Intermolecular metal-free cyclopropanation of alkenes using tosylhydrazones

Article abstract of DOI:10.1002/ejoc.201200149

We describe the first general method for the metal-free cyclopropanation of alkenes by using N-tosylhydrazones as an in situ source of diazo compounds. This new method works with a wide variety of alkenes (styrene derivatives, dienes, enynes, and electron-deficient alkenes) by using N-tosylhydrazones derived from various ketones or aldehydes (aromatic, aliphatic, enones). The reaction is performed with the use of K₂CO₃ as a base to form the diazo species and is compatible with a wide array of functional groups. A new procedure for the synthesis of cyclopropanes by the formal cyclopropanation of carbonyl compounds and alkenes is described. This metal-free reaction proceeds through the base-promoted decomposition of tosylhydrazones. There is significant tolerance of the functional groups, enabling cyclopropanation in the presence of functionalities often not compatible with other methodologies.

Full text of DOI:10.1002/ejoc.201200149

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201200149
Intermolecular Metal-Free Cyclopropanation of Alkenes Using
Tosylhydrazones
José Barluenga,*[a] Noelia Quiñones,[a] María Tomás-Gamasa,[a] and María-Paz Cabal*[a]
Keywords: Diazo compounds / Hydrazones / Small ring systems / Alkenes
We describe the first general method for the metal-free cyclo-
propanation of alkenes by using N-tosylhydrazones as an in
situ source of diazo compounds. This new method works with
a wide variety of alkenes (styrene derivatives, dienes, en-
ynes, and electron-deficient alkenes) by using N-tosyl-
hydrazones derived from various ketones or aldehydes (aro-
matic, aliphatic, enones). The reaction is performed with the
use of K2CO3 as a base to form the diazo species and is com-
patible with a wide array of functional groups.
cious metals and ligands and the need to dispose of or to
eliminate the sometimes toxic metals. For this reason,
metal-free reactions that could exhibit the same levels of
efficiency and selectivity are highly desirable.
The limitation of this method is the need to synthesize
and handle potentially toxic, and in some cases explosive,
diazo compounds.[5] To solve this problem, sulfonylhydraz-
ones are versatile synthetic intermediates that have been
used as an in situ source of diazo compounds in different
types of transition-metal-catalyzed processes, such as ole-
fination, epoxidation, C–H and N–H insertion reactions,
and cyclopropanations.[6]
Introduction
The cyclopropane unit is found as a basic structural ele-
ment in many biologically important compounds.[1] Its
unique reactivity enables the cyclopropane ring to be used
as a versatile building block or intermediate in the synthesis
of molecules with increased complexity.[2] Among the meth-
ods commonly used for its construction, the most general
are transition-metal-catalyzed decomposition of diazo com-
pounds in the presence of an olefin, a process involving
metal carbene intermediates derived from Cu, Rh, Ru, Co,
and other metal catalysts (Scheme 1).[3]
In the last five years our group has demonstrated that in
the presence of a Pd catalyst, tosylhydrazones can be used
as a general source of diazo compounds without any limita-
tion in the structure of the carbonyl precursor, and these
compounds have found utility in important transformations
such as cross-coupling reactions, oxidative cross-couplings,
and cascade reactions.[7] We have also discovered that the
same strategy can be applied in the absence of a metal cata-
lyst; thus, we have recently reported new metal-free carbon–
carbon (Scheme 2a) and carbon–oxygen (Scheme 2b) bond-
forming reactions between tosylhydrazones and boronic ac-
ids or alcohols, respectively.[8] In continuing with our inter-
est in metal-free processes employing tosylhydrazones, the
synthesis of cyclopropanes from alkenes has emerged as an
attractive synthetic transformation (Scheme 2c).
As far as we know, two examples of cyclopropanations
have been reported in the literature for the thermal decom-
position of sulfonylhydrazones in the presence of alkenes
without a metal catalyst present: Aggarwal reported an
intermolecular cyclopropanation of dehydroamino acids,[6b]
and Taber developed an intramolecular cyclopropanation
reaction between ketones and dienes.[9]
Scheme 1. Cyclopropanation by transition-metal-catalyzed decom-
position of diazo compounds.
It has been proposed that highly reactive metal carbene
reagents are required to overcome the ring strain generated
in the newly formed cyclopropane unit.[4] Most of the ex-
amples involve diazo compounds stabilized by electron-
withdrawing groups such as diazoketones or diazoesters.
Aryl diazomethanes generally perform less effectively due
to their greater tendency to dimerize in the absence of nu-
cleophilic alkenes. However, metal-catalyzed reactions may
also present problems associated with the high cost of pre-
[a] Instituto Universitario de Química Organometálica “Enrique
Moles”. Unidad Asociada al CSIC, Universidad de Oviedo
c/ Julián Clavería 8, 33006 Oviedo, Spain
Fax: +34-98-510-3446
E-mail: barluenga@uniovi.es
Here, we describe a new and general procedure for the
synthesis of cyclopropanes by base-promoted decomposi-
tion of tosylhydrazones in the presence of alkenes. An at-
pcabal@uniovi.es
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200149.
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Intermolecular Metal-Free Cyclopropanation of Alkenes
Scheme 2. Free-metal C–C and C–O bond-forming reactions from tosylhydrazones.
tractive feature is that the reaction is general and allows the
The scope of the process was studied under the opti-
use of tosylhydrazones readily prepared from simple, non- mized reaction conditions shown in Scheme 3. The trans-
stabilized, carbonyl compounds.
formation proceeds very efficiently with a wide range of tos-
ylhydrazones derived from ketones or aldehydes having aro-
matic, heteroaromatic, or alkyl substituents (Table 1).
Hydrazones derived from aryl ketones afford the desired
products in high yields, regardless of steric or electronic
variations (Table 1, Entries 1–11). Hydrazones derived from
aliphatic ketones afford more moderate yields (Table 1, En-
tries 12 and 13). Hydrazones derived from aromatic and
heterocyclic aldehydes proceed with high conversions when
electron-withdrawing substituents are located at the meta or
para positions (Table 1, Entries 19–22). It is important to
point out that the reaction takes place even with p-nitro-
and p-fluoroaryl tosylhydrazones (Table 1, Entries 9 and
19), which are not accessible by other methodologies.[6d]
With regard to the aryl-substituted alkene, there is a
broad substrate tolerance, which allows the reaction to be
carried out even with electron-deficient benzene derivatives
(Table 1, Entries 3–5, 11, 16–17, and 22) as well as highly
hindered 1,1-disubstituted aryl substrates (Table 1, En-
try 23).
Results and Discussion
We first focused on the reaction of the tosylhydrazone
derived from p-tolyl methyl ketone (1a) and styrene (2a,
Scheme 3). Our first attempts gave encouraging results. The
reaction run in the presence of K2CO3 with the use of diox-
ane as the solvent at 110 °C afforded aryl cyclopropane 3a
as a diastereomeric mixture (cis/trans = 0.4:1) in 71% yield
(Scheme 3, Entry 1). The cyclopropanation is dependent on
the concentration of the reagents, with the optimal being
2 equiv. of styrene, 1.5 equiv. of K2CO3, and 3 mL of diox-
ane, to afford adduct 3a in 87% yield (Scheme 3, Entry 2).
Several additional bases were screened, including Na2CO3,
K3PO4, KOH, and NaOtBu, but none of them provided
desired cyclopropane 3a. The reaction proceeds with
CsCO3 and LiOtBu, albeit with a decrease in yield (67 and
58%, respectively). Similar results were obtained when the
reaction time was doubled from 6 to 12 h. The reaction also
proceeds at lower temperatures (70–90 °C) but with a sub-
We next investigated the cyclopropanation reaction by
stantial decrease in the yield due to the formation of side using aliphatic substituted alkenes. Unfortunately, under
products such as azine 4a and alkenes 5a and 6a, resulting the same reaction conditions previously used for the aryl
from the dimerization and elimination (Bamford–Stevens alkenes, a complex mixture of products was obtained. Thus,
reaction),[10] respectively, of the starting tosylhydrazone. At a new optimization of the reaction conditions was carried
higher temperatures (150 °C) with the use of microwave ir- out. The influence of the temperature was also investigated,
radiation (MW), the yield was not improved (69%), and an and it was confirmed that reactions run at 150 °C gave the
increase in the formation of byproduct 4a was found in the best results. The microwave-promoted reactions are advan-
crude product mixture.
tageous in this particular transformation when compared
Scheme 3. Influence of the reagent concentrations in the synthesis of 3a.
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J. Barluenga, N. Quiñones, M. Tomás-Gamasa, M.-P. Cabal
Table 1. (continued)
SHORT COMMUNICATION
Table 1. Synthesis of arylcyclopropanes 3.[a]
[a] Reaction conditions: Tosylhydrazone 1 (0.3 mmol), aryl alkene
2 (0.6 mmol), K2CO3 (0.45 mmol), dioxane (3 mL), 110 °C, 6–12 h.
[b] Yield of isolated cyclopropane 3 as a mixture of diastereoiso-
mers (cis/trans = 0.3–0.7:1).
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Intermolecular Metal-Free Cyclopropanation of Alkenes
Table 2. Synthesis of alkylcyclopropanes 8.[a]
Table 3. Synthesis of alkenyl- and alkynylcyclopropanes 10.[a]
[a] Reaction conditions: Tosylhydrazone 1 (0.3 mmol), alkyl alkene
7 (0.3 mmol), K2CO3 (1.5 equiv.), dioxane (1.5 mL), H2O (10 μL),
150 °C (MW), 1 h. [b] Yield of isolated cyclopropane 8 as a mixture
[a] Reaction conditions: Tosylhydrazone 1 (0.3 mmol), diene 9a–c
or enyne 9d (1.5 mmol), K2CO3 (1.5 equiv.), dioxane (2 mL),
110 °C, 6 h. [b] Dienes 9a and 9c are a Z/E mixture of diastereoiso-
mers. [c] Yield of isolated cyclopropane 10 as a mixture of dia-
stereoisomers (cis/trans = 0.4–0.6:1). [d] K2CO3 (3 equiv.), 12 h.
of diastereoisomers (cis/trans
=
0.3–0.8:1). [c] Alkene 7b
(0.6 mmol), K2CO3 (3 equiv.), 110 °C, 6 h. [d] Yield of the crude
reaction mixture.
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J. Barluenga, N. Quiñones, M. Tomás-Gamasa, M.-P. Cabal
SHORT COMMUNICATION
to conventional heating: the higher reaction temperature al- after heating carbonyl compound 13a or 13b and tosylhyd-
lowed the process to take place faster and with higher yields razine for 60 min at 70 °C, the base and the alkene were
(Table 2). Also, an excess amount of the alkene was not then added, and the mixture was heated for an additional
required to deliver the highest conversion. Again the reac- 6 h. Cyclopropanes 3g and 3s were isolated in 66 and 34%
tion was general for tosylhydrazones derived from aromatic yield, respectively.
ketones (Table 2, Entries 1–4), aliphatic ketones (Table 2,
Entries 5–7), or aromatic aldehydes (Table 2, Entries 8–11).
Good results were obtained when electron-withdrawing
substituents on the alkene were used, but neutral or elec-
tron-donating substituents afforded poor yields (Table 2,
Entries 12 and 13).
Moreover, the cyclopropanation reaction is not restricted
to aryl-substituted alkenes or aliphatic-substituted alkenes,
as it can be successfully applied to conjugated dienes and
Scheme 5. One-pot procedure for the synthesis of cyclopropanes.
enynes, provided that an excess amount of the substrate
(5 equiv.) is used (Table 3). Under MW irradiation, lower
yields were obtained, but with conventional heating at
110 °C, the cyclopropanes were obtained in fair to good
yields. The regioselectivity of the reaction is sensitive to
Conclusions
The results presented above show that the reaction of
tosylhydrazones with alkenes is a very general method for
the creation of cyclopropane products. The methodology
can be applied to aryl and aliphatic alkenes, as well as con-
jugated dienes and enynes. The high functional group toler-
ance allows the reaction to be carried out on substrates not
normally compatible with other methodologies. For in-
stance, the reaction proceeds successfully in the presence of
esters and nitriles. Moreover, halogen substitution on the
aromatic ring is also tolerated and enables further derivati-
zation through metal-catalyzed cross-coupling techniques.
Also, the cyclopropanation reaction can be carried out di-
rectly from the carbonyl compound by generating the tos-
ylhydrazone in situ, in a multicomponent fashion.
In summary, we have described a new procedure for the
synthesis of cyclopropanes by base-promoted decomposi-
tion of tosylhydrazones in the presence of alkenes. Notably,
the starting materials are readily available and stable; tos-
ylhydrazones are easily synthesized from carbonyl com-
pounds on a large scale and can be stored at room tempera-
ture without decomposition. The major advantages of this
procedure are the operational simplicity, the preclusion of
an inert atmosphere or ultra-dry solvents, and the high
functional group tolerance. In this study we demonstrate
for the first time that electron-deficient alkenes react with
non-stabilized diazo compounds to overcome the limitation
of previously reported metal-catalyzed intermolecular reac-
tions between diazoesters and electron-deficient alkenes.[6b]
We believe that this new methodology may become a useful
tool in organic synthesis.
temperature, as at higher temperatures (150 °C, MW) the
cyclopropanation occurs at both double bonds, but at
110 °C the reaction is regioselective for the terminal alkene.
The reaction is general for N-tosylhydrazones derived from
aromatic ketones with electron-donating (Table 3, En-
tries 1–3) or electron-withdrawing substituents (Table 3, En-
tries 4–6), as well as with aliphatic ketones (Table 3, En-
tries 7 and 8) and aryl aldehydes (Table 3, Entries 9–11).
Furthermore, 1-buten-3-ynes are good substrates, and
the reaction occurred regioselectively to afford high yields
of the alkynylcyclopropanes by using tosylhydrazones de-
rived from ketones or aldehydes (Table 3, Entries 12 and
13).
In Scheme 4, we consider two alternative pathways for
these cyclopropanation reactions: (path a) carbene addition
to the double bond or (path b) 1,3-dipolar cycloaddition
followed by N2 extrusion.
Scheme 4. Synthesis of cyclopropanes from tosylhydrazones by 1,3-
dipolar cycloaddition.
Path b has been proposed in the literature for the forma-
tion of cyclopropanes in non-metal-catalyzed reactions.[11]
In this case, the reaction is postulated to proceed through
diastereoselective construction of a pyrazoline ring followed
by extrusion of nitrogen, with retention of the configuration
of the pyrazoline stereocenters.[12]
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures and spectroscopic data for cyclopro-
panes 3, 8, and 10.
Acknowledgments
Lastly, we examined the possibility of generating the
hydrazones in situ from carbonyl compounds to develop a
This research was funded by the Ministerio de Ciencia e Innova-
ción of Spain (MICINN, grant nos. CTQ 2007–61048 and CTQ
one-pot cyclopropanation procedure (Scheme 5). Therefore, 2010–16790). A “Severo Ochoa” predoctoral fellowship from the
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Intermolecular Metal-Free Cyclopropanation of Alkenes
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Received: February 8, 2012
Published Online: March 14, 2012
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