N-Nosylhydrazones and 1,2-
Diarylalkenes
a
a
Reaction conditions: 1a (0.3 mmol), NaH (0.45 mmol), and DCM
(6 mL) were stirred at rt for 1 h, and then the catalyst and 2a (0.45
mmol) were added, after which the mixture was stirred at 40 °C for 18
b
h. Yields were calculated from 1H NMR spectroscopy with CH2Br2 as
c
the internal standard. Isolated yield in parentheses.
palladium, copper, gold, zinc, and iron salts, did not promote
the desired cyclopropanation reaction.13 In contrast, all of the
tested silver salts proved to be suitable for the reaction,
affording 1,2,3-triphenylcyclopropane (3a) in good to excellent
yields (as estimated by 1H NMR analysis of the crude
mixtures). Notably, the cyclopropanation of alkenes with aryl
diazomethanes has been achieved both by photolysis14a and
with transition metal catalysts, such as dirhodium,14b copper,14c
ruthenium,14d osmium,14e zinc,14f,g and iron salts,14h but none
of them proved to be suitable for 1,2-diarylalkenes. Given these
observations, the success of the [2 + 1] cycloaddition of
sterically hindered 1,2-diarylalkenes with N-nosylhydrazones
was far from certain. Although the exact reason for the unique
catalytic activity of silver for aryl diazomethanes remains
unclear, this may be due to the dual role of the silver salt as a
Lewis acid to activate alkene substrates and as a transition metal
to form silver carbenoids with the in situ-released aryl
diazomethanes.15
With the optimal reaction conditions in hand, we set out to
explore the scope and generality of the reaction with various
substituted N-nosylhydrazones and 1,2-diarylalkenes. As
depicted in Scheme 2, the cyclopropanation of trans-stilbene
(2a) proceeded effectively with a wide range of N-
nosylhydrazones derived from aldehydes. Both electron-
donating (3b, 3c) and electron-withdrawing (3d, 3e)
substituents on the phenyl moiety were well-tolerated at either
the para (3c, 3d, 3e) or meta position (3b). N-Nosylhy-
drazones with an ortho-substituted aryl ring gave the related
products (3f, 3g) in slightly reduced yields, possibly because of
steric hindrance. Remarkably, phenyl-disubstituted N-nosylhy-
drazones also provided the desired cyclopropanated products
(3h, 3i) in good yields. Fused aromatic 2-naphthyl-N-
nosylhydrazone also served as a substrate for this cyclo-
propanation, providing the desired product 3j in 64% yield. A
range of medicinally relevant heterocycles, such as quinolone-,
indole-, thiophene-, and furan-based N-nosylhydrazones, also
reacted efficiently, providing the corresponding products (3k,
3l, 3m, and 3n) in 52−78% yield. In addition to N-
nosylhydrazones generated from (hetero)aryl aldehydes, those
derived from selected α,β-unsaturated aldehydes could actively
participate in the reaction with trans-stilbene, affording valuable
alkynyl and vinyl cyclopropanes in synthetically useful yields
(3o and 3p, 43% and 80%, respectively). However, the product
arising from an aliphatic N-nosylhydrazone (3q) could not be
isolated because of the competing Bamford−Stevens reaction
a
Reaction conditions: 1 (0.3 mmol), NaH (0.45 mmol), and DCM
(6.0 mL) were stirred at rt for 1 h, and then 2 (0.45 mmol) and
AgOTf (0.06 mmol) were added, after which the mixture was stirred at
b
40 °C for 18 h. Isolated yields are shown. Gram-scale synthesis.
that leads to a terminal olefin and olefinic dimers.3a,5b To
establish practical laboratory-scale utility, the reaction of N-
nosylhydrazone 1e and trans-stilbene was performed on a 5
mmol scale, providing the corresponding product 3e in only a
slightly decreased yield (1.4 g, 90%). Subsequently, the scope of
1,2-diarylalkenes for this cyclopropanation reaction was
investigated by treating differently substituted alkenes with 3-
methoxyphenyl-N-nosylhydrazone (1b). As summarized in
Scheme 2, trans-1,2-diaryl olefins bearing methyl, trifluoro-
methyl, and chloride substituents afforded the corresponding
products (3r−v) in good to excellent yields (66−93%). A
further increase in the steric hindrance of alkenes was also
possible; for instance, (E)-1-methyl-1,2-diphenylethene effi-
ciently reacted with 1b to give the desired product 3w in 76%
yield with a dr value of 1.5:1.
Unfortunately, N-nosylhydrazone 1r derived from acetophe-
none was unreactive with sterically hindered alkene 2b, but
terminal alkene 2h efficiently reacted with N-nosylhydrazone 1r
to give the product 3y in 75% yield with excellent
diastereoselectivity (trans:cis = 20:1).16
B
DOI: 10.1021/acs.orglett.7b03374
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Further assessment of the substrate scope for this protocol
was performed by treating N-nosylhydrazone 1b with various
substituted alkenes 4, including chalcones and mono-, di-, tri-,
and fully substituted olefins. As shown in Scheme 3, all of the
a
Scheme 3. Variation of Alkenes
Scheme 4. Intramolecular Cyclopropanation
affording the corresponding cyclopropanes 7a−d in good to
excellent yields (78−95%). The exclusively exo configuration
was confirmed by the X-ray crystal structure of 7c.
a
Reaction conditions: 1b (0.3 mmol), NaH (0.45 mmol), and DCM
(6.0 mL) were stirred at rt for 1 h, and then 4 (0.45 mmol) and
AgOTf (0.06 mmol) were added, after which the mixture was stirred at
40 °C for 18 h. The trans/cis diastereoisomeric ratios shown in
In summary, we have developed a highly effective and
practical one-pot method for the [2 + 1] cyclopropanation of
sterically hindered internal olefins, especially for the challenging
1,2-diarylethenes. A unique catalytic activity of selected silver
salts was observed for this transformation, which was ascribed
to their dual function as Lewis acids and transition metals. The
method described here features several advantages, such as easy
accessibility of the starting materials, simple operation, high
steroselectivity, broad substrate scope, high reaction efficiency,
and high product yields. Overall, this work represents an
extremely simple method for the [2 + 1] cyclopropanation of
alkenes, including both internal and terminal alkenes, in both
intramolecular and intermolecular reaction patterns.
1
parentheses were determined by H NMR spectroscopy.
screened alkenes proved reactive, delivering the target products
(5a−i) in satisfactory yields (40−98%). In the case of
trisubstituted and tetrasubstituted alkenes, the desired products
(5c and 5d) were formed in excellent yields. Notably, cyclic and
bicyclic olefins are also suitable substrates, affording the
corresponding bridged cyclic cyclopropanes (5e−g) in high
yields. In particular, extension of the method to an alkyl-
substituted terminal olefin gave the product in high yield with
moderate selectivity (5h). It is worth mentioning that both
cyclohexene (4f) and 1-octene (4h) were poor cyclopropana-
tion substrates with rhodium5b and iron catalysts.17 In contrast,
the cyclopropanation of osthole, a representative naturally
occurring internal alkene, with 1b chemoselectively led to
product 5i in 85% yield, wherein only the terminal moiety
underwent cyclopropanation.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b03374.
Experimental procedures and copies of spectra (PDF)
With regard to the effect of the alkene geometry on the
reaction outcome, we wondered how the structure of the
reactant alkene would control the stereochemistry in the
product of cyclopropanation. Under the optimized catalytic
conditions, (Z)-4-octene (4j) afforded the cis-cyclopropane
product in 86% yield as a 2.5:1 isomeric mixture (5j).
Conversely, with (E)-4-octene (4k), the exclusive formation
of corresponding trans-cyclopropane (5k) was observed in
excellent yield (89%). These experimental results showed that
silver-catalyzed cyclopropanation took place with complete
stereospecificity and suggested that the cycloaddition of silver
carbenes to alkenes may proceed in a concerted manner.18
Finally, we expanded our approach to intramolecular
cyclopropanation of N-nosylhydrazones with a tethered olefin
moiety at the ortho position (6a−d) in order to synthesize
highly strained bicyclic systems (Scheme 4).19 AgOTFA was
superior to AgOTf as a catalyst for this transformation,
Accession Codes
CCDC 1522924 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by e-mailing
data_request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, U.K.; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: bixh507@nenu.edu.cn. Home page: www.bigroup.-
top/.
ORCID
Zhaohong Liu: 0000-0001-9951-8675
Xihe Bi: 0000-0002-6694-6742
C
DOI: 10.1021/acs.orglett.7b03374
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Chem. Soc. Rev. 2015, 44, 8124. (d) Fang, G.; Cong, X.; Zanoni, G.;
Liu, Q.; Bi, X. Adv. Synth. Catal. 2017, 359, 1422.
(16) When N-tosylhydrazone was used as the diazo source, 3y was
Notes
The authors declare no competing financial interest.
obtained with poor diastereoselectivity (dr = 2:1). See: Barluenga, J.;
Quinones, N.; Tomas
2012, 2012, 2312.
(17) Doyle, M. P.; Griffin, J. H.; Bagheri, V.; Dorow, R. L.
Organometallics 1984, 3, 53.
́
-Gamasa, M.; Cabal, M.-P. Eur. J. Org. Chem.
̃
ACKNOWLEDGMENTS
■
This work was supported by the NNSFC (21522202,
21502017).
(18) (a) Wulfman, D. S.; McDaniel, R. S.; Peace, B. W. Tetrahedron
1976, 32, 1241. (b) Hansen, J.; Autschbach, J.; Davies, H. M. L. J. Org.
Chem. 2009, 74, 6555.
(19) (a) Taber, D. F.; Guo, P.; Guo, N. W. J. Am. Chem. Soc. 2010,
132, 11179. (b) Taber, D. F.; Guo, P. J. Org. Chem. 2008, 73, 9479.
REFERENCES
■
(1) For selected reviews, see: Rubin, M.; Rubina, M.; Gevorgyan, V.
Chem. Rev. 2007, 107, 3117. (b) Cavitt, M. A.; Phun, L. H.; France, S.
Chem. Soc. Rev. 2014, 43, 804. (c) Reissig, H.-U.; Zimmer, R. Chem.
Rev. 2003, 103, 1151.
(2) For selected reviews, see: Chen, D. Y.-K.; Pouwer, R. H.; Richard,
J.-A. Chem. Soc. Rev. 2012, 41, 4631. (b) Wessjohann, L. A.; Brandt,
W.; Thiemann, T. Chem. Rev. 2003, 103, 1625. (c) Faust, R. Angew.
Chem., Int. Ed. 2001, 40, 2251.
(3) (a) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic
Methods for Organic Synthesis with Diazo Compounds: From Cyclo-
propanes to Ylides; Wiley-Interscience: New York, 1998. (b) Lebel, H.;
Marcoux, J.-F.; Molinaro, C.; Charette, A. B. Chem. Rev. 2003, 103,
977.
(4) (a) Davies, H. M. L.; Antoulinakis, E. G. Org. React. 2001, 57, 1.
(b) Kamimura, A. [2 + 1]-Type Cyclopropanation Reactions. In
Methods and Applications of Cycloaddition Reactions in Organic
Syntheses; Nishiwaki, N., Ed.; John Wiley & Sons: Hoboken, NJ, 2014.
(5) For cyclopropanation of terminal, activated, or aliphatic internal
olefins with N-tosylhydrazones, see: Aggarwal, V. K.; Alonso, E.; Fang,
G.; Ferrara, M.; Hynd, G.; Porcelloni, M. Angew. Chem., Int. Ed. 2001,
40, 1433. (b) Aggarwal, V. K.; de Vicente, J.; Bonnert, R. V. Org. Lett.
2001, 3, 2785. (c) Zhang, J.; Chan, P. W. H.; Che, C. Tetrahedron Lett.
̂ ́
2003, 44, 8733. (d) Cyr, P.; Cote-Raiche, A.; Bronner, S. M. Org. Lett.
2016, 18, 6448. For recent examples of epoxidation using N-
tosylhydrazones, see: (e) Zhu, C.; Chen, P.; Wu, W.; Qi, Y.; Ren, Y.;
Jiang, H. Org. Lett. 2016, 18, 4008. (f) Zhu, C.; Zhu, R.; Chen, P.;
Chen, F.; Wu, W.; Jiang, H. Adv. Synth. Catal. 2017, 359, 3154.
(6) Li, J.; Liao, S.; Xiong, H.; Zhou, Y.; Sun, X.; Zhang, Y.; Zhou, X.;
Tang, Y. Angew. Chem., Int. Ed. 2012, 51, 8838.
(7) (a) Blatchford, J. K.; Orchin, M. J. Org. Chem. 1964, 29, 839.
(b) Jeganathan, A.; Richardson, S. K.; Mani, R. S.; Haley, B. E.; Watt,
́
D. S. J. Org. Chem. 1986, 51, 5362. (c) Perez, J.; Morales, D.; García-
Escudero, L. A.; Martínez-García, H.; Miguel, D.; Bernad, P. Dalton
Trans. 2009, 375. (d) Thompson, J. L.; Davies, H. M. L. J. Am. Chem.
Soc. 2007, 129, 6090.
(8) Brookhart, M.; Humphrey, M. B.; Kratzer, H. J.; Nelson, G. O. J.
Am. Chem. Soc. 1980, 102, 7802.
(9) Sugawara, M.; Yoshida, J.-I. J. Am. Chem. Soc. 1997, 119, 11986.
(10) Solorio-Alvarado, C. R.; Wang, Y.; Echavarren, A. M. J. Am.
Chem. Soc. 2011, 133, 11952.
(11) Gonzal
Chem., Int. Ed. 2015, 54, 12139.
́ ́ ́
ez, M. J.; Gonzalez, J.; Lopez, L. A.; Vicente, R. Angew.
(12) (a) Liu, Z.; Li, Q.; Liao, P.; Bi, X. Chem. - Eur. J. 2017, 23, 4756.
(b) Liu, Z.; Li, Q.; Yang, Y.; Bi, X. Chem. Commun. 2017, 53, 2503.
(c) Yang, Y.; Liu, Z.; Porta, A.; Zanoni, G.; Bi, X. Chem. - Eur. J. 2017,
23, 9009. (d) Liu, Z.; Liu, B.; Zhao, X.; Wu, Y.; Bi, X. Eur. J. Org. Chem.
2017, 2017, 928.
(13) For detailed experiments, see the Supporting Information.
(14) (a) Closs, G. L.; Moss, R. A. J. Am. Chem. Soc. 1964, 86, 4042.
(b) Verdecchia, M.; Tubaro, C.; Biffis, A. Tetrahedron Lett. 2011, 52,
1136. (c) Dai, X.; Warren, T. H. J. Am. Chem. Soc. 2004, 126, 10085.
(d) Maas, G.; Seitz, J. Tetrahedron Lett. 2001, 42, 6137. (e) Li, Y.;
Huang, J.; Zhou, Z.; Che, C. J. Am. Chem. Soc. 2001, 123, 4843.
(f) Goudreau, S. R.; Charette, A. B. J. Am. Chem. Soc. 2009, 131,
́
́
15633. (g) Levesque, E.; Goudreau, S. R.; Charette, A. B. Org. Lett.
2014, 16, 1490. (h) Seitz, W. J.; Hossain, M. M. Tetrahedron Lett.
1994, 35, 7561.
(15) (a) Zheng, Q.; Jiao, N. Chem. Soc. Rev. 2016, 45, 4590.
(b) Pellissier, H. Chem. Rev. 2016, 116, 14868. (c) Fang, G.; Bi, X.
D
DOI: 10.1021/acs.orglett.7b03374
Org. Lett. XXXX, XXX, XXX−XXX