Cyclopropanation of alkenes with metallocarbenes generated from monocarbonyl iodonium ylides

Article abstract of DOI:10.1039/C8OB02636J

Reacting Wittig reagents and the hypervalent iodine reagent iodosotoluene, in the presence of 10 mol% Cu(tfacac)₂ and 5 equiv. of alkene, results in a novel cyclopropanation reaction. The reagent combination is believed to generate a transient monocarbonyl iodonium ylide (MCIY) in situ, which can be intercepted by the copper catalyst to give a metallocarbene. Both ester and ketone derived phosphoranes can be used, as can styrenyl and non-styrenyl alkenes, which provides cyclopropanes in yields up to 81%.

Full text of DOI:10.1039/C8OB02636J

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Cyclopropanation of alkenes with metallocarbenes
generated from monocarbonyl iodonium ylides†
Cite this: Org. Biomol. Chem., 2018,
16, 8486
Tristan Chidley
and Graham K. Murphy
*
Received 10th October 2018,
Accepted 25th October 2018
DOI: 10.1039/c8ob02636j
rsc.li/obc
Reacting Wittig reagents and the hypervalent iodine reagent to the decreased relative acidity of this proton when only one
iodosotoluene, in the presence of 10 mol% Cu(tfacac)2 and 5 equiv. electron-withdrawing group is present. Owing to the extremely
of alkene, results in a novel cyclopropanation reaction. The reagent high nucleofugality of the phenyliodonio group,12 α-carbonyl
combination is believed to generate a transient monocarbonyl functionalization typically occurs at the expense of ylide for-
iodonium ylide (MCIY) in situ, which can be intercepted by the mation.13 This has resulted in long-standing problems for the
copper catalyst to give a metallocarbene. Both ester and ketone isolation, characterization and systematic evaluation of MCIYs
derived phosphoranes can be used, as can styrenyl and non-styrenyl in synthesis.
alkenes, which provides cyclopropanes in yields up to 81%.
Though their isolation has yet to be achieved, MCIYs have
be generated in situ and characterized spectroscopically. This
was first achieved by Ochiai and co-workers, who unmasked a
MCIY at low-temperature through an acyl transfer reaction on
a (2-acetoxyvinyl)iodonium salt (Scheme 1A, a).10 Ochiai sub-
sequently demonstrated the utility of these MCIYs, reacting
them with carbonyl compounds to give α,β-epoxy ketones,10 or
with activated imines to give 2-acylaziridines (Scheme 1A, b
and c).14 They also reported another example of this ionic reac-
tivity, effecting an α-alkylation reaction with trialkylboranes
(Scheme 1A, d).15 The precursors required to generate MCIYs
in this fashion is a significant limitation, as only α-keto
iodonium ylides appear to be accessible.16 Furthermore, the
conditions used to generate these MCIYs (LiOEt at low tem-
perature) would also be prohibitive for investigating them in
metallocarbene reactivity.
Iodonium ylides,1 an important subset of hypervalent iodine
(HVI) compounds, are amenable to many different types of
reactions, including cycloaddition reactions2 or as electro-
philes in nucleophilic substitutions.3 Most commonly, iodo-
nium ylides are employed as less hazardous surrogates for
diazo compounds in metallocarbene chemistry,1,4 or more
recently, in metal-free cyclopropanation reactions.5 In addition
to the versatility offered by these reagents, key benefits of
hypervalent iodine-mediated reactions include their mild and
selective oxidizing ability and often their environmentally
friendly reaction conditions.6
Iodonium ylides containing two stabilizing groups (Fig. 1,
A) are predominately found in the literature, owing to their
increased thermal stability,1,7 and their easy synthesis from
active methylene compounds and PhI(OAc)2 under basic con-
ditions.8 The stability of A results from the delocalization of
the anionic charge across the two electron-withdrawing groups
attached to the ylidic carbon.9 Conversely, monocarbonyl iodo-
nium ylides (MCIYs, B) are significantly less stable due to the
lone electron-withdrawing group present,10 which makes them
extremely rare. A consequence of only possessing one electron-
withdrawing group is that the straightforward approach for
generating other monocarbonylonium ylides fails (e.g. proton
abstraction from the α-carbon of an onium ion).11 This is due
A long-standing pursuit in our lab was to develop an in situ
synthesis of these ylides, under conditions where the potential
of these as metallocarbene precursors could be assessed. In a
previous proof-of-concept paper, we reported
a reaction
between iodosobenzene (2a) and ester-derived Wittig reagent
Department of Chemistry, University of Waterloo, 200 University Ave. W, Waterloo,
ON, Canada N2L3G1. E-mail: graham.murphy@uwaterloo.ca
†Electronic supplementary information (ESI) available: Experimental procedures
and NMR spectra of new compounds. See DOI: 10.1039/c8ob02636j
Fig. 1 Structures of dicarbonyl iodonium ylides and monocarbonyl
iodonium ylides (MCIYs).
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sioned to arise when phosphorane 1a and iodane 2a combined
to give a transient MCIY which, upon being intercepted by the
transition metal catalyst, undergoes transylidation to give a
metallocarbene. Herein, we report the first systematic evalu-
ation of this strategy for generating MCIYs, and employing
these as metallocarbene precursors in cyclopropanation reac-
tions. This new strategy provided access to both ester- and
ketone-derived MCIYs, and was effective with a broad scope of
alkenes.
We began this study by testing various iodosoarenes, iodox-
ylarenes and other iodanes in the reaction. First, we focused
on the ortho-stabilized, soluble iodane 2b reported by
Protasiewicz and co-workers.18 The polymeric nature common
to iodosoarene compounds renders them insoluble in many
organic solvents, and we believed that using a soluble variant,
where the polymeric structure is disrupted by an ortho-sulfonyl
moiety, might result in an improvement over the 17% yield
realized with iodosobenzene 2a (Table 1, entry 1). Reacting 1a
and 2b at room temperature in CHCl3 without a catalyst gave a
homogeneous mixture, but no cyclopropanation product was
observed (Table 1, entry 2). A variety of copper- or rhodium-
derived catalysts were tested, but again, none of the desired
cyclopropane was recovered (Table 1, entries 3–7). Further vari-
ation of reaction parameters (e.g. time for syringe addition,
temperature or iodane loading) were also fruitless (see ESI†).
We also tested the partially-soluble ortho-tolyliodoso com-
pound (2c), which again did not improve the reaction. Various
other substituted iodanes were tested, and while para-anisyl
derivative 2d failed, the para-tolyl (2e), para-nitrophenyl (2f)
Scheme 1 Synthesis and reactivity of MCIYs.
1a, carried out in the presence of a copper catalyst and styrene,
which provided low yields (by %GC) of cyclopropane 4a
(Scheme 1B).17 This novel cyclopropanation reactivity was envi-
Table 1 Optimization of the cyclopropanation reactiona
Entry
Iodosoarene 2 (G=)
2a (H)
2b (o-SO2 Bu)
2b
2b
2b
2b
2b
2 (equiv.)
Solvent
Time (h)
Catalyst (mol%)
Yield (%)
1
2
3
4
5
6
7
8
1.2
1.0
1.2
1.2
1.2
1.2
1.2
2
2
2
2
2
1.2
3
4
2
2
2
2
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CH2Cl2
CH3CN
CHCl3
CHCl3
1.5
20
20
24
2
2
5
1.5
1.5
1.5
1.5
1.5
1.5
1
1.5
1.5
1.5
1.5
1.5
Cu(tfacac)2 (10)
—
17
0
0
0
0
0
0
0
0
53
48
45
34
30
0
43
0
0
t
Cu(acac)2 (10)
Cu(tfacac)2 (10)
Cu(hfacac)2 (10)
Rh2(OAc)4 (5)
Rh2(tpa)4 (5)
Cu(tfacac)2 (10)
Cu(tfacac)2 (10)
Cu(tfacac)2 (10)
Cu(tfacac)2 (10)
Cu(tfacac)2 (10)
Cu(tfacac)2 (10)
Cu(tfacac)2 (10)
Cu(tfacac)2 (10)
Cu(tfacac)2 (10)
Cu(tfacac)2 (10)
Rh2(OAc)4 (5)
Cu(tfacac)2 (10)
2c (o-Me)
2d (p-OMe)
2e (p-Me)
9
10
11
12
13
14
15
16
17
18
19b
2f (p-NO2)
2g (p-tBu)
2e
2e
2e
2e
2e
2e
2e
0
a Reaction conditions: 1a is added dropwise via syringe pump over one hour to a solution of 2, catalyst and styrene (5 equiv.) in solvent (0.1 M) at
room temperature. The reaction is further stirred until the indicated length of time is reached. Isolated yields of 2.3 : 1 trans : cis mixtures. b The
tri-n-butyl variant of 1a was used.
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and para-t-butylphenyl (2g) derivatives all worked, giving the groups on styrene were investigated. The para-chloro and para-
desired product 4a in 45–53% yield (entries 10–12). Further t-butyl derivatives gave the corresponding cyclopropanes 4b
trials, including using additives to break the polymeric iodo- and 4c in moderate yield, but a significant increase was
soarene structure,19 using other iodanes (e.g. PIDA) or iodoxy- observed with the para-methoxy derivative, which gave 4d in
larene (ArIO2) derivatives also failed to improve the reaction 57% yield (Scheme 2). Further methoxy substitution on the
outcome (see ESI†). Contrary to expectation, the solubility of styrene gave increasingly higher yields, with dimethoxy 4e and
the iodosoarene did not prove critical to achieving good reac- trimethoxy 4f being recovered in 68% and 74% yield, respect-
tivity, and while iodosoarenes possessing strongly electron- ively. Both α-methyl and α-trimethylsiloxy substitution
donating substituents failed in the reaction (2c), electron-poor on styrene was tolerated, giving 4g and 4h in 63% and 56%
substrates (2f) were effective. Finally, steric hindrance between yield. Styrene bearing a β-methyl group was also viable
the ortho-substituent on the iodosoarene and the phosphorane (4i, 59% yield), however, β-nitro substitution caused the reac-
appears to be important, as the ortho-tolyl derivative 2c failed, tion to fail (4j, 0% yield). The cis and trans isomers of the
whereas the para-tolyl derivative 2e proved the most effective, β-methoxy-substituted styrenes 3k and 3l were individually
with the increased yield (over 2a) presumably arising from subjected to the reaction, which gave 4k and 4l in 60% and
mild electronic stabilization by the methyl group.
61% yield. The highest yield was observed with a tetramethoxy-
Having identified 2e as the most productive iodosoarene, styrene derivative, which resulted in a single diastereomer of
we attempted to improve the reaction by testing the various cyclopropane 4m in 81% yield. These results are consistent
reaction parameters. Changing the loading of the iodane was with an electrophilic metallocarbene being generated in the
not beneficial, and we found that using more than 3 equiv. of reaction, which would react most effectively with an electron-
2e resulted in a reaction mixture containing an overwhelming rich alkene.
amount of insoluble material, which did not give any cyclopro-
The nature of the Wittig reagent was next investigated, and
pane products (entry 15). Varying the solvent did not improve we found both the benzyl ester derivative (1b), as well as the
the yield of 4a (entries 16 and 17), neither did using other acetyl derivative (1c) were effective at cyclopropanating styrene,
copper or rhodium catalysts (e.g. Rh2(OAc)4, entry 18, also see giving 4n and 4o in 55% and 46% yield. The yield decreased
ESI†). Out of curiosity, we also attempted the cyclopropanation significantly when benzoyl derivative 1d was used (4p, 30%
reaction using the less bulky tri-n-butyl-phosphorane yield), but the reactivity was restored with increased methoxy-
(entry 19), and while the starting material was consumed, no substitution on the alkene, giving 4q in 54% yield and 4r in
cyclopropanation product was formed.
78% yield, both as single diastereomers.
After determining the optimal reactions conditions, we
Non-styrenyl alkenes were also investigated, and we found
then expanded the reaction scope to discover what other types 1-phenyl-1,3-butadiene would undergo regioselective cyclopro-
of cyclopropane motifs could be synthesized. First, the effect panation at the terminal alkene, giving 4s in 61% yield. We
of various electron-poor, -neutral, and electron-rich functional were pleased to find that allylbenzene could undergo cyclo-
Scheme 2 Synthesis of cyclopropanes from Wittig reagent precursors 1a–d. aThe alkene stereochemistry is indicated in the product drawn.
bProducts typically recovered as ∼2–3 : 1 mixtures of diastereomers, except 4k,m,q,r which were single diasteromers by 1H NMR.
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Acknowledgements
We would like to thank the Natural Sciences and Engineering
Research Council of Canada and the University of Waterloo for
funding.
Fig. 2 Proposed reaction mechanism.
propanation, giving 4t in 49% yield, as could dihydropyran
and the TMS-enol ether of cyclohexanone, which gave 4u and
4v in 60% and 63% yield, respectively. Therefore, it appears
that usable yields can also be obtained with non-styrenyl ali-
phatic alkenes and enol ethers, without observing products of
competing C–H insertion, oxonium ylide formation or cyclo-
addition processes.20
Finally, the viability of an intramolecular cyclopropanation
reaction was also investigated (eqn (1)). The Wittig reagent 1c
was allylated in 86% yield to give 1e,21 and when this was sub-
jected to 2e and Cu(tfacac)2, it underwent cyclopropanation to
give 4w in 63% yield.
Notes and references
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ð1Þ
We propose that the cyclopropanation reactions occur by
the sequence of reactions illustrated in Fig. 2. Upon combining
Wittig reagent 1a with iodosotoluene 2e, a formal Wittig reac-
tion could occur to generate the monocarbonyl iodonium ylide
C and phosphine oxide. Attack by this ylide on the electrophi-
lic copper catalyst leads to ylide decomposition with expulsion
of iodotoluene, generating copper carbene D. Upon engaging
with styrene, the cyclopropanation reaction occurs, regenerat-
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Conclusions
In conclusion, we report here the first systematic evaluation of
in situ generated monocarbonyl iodonium ylides as metallocar-
bene precursors, and show for the first time their use as diazo
surrogates in metallocarbene reactions. The combination of
Wittig reagents and para-iodosotoluene leads to transient
MCIYs, which readily undergo cyclopropanation reactions
with alkenes. The optimized procedure was catalyzed by
Cu(tfacac)2, and yields up to 81% were achieved. The reaction
was tolerant to both ketone- and ester-derived Wittig reagents,
and the scope of alkenes was broad, with the highest yields
being obtained with the most electron-rich olefins. We are con-
tinuing to investigate MCIYs in metallocarbene and metal-free
reactivity, and we will disclose the results in due course.
Conflicts of interest
There are no conflicts to declare.
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