Metal-free intramolecular cyclopropanation of alkenes through iodonium ylide methodology

Article abstract of DOI:10.1016/j.tet.2010.05.005

Intramolecular cyclopropanation of alkenes occurs thermally with iodonium ylides in the absence of conventional metal catalysts such as Rh(II) and Cu(II). In rigid molecular systems conversions are near quantitative. A mechanism is proposed involving formal 2+2 cycloaddition followed by reductive elimination of PhI to yield the cyclopropane. Intramolecular cyclopropanation of alkenes occurs thermally with iodonium ylides in the absence of conventional metal catalysts such as Rh(II) and Cu(II). In rigid molecular systems conversions are near quantitative. A mechanism is proposed involving formal 2+2 cycloaddition followed by reductive elimination of PhI to yield the cyclopropane.

Full text of DOI:10.1016/j.tet.2010.05.005

Tetrahedron 66 (2010) 5801e5810
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Metal-free intramolecular cyclopropanation of alkenes through
iodonium ylide methodology
*
Robert M. Moriarty , Sachin Tyagi, Mark Kinch
University of Illinois at Chicago, 845 W. Taylor St., Chicago, IL 60607, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Intramolecular cyclopropanation of alkenes occurs thermally with iodonium ylides in the absence of
conventional metal catalysts such as Rh(II) and Cu(II). In rigid molecular systems conversions are near
quantitative. A mechanism is proposed involving formal 2þ2 cycloaddition followed by reductive
elimination of PhI to yield the cyclopropane.
Received 21 April 2010
Received in revised form 30 April 2010
Accepted 4 May 2010
Available online 7 May 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Metal-free
Hypervalent iodine
Cyclopropanation
Cyclopropyl keto-esters
Iodonium ylide
1. Introduction
In terms of chemical reactivity, cyclopropanes substituted with
donor and acceptor groups (Fig. 3) dramatically activate the cy-
The cyclopropane ring can be regarded as a unique functional
group that can undergo transformations that are more difficult or
impossible with many of the conventional carbon-based functional
groups. Due to inherent ring strain, i.e., 27.5 kcal/mol, cyclopropane
is unparalleled among carbocycles in both its properties and re-
activity.1 Thus, cyclopropane derivatives provide building blocks of
considerable synthetic potential.2 Many synthetic and metabolite
cyclopropane ring containing natural products such as curacin A,3,4
cilastatin,5 ambruticin,6,7 and solandelactone A8 possess biological
properties ranging from enzyme inhibition to antibiotic, antiviral,
antitumor, and neurochemical properties (Fig. 1).9
clopropane ring toward substitution and hence, a high versatility of
products may be formed after ring cleavage.12,13 Since the two
charges of synthon 6 are carbon atoms in a 1,3-relationship, re-
actions employing 3 may be regarded as processes, which provide
products not easily available by alternative methods.14
Me
Me
Me
H
H
N
S
H
OMe
N
O
S
H
HO2C
NH2
CO2Na
H
Me
Cilastatin
Curacin A
Staudinger et al. isolated and characterized the cyclopropane-
containing natural insecticide, (þ)-trans-chrysanthemic acid 1
(Fig. 2), from the pyrethrum flowers (Chrysanthemum cinerar-
iaefolium and Chrysanthemum coccineum).10 The active insecticidal
compounds are the esters of 1, which have been commercially
marketed to produce one of the most successful classes of bio-
mimetic insecticides, the pyrethroids. It could be argued that the
highly strained three-membered carbocycle is ubiquitous. It occurs,
for example, in every green plant in the form of 1-amino-
cyclopropanecarboxylic acid (ACC) 2 (Fig. 2), a direct precursor to
the plant hormone ethylene.11
H
H
H
OH
Me Me
Me
H
H
Me
O
H
O
O
HO2C
H
O
H
OH
H
Me
nC5H11
OH
Ambruticin
OH
Solandelactone A
Figure 1. Cyclopropane ring containing natural products and drugs.
Me
Me
H
H2N CO2H
H
CO2H
Me Me
1
2
* Corresponding author. Tel.: þ1 312 996 2364; fax: þ1 312 996 0431; e-mail
address: moriarty@uic.edu (R.M. Moriarty).
Figure 2.
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.05.005

5802
R.M. Moriarty et al. / Tetrahedron 66 (2010) 5801e5810
R
or nitrogen and subsequent transfer of the carbene to an appropriate
R
R
Acc
Acc
R
Acc
Don
substrate. The mechanism of these reactions is, however, controver-
sial. Carbene or carbenoid pathways have often been proposed or
assumed, but experimental support of these hypotheses is scarce.
Enantiocontrol in the carbene transfer step may be achieved by chiral
ligands surrounding the metal center of the catalyst. Iodonium ylides
are readily accessible by reaction of CeH acidic compounds with
iodobenzene diacetate, PhI(OAc)2.27 They occur as amorphous solids
or oils. Often, their decomposition occurs at temperatures well below
than those required for diazo decomposition.
Don
Acc
Don
4
Acc
5
3
6
Don = Donor
Acc = Acceptor
Figure 3.
1.1. Preparation of cyclopropane rings from diazo compounds
Since their discovery, carbene transfer to alkenes has been
a method of choice for the preparation of cylopropane rings. The for-
mal addition of a carbene group from a diazo compound to an un-
saturated double bond has been extensively developed in the last
decades.15e17 Although such a process was initially induced either
thermally or photochemically, further use of transition-metal catalysts
(metal carbenoids or metallo-carbenes) allowed exerting a certain
control in the selectivity of this reaction. Figure 4 shows the catalytic
cycle of a typical olefin cyclopropanation reaction, in which an olefin
reacts with a diazo compound in the presence of a metal catalyst.
1.3. Copper-catalyzed cyclopropanation
The majority of the synthetically useful transformations with
phenyliodonium ylides have been carried out under Cu-catalysis, and
for Cu-catalysts the mechanism is not established. Moriarty et al. in-
vestigated the intramolecular cyclopropanation of ylide 10 (Scheme 1)
to the tricyclic ketone 11 in the presence of copper(I) chloride.28e31
Figure 4.
Substituted olefins lead to the formation of two di-
astereoisomers, cis and trans (assuming that the substituents of the
diazo compound are different), each of them corresponding to
a mixture of two enantiomers. The transition metal-catalyzed de-
composition of diazo compounds leads to metallo-carbenes, which
are not isolable, but transfer the carbene moiety to a suitable ac-
ceptor molecule or to an appropriate acceptor site within the
metallo-carbene.18 Also, the metal catalysts based on copper(I),
copper(II), and rhodium(II) can induce the catalytic coupling of the
diazo compound, an undesired reaction that diminishes the yields
of cyclopropanes. Thus, the use of diazo compounds might be
avoided if it were possible to generate the metallo-carbenes from
other sources, i.e., iodonium ylides. Sometimes diazo compounds
fail to afford desired products even in presence of metal catalysts as
in the case of the diazo analogue of Meldrum’s acid ylide 25
(Scheme 4), which failed to undergo diazo decomposition when
exposed to Rh(II) carboxylate catalysts even at elevated tempera-
tures. However, iodonium ylide 25, as discussed below, afforded the
cyclopropane at relatively low temperatures.19
Scheme 1.
The authors demonstrated the application of intramolecular
copper(I) catalyzed cyclopropanation of iodonium ylides by initially
synthesizing 9. They used it for the preparation of compound 14,
which was the precursor for 17. Using this methodology 18 was
converted as mixture of diastereomers 19 and 20 of natural prod-
ucts such as prostaglandins and vitamin D, respectively (Scheme 2).
1.2. From iodonium ylides
Iodoniumylidesprovideasaferalternativetothehighlyhazardous
(explosive carcinogens) diazo compounds. The photochemical,20
thermal21e23 or transition metal-catalyzed20,24e26 decomposition of
phenyliodonium ylides affords products typical for carbene or metal
carbenoid intermediates. A large number of efficient and selective
catalysts, mostly based on Cu(I) or Rh(II), are now available for car-
benoid reactions, such as cyclopropanation of olefins. The reaction
mechanism involves interaction of the catalyst with the phenyl-
iodonium ylide or corresponding diazo compound, to afford a met-
allo-carbene intermediate with concomitant release of iodobenzene
Scheme 2.
However, a controversy ensued over the reaction mechanism.
Moriarty et al. found that the reaction worked in absence of any
metal catalysts; the authors suggested that the reaction may not be
occurring via a copperecarbenoid intermediate; but rather copper
plays a role in electron transfer. Mueller et al. did a comparative
study with diazomalonates and diazoacetoacetates and corre-
sponding iodonium ylides in the presence of chiral copper catalysts
(Scheme 3).32

R.M. Moriarty et al. / Tetrahedron 66 (2010) 5801e5810
5803
Scheme 3.
These authors reported the observation of asymmetric in-
duction in the Cu-catalyzed reactions of the ylides 21 and 23, which
is consistent with a carbenoid mechanism; however, the discrep-
ancy of the enantioselectivities observed between diazo com-
pounds 21a and 23a and corresponding ylides 21b and 23b
(Scheme 3) suggests a competing nonselective pathway for cyclo-
propanation outside of the coordination sphere of copper. The au-
thors claimed, “However, irrespective of the reaction mechanism,
the observation of significant levels of enantioselectivity implies
that the reaction must take place within the coordination sphere of
the metal and the ionic mechanism proposed by Moriarty can not
apply.”33 These observations imply that the copper-catalyzed
mechanism may involve intermediacy of a copper-carbenoid, but
the same argument cannot be applied to the metal-free route.
Scheme 4.
some stabilization. This is consistent with the observation of lower
enantioselectivity for reactions involving diazo ketones37 in com-
parison with diazo esters or diazo amides, although a few enan-
tioselective catalysts for diazo ketones have been reported.38e40
1.4. Rhodium-catalyzed cyclopropanation
1.5. Metal-free cyclopropanation
Phenyliodonium ylides are also known to undergo diverse re-
actions in the presence of various Rh(II) catalysts. The stereo-
selectivity in rhodium-catalyzed intermolecular cyclopropanation is
dependent on both the alkenes and ylides used. For example, the
reaction of 2-diazodimedone 25a and the ylide 25b exhibit very poor
enantioselectivity in cyclopropanations of terminal olefins
(Scheme 4). The Rh2(OAc)4-catalyzed cyclopropanation of cis- and
trans-pent-2-ene (28a and 28b) with phenyliodnium ylide of Mel-
drum’s acid 25b was stereospecific and yielded the cyclopropanes
29a and 29b, respectively.34 In the presence of [Rh2{(S)-nttl}4], pen-
tene 31a and styrene 31b reacted with 30 to afford the cyclopropanes
32a and 32b with 59% and 37% ee, respectively (Scheme 4).34
These ee’s are very similar (50%) to those obtained with corre-
sponding diazo compounds35 and are indicative of the similar re-
Although transition metal-catalyzed organic transformations
are highly stereoselective and efficient processes, however, due to
environmental and health concerns contemporary organic chem-
istry strives to be metal-free. An example of metal-free cyclo-
propanation using phenyliodonium ylides was reported by
Camacho et al.41 Heating phenyliodonium bis(ethoxycarbonyl)
methanide 34 (Scheme 5) in cis-heptene 33 at 100 ꢀC afforded the
cis-cyclopropane 35, iodobenzene, and several minor products,
while in the presence of trans-hept-2-ene 36, the trans-cyclopro-
pane 38 was formed.41 According to the authors, the high stereo-
specificity of the reaction suggests cyclopropanation of the double
bond by a singlet carbene, cyclopropanation being faster than in-
tersystem crossing.
action mechanism, i.e., formation of
a rhodium-carbenoid
intermediate in both diazo compounds and corresponding iodo-
nium ylides. A tentative explanation for the low enantioselectivity
of the diazodimedone 25a, and the corresponding phenyliodonium
ylide 25b may be explained on the grounds of the investigations of
Davies and Panaro36 It was found that diazo esters, that are known
to involve carbenoid intermediates, carrying stabilizing sub-
stituents such as phenyl or vinyl groups, exhibit significantly higher
r-values in the cyclopropanation of substituted styrenes than the
unsubstituted diazoacetate esters. A higher -value implies higher
r
selectivity, owing to a transition state occurring later on the re-
action coordinate. Interestingly, the more stabilized carbenoids also
exhibit higher enantioselectivities. Applying the same argument to
carbenoids derived from 25a,b, the absence of selectivity may be
attributed to their higher reactivity in comparison, for example, to
the carbenoids derived from 30, where the oxygen atoms provide
Scheme 5.

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R.M. Moriarty et al. / Tetrahedron 66 (2010) 5801e5810
Contrary to the Camacho’s assertions, Gallos et al. claimed that
the absence of these metals.19,28,42e44 Treatment of phenyl-
iodonium ylide 43 with 10 mol % of CuCl catalyst resulted in a 90%
yield of tricyclic ketone 46 (Scheme 7). The possibility of in-
volvement of carbenoid intermediate was ruled out on the basis of
the fact that no Wolff-type rearrangement products were obtained
the metal-free cyclopropanation does not involve a carbene in-
termediate.42 They found that refluxing ethyl 2-diazo-4,5-iso-
propylidene-dioxy-3-oxo-6-heptenoate 39 in toluene with a 5%
molar ratio of CuI for 3 h (Scheme 6) gave a mixture of the
cyclopropanation products 41 and 42 (81%, 41/42¼4.5:1 di-
astereoisomeric ratio). However, when Rh2(OAc)4 was employed
as a catalyst, diazo compound 39 decomposed in 1.5 h to the
same cyclopropanation products, but with opposite diaster-
eoselectivity (74%, 41/42¼1:3 diastereoisomeric ratio). The phe-
nyliodonium ylide 40, without a metal catalyst, decomposed
within 30 min in DCM solution at 20 ꢀC, under an argon atmo-
sphere, to again give 41 and 42, in moderate yield and a slight
preference of 42 (45%, 41/42¼1:1.5 diastereoisomeric ratio). Sur-
prisingly, the same results were found with either CuI and
Rh2(OAc)4.
in these reactions, although corresponding
a-ketocarbene derived
from
a
-diazoketones has been shown to follow this pathway.20,45
Also, since the reaction proceeds in the absence of the catalyst,
the catalytic effect of Cu(I), in turn, was ascribed to electron
transfer.
Scheme 7.
A stepwise mechanism was proposed, in which the electrophilic
iodonium center of 43 attacks the C]C bond to afford a carbenium
ion 44, which, subsequently, undergoes transannular alkylation to
yield 46. In order to understand the reaction mechanism various
intramolecular cyclopropanation reactions were explored. The fol-
lowing table shows previous attempts in our lab for intramolecular
cyclopropanation of phenyliodonium ylide 43 under various cata-
lytic, thermal and photochemical conditions (Table 1).44
Scheme 6.
The Gallos results suggest that the reactions may not be pro-
ceeding through a carbene intermediate. The variation of diaster-
eoselectivities observed should originate from the different
reaction mechanisms followed by the diazo compounds and iodo-
nium ylides, under the applied conditions. The metal-catalyzed
decomposition of diazo compounds proceeds most probably via
a metallo-carbenoid intermediate, whereas the iodonium ylide
decomposition is, in this particular case, a stepwise process with
possible formation of intermediates 1 or 2 (Fig. 5). Further reductive
elimination of iodobenzene affords the cyclopropane ring. Since the
decomposition reaction of iodonium ylide is independent of the
catalyst used (or absence of catalyst), being completed at the same
time (within 30 min) and giving the same yields and diaster-
eoselectivity, it is apparent that the metal is not coordinated with
these intermediates. Furthermore, intermediate 1 leading to the
formation of 42 looks less favored compared to intermediate 2,
because of the stronger interactions of the bulkier iodophenyl
group with one methyl of the acetonide group in intermediate 1
than the respective ones of the ethoxycarbonyl group in in-
termediate 2.
Table 1
Intramolecular cyclopropanation of phenyliodonium ylidesa
O
O
O
O
I
Ph
CO2Me
46
43
Entry
Metal catalyst
Conditions
Yield %
1
2
3
4
5
6
7
8
CuCl
CuCl2
DCM, Ar, 0 ꢀC to rt, 2 h
DCM, Ar, 0 ꢀC to rt, 2 h
DCM, Ar, 0 ꢀC to rt, 2 h
DCM, Ar, 0 ꢀ;C to rt, 2 h
95%
58e65%
58e60%
Cu(acac)2
Rh2(OAc)4
Rh2(OAc)4
Thermal
Thermal
Sunlamp
UV reactor
Pd(OAc)2
ZnBr2
w20%,b complex mix
w50%,b complex mix
w10e12%
75%
DCM, Ar, ꢁ40 ꢀC to rt, 2 h
DCM, reflux, 2 h
DCM, reflux, 12 h
H
H
CO2Et
Ph
I
O
O
hv, CDCl3, Ar, 3 h (heat)
hv, CDCl3, Ar, 3 h (cooled)
DCM, Ar, 0 ꢀC to rt, 2 h
DCM, Ar, 0 ꢀC to rt, 2 h
DCM, Ar, 0 ꢀC to rt, 2 h
DCM, Ar, 0 ꢀC to rt, 2 h
65%
58e60%
H
H
Me
Me
9
I
CO2Et
O
O
Me
Ph
10
11
12
13
Complex rxn mixb
60e65%
O
Me
O
Intermediate 1
Intermediate 2
Zn(OTf)2
AlCl3
16e20%a
15e20%a
Figure 5.
a
These catalysts do have an effect on decomposition of the ylide, but the cyclo-
propanated product is not the major product.
b
The reaction mixture formed was too complicated to resolve by either HPLC or
2. Results and discussion
standard flash column chromatography.
Earlier, we and others found that in the case of certain intra-
molecular cyclopropanation processes, conventionally effected us-
ing copper or rhodium catalysis, the reaction occurred efficiently in
Entry
7 in above table shows the intramolecular cyclo-
propanation in good yields, i.e., 75% (second best to CuCl catalyzed

R.M. Moriarty et al. / Tetrahedron 66 (2010) 5801e5810
5805
Table 2
process) under thermal conditions. In this study only one substrate
Preparation of phenyliodonium ylides
was studied in detail. Given the synthetic and biological impor-
tance of cyclopropane rings and the need for a greener route for
their synthesis, we decided to study the metal-free route and ex-
tend the scope of the metal-free cyclopropanation of phenyl-
iodonium ylides. In order to check the generality of process, various
phenyliodonium ylides were prepared using methodology de-
scribed in Scheme 8.
Entry
1
Ketoester
Ylide
Temp (ꢀC) Yield %
0
80
2
ꢁ78
69 (unstable)
3
4
5
R1¼H, R2¼H 56c
51c
51d
0
0
ꢁ30
83
75
R1¼CH3, R2¼H 56d
R1¼CH3, R2¼CH3 56e 51e
60 (unstable)
Scheme 8.
A DielseAlder reaction between acryloyl chloride and different
1,3-dienes in presence of small amount of propylene oxide, afforded
mono and bicyclic acid chlorides in almost quantitative yields. In
the case of bicyclic acid chlorides mixture 48a and 48b isomers
were obtained, which were separated by converting them to the
corresponding acids (Scheme 9), followed by iodolactonization to
yield 52 and 53. Separation of the sodium salt of the exo-acid fol-
lowed by dehalogenation using Zn gave pure endo isomers 54a,b.
These acids were then converted to the corresponding acid chlo-
rides endo-55a,b, and were further used for the next step, i.e.,
condensation with Meldrum’s acid in presence of base, without
purification. For example, the resulting Meldrum’s acid adduct 49
was refluxed in methanol for 4e5 h to yield substituted
6
ꢁ10
93
2.1. Metal-free intramolecular cyclopropanation
Metal-free cyclopropanation was achieved by stirring above
phenyliodonium ylides in dry dichloromethane for the stipu-
lated time (Table 3). Reaction of ylide 51a was monitored by
Table 3
Metal-free intramolecular cyclopropanation unsaturated phenylidonium ylides of
dicarbonyl compounds
b-
b
-ketoesters 56a,b (Scheme 9).
Entry
1
Ylide
Cyclopropane
Time
4 h
Yield %
95
2
Scheme 9.
15 min
55
The resulting b-ketoesters 56 were treated with 10% methanolic
solution of KOH, at below 0 ꢀC for half an hour followed by addition
of IBD at the same temperature to afford substituted phenyl-
iodonium ylides (Scheme 8). Most phenyliodonium ylides were
prepared at ꢁ10 ꢀC to 0 ꢀC and are solid at room temperature.
Ylides 51 (Table 2) were very unstable at room temperature and
were prepared at ꢁ78 ꢀC and ꢁ40 ꢀC, respectively. The crude 1H
NMR showed all peaks corresponding to a phenyliodonium ylide,
but after keeping the samples for as little as 15 min at room tem-
perature, decomposition of these ylides to form cyclopropanes as
well as dimerization products were seen.
3
4
5
R1¼H, R2¼H
46c
46d
46e
8 min
6 min
30 min
80
68
54
R1¼CH3, R2¼H
R1¼CH3, R2¼CH3
6
8 h
95

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R.M. Moriarty et al. / Tetrahedron 66 (2010) 5801e5810
using 1H NMR: a 10 mg sample was placed in an NMR tube and
0.8 mL of dry CDCl3 was added. The 1H NMR spectra were
recorded at room temperature at 1-h intervals for 3 h. Figure 6
shows a complete conversion of starting material to cyclopro-
pane product with a negligible amount of side products.
a carbene transition state 58, which could be generated by thermal
cleavage of CeI bond of between ylidic carbon and iodobenzene.
2.2.1. Carbene pathway. It is well documented that the copper-cat-
alyzed, inter as well intramolecular cyclopropanation of phenyl-
Figure 6.
2.2. Mechanism of metal-free intramolecular
cyclopropanation
iodonium ylides, involves formation of reactive copper-carbenoids.46
A similar kind of reactivity is expected if non-metal reactions proceed
via a free carbene intermediate. Camacho et al. showed that the dis-
sociation of iodineecarbon bond to generate a free carbene has a high
activation energy and occurs only at elevated temperatures.41 When
the intermolecular cyclopropanation of iodonium ylides generated
from dimedone and various alkenes (cyclohexene, styrene, etc.) was
attempted, only 1,4-phenyl migration 64 along with dimerization of
Theoretically there are four possible routes for metal-free intra-
molecular cyclopropanation: (a) carbene, (b) ionic, (c) radical, and (d)
concerted (Scheme 10). The reaction may involve a four-membered
iodocyle 62 that can be formed via ionic 59, radical 60, or in a sigma-
tropic fashion 61. Another possibility is that the reaction may involve

R.M. Moriarty et al. / Tetrahedron 66 (2010) 5801e5810
5807
a) Carbene
O
O
O
O
58
b) Ionic
O
I
O
Ph
59
O
O
I
Ph
O
c) Radical
O
O
O
O
57
O
O
I
I
O
O
Ph
Ph
O
63
60
62
d) Concerted
O
I
O
Ph
O
61
Scheme 10.
ylide 65 was observed (Scheme 11). Only intramolecular reactions
with fixed carbon chain length afforded cyclopropanation in good
yields (Table 3). However, when the same reaction was carried out in
the presence of Rh(II), substituted cyclopropane 66 (Scheme 11) was
obtained in very good yields.
be obtained when these iodonium ylides were heated with hy-
drogen peroxide. Again, the absence of any rearranged products
that could possibly arise from a rearrangement of free radicals in-
dicates that reaction may not involve free radical intermediates.
2.2.4. Sigmatropic pathway. Although, there is now no concrete
mechanistic proof available to show that the reaction is sigmatropic
in nature, conformational rigidity (entropy) appears to be playing
an important role in the reaction. When substrates with a double
bond one carbon away or closer to the reaction center were
attempted, the reaction failed to provide cyclopropanes, and only
dimers or phenyl migration products were obtained. It is plausible
to assume that the reaction may be proceeding through a well or-
ganized transition state. Taking into account all of the above ob-
servations, it is likely that a concerted [2þ2] cycloaddition of the
alkene to the carboneiodine double bond, to form a four-mem-
bered iodocyle followed by reductive elimination of iodobenzene is
likely to be actual mechanism. Four-membered iodocyles have also
been reported in literature.49
Scheme 11.
Based on the above observations, the probability of involvement
of the free carbene intermediate is highly unlikely.
2.2.2. Ionic pathway. The second possibility is that reaction may be
3. Conclusion
occurring via
a stepwise ionic route. The metal-free cyclo-
propanation of ylides 46aee was carried out in a variety of solvents
including THF, DCM, chloroform, DMF, acetonitrile, etc., and there
was no significant effect of the polarity of the solvent on either the
yields of product or the rate. An ionic pathway would involve the
nucleophilic attack of the double bond on the electron deficient io-
dine atom along with formation of carbocation. It is well known that
rate of alkyl and hydride shifts in bicyclic systems is faster than other
reactions.47 However, in the case of phenylidonium ylide 57, none of
expected WagnereMeerwein rearrangement products was ob-
served.48 Also, we didn’t observe any [3þ2] cycloaddition product,
which potentially could result from the zwitterionic form of ylides.
These observations strongly suggest the absence of ionic pathway.
Cyclopropanes are very valuable to organic chemists and offer an
exploitable synthon for the construction a variety of biologically
active compounds. We have productively pursued a metal-free, en-
vironmentally friendly route for the synthesis of cyclopropanes and
the reaction mechanism was studied in detail using various control
experiments. A salient feature of the non-metal route is that it works
efficiently for conformationally rigid systems. Out of many possible
reaction pathways, a carbene pathway is categorically ruled out. A
more detailed study of the mechanism is a work in progress in our
lab that involves DFTcalculations and optimization studies to further
develop a stereoselective non-metal route for the synthesis of cy-
clopropanes. Undoubtedly, these results open a path for the less
stable, but often more reactive, chloronium and bromonium ylides to
develop intermolecular metal-free cyclopropanation.
2.2.3. Radical pathway. The third possibility is that the reaction
may involve free radicals that could be generated by homolytic
cleavage of the carboneiodine double bond with visible light. To
check the affect of light on the reaction, we conducted the cyclo-
propanation in the dark, but the reaction proceeded with same ease
as it did under visible light. Also, the ESR spectrum of phenyl-
idonium ylides failed to show any signal to indicate the presence of
unpaired electrons, even at high temperatures. Signals could only
4. Experimental section
4.1. General
NMR spectra were recorded on a Bruker Avance DRX-500
(500 MHz) or DPX-400 (400 MHz) instrument at 25 ꢀC. Column

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R.M. Moriarty et al. / Tetrahedron 66 (2010) 5801e5810
chromatography was carried out using Silicycle Silica-P Flash silica
gel (40e63 m). Pre-coated silica gel plates F-254 were used for
same procedure as for 5-norbornene-2-carboxylic acid. 1H NMR
(500 MHz, CDCl3)
3H), 3.09 (d, J¼5.5 Hz, 1H), 2.63 (ddd, J¼11.2, 5.8, 2.1 Hz, 1H), 2.24
(ddt, J¼13.9, 5.8, 2.9 Hz, 1H), 2.17 (dd, J¼5.8, 2.9 Hz, 1H), 2.04e1.87
(m, 3H), 1.79e1.69 (m, 1H), 1.69e1.58 (m, 2H), 1.58e1.47 (m, 1H). 13C
m
d
4.31 (s, 1H), 4.25 (dd, J¼3.9, 2.1 Hz, 1H), 3.72 (s,
thin-layer analytical chromatography. All reactions were done un-
der positive pressure of argon unless otherwise stated. Acetonitrile
was dried by refluxing over calcium hydride; dichloromethane was
dried by refluxing over CaH2. NMR solvents (Cambridge Isotopes
Laboratories) were used without purification. Melting points were
recorded on a Fisher Johns apparatus and are uncorrected. FTIR
spectra were recorded using thin film over KBr pellets on a Varian
1000 FTIR instrument at 25 ꢀC. LRMS (ESI) of all new compounds
were recorded on a Thermo-Finnigan LTQ FT spectrometer and
(FAB) LRMS was recorded on JEOL GCMATE II spectrometer.
NMR (126 MHz, CDCl3)
d 178.02, 81.89, 52.69, 39.49, 38.31, 35.62,
35.39, 29.37, 24.46, 21.28.
4.3. Preparation of
b
-ketoesters52
All -ketoesters were prepared by using following representa-
b
tive procedure.
4.2. Preparation of acid chlorides
4.3.1. Methyl-3-(bicyclo[2.2.1]hept-5-en-2-yl)-3-oxopropanoate
(56a). To the solution of 2.79 g (17.4 mmol) of Meldrum’s acid in
11.8 mL of dry pyridine and 25 mL of dry dichloromethane at 0 ꢀC
was slowly added the solution of above acid chloride in 30 mL of
dry dichloromethane. Stirring was continued for 2 h at room tem-
perature. The resulting blood red colored reaction mixture was
diluted with 50 mL of dichloromethane and was washed with 4 N
HCl followed by water and brine. After drying over anhydrous
Na2SO4, the solvent was removed under reduced pressure and the
Acid chlorides were prepared by using Scheme 8 or by using
known literature procedures.50,51 Separation of endo and exo-iso-
mer was done by the reported procedures.48
4.2.1. 5-Iodo-bicyclo[2.2.1]hept-5-ene-2-lactone (52a). To the mix-
ture of endo and exo-norbornenecarboxylic acid (Scheme 8) 3 g
(21 mmol) in 64 mL of 5% aqueous NaHCO3 solution were added 6 g
(27 mmol) of iodine and 11 g (67 mmol) of potassium iodide. The
resulting dark brown mixture was stirred overnight at room tem-
perature. The reaction mixture was extracted with chloroform
(100 mLꢂ5). The organic layer was washed with aqueous NaHCO3
solution and with aqueous sodium thiosulfate solution to remove
the excess iodine. Sodium salt of exo-isomer was removed by
washing organic layer with NaHCO3 and water. The colorless or-
ganic layer was then washed with brine and dried over anhydrous
sodium sulfate. The organic layer was concentrated and iodo-
lactone was purified using column chromatography to obtain 4.75 g
of iodolactone 52a as colorless oil (2:8, EtOAc/hexanes) (83%). 1H
residue was refluxed in dry methanol for 8 h. The crude b-ketoester
56a was purified using flash column chromatography using 1:9
EtOAc/hexanes mixture to yield 1.8 g of colorless oil (60% over two
steps). 1H NMR (500 MHz, CDCl3)
d 5.77e5.72 (m, 1H), 5.59e5.50
(m, 1H), 3.76 (s, 3H), 3.48 (s, 2H), 2.72e2.65 (m, 1H), 2.57e2.53 (m,
2H), 1.95e1.93 (m, 2H), 1.88e1.86 (m, 1H), 1.72e1.70 (m, 1H),
1.53e1.45 (m, 1H), 1.36e1.28 (m, 1H), 1.28e1.20 (m, 1H). 13C NMR
(126 MHz, CDCl3) d 198.8, 168.25, 130.6, 128.2, 52.5, 49.2, 32.1, 29.5,
28.0, 24.1, 21.7. IR: nmax (neat)/cmꢁ1 (KBr) 3019, 2977, 2844, 1747,
1716, 1649, 1628, 1406, 1317, 993. ESI (LRMS): MþNa: 217.17.
NMR (400 MHz, CDCl3)
d 5.12 (s, 1H), 3.88 (s, 1H), 3.19 (s, 1H), 2.72
(s, 1H), 2.57 (dd, J¼7.1, 3.9 Hz, 1H), 2.37 (d, J¼9.9 Hz, 1H), 2.07 (ddd,
4.3.2. Methyl-3-(bicyclo[2.2.2]oct-5-en-2-yl)-3-oxopropanoate
J¼13.6, 11.3, 3.9 Hz, 1H), 1.94e1.73 (m, 3H). 13C NMR (101 MHz,
(56b). The crude
b-ketoester was purified using flash column
CDCl3)
d
179.7, 89.4, 47.2, 47.0, 37.8, 37.9, 34.9, 30.2. ESI (LRMS):
chromatography using 1:9 EtOAc/hexanes mixture to yield 0.65 g of
MþNa: 287.12.
colorless oil (80% over two steps). 1H NMR (500 MHz, CDCl3)
d
6.30e6.24 (m, 1H), 6.08 (t, J¼7.3 Hz, 1H), 3.70 (s, 3H), 3.45 (s, 2H),
4.2.2. Bicyclo[2.2.1]hept-5-ene-2-carboxylic acid (54a). To the so-
lution of 4.7 g (17 mmol) iodolactone 52 in 30 mL of anhydrous
methanol, 1.74 g (27 mmol) of activated zinc powder was added.
The resulting suspension was stirred for 3 h at room temperature.
The reaction mixture was filtered over Celite and solvent was
concentrated. To the residue 30 mL of 1:1 mixture of dichloro-
methane and water was added and the mixture was acidified to
pH¼2 using aqueous HCl followed by extraction with dichloro-
methane (20 mLꢂ3). The organic layer was washed with water and
brine and dried over anhydrous Na2SO4. After removal of solvent,
1.89 g of foul smelling, colorless oil was obtained (77%). ESI (LRMS):
MþNa: 161.08.
2.92e2.85 (m, 1H), 2.85e2.76 (m, 1H), 2.60 (dt, J¼6.5, 2.8 Hz, 1H),
1.68e1.62 (m, 2H), 1.62e1.55 (m, 1H), 1.53e1.45 (m, 1H), 1.36e1.28
(m, 1H), 1.28e1.20 (m, 1H). 13C NMR (126 MHz, CDCl3)
d 203.8,
168.2, 135.7, 131.2, 51.5, 47.6, 32.2, 29.8, 28.9, 26.1, 24.7. IR: nmax
(neat)/cmꢁ1 (KBr) 3061, 2944, 2865, 1749, 1710, 1653, 1623, 1436,
1324, 1261, 1151, 1091. ESI (LRMS): MþNa: 231.24.
4.3.3. Methyl-3-(cyclohex-3-enyl)-3-oxopropanoate
crude -ketoester was purified using flash column chromatography
using 1:9 EtOAc/hexanes mixture to yield 1.7 g of colorless oil (68%
over two steps). 1H NMR (400 MHz, CDCl3)
5.74e5.65 (m, 2H),
(56c). The
b
d
3.73 (s, 3H), 3.54 (s, 2H), 2.85e2.58 (m, 1H), 2.31e2.24 (m, 1H), 2.18
(dt, J¼3.7, 2.4 Hz, 1H), 2.10 (tdd, J¼14.3, 8.5, 5.9 Hz, 2H), 2.03e1.94
(m, 1H), 1.58 (dddd, J¼13.0, 11.3, 9.5, 6.6 Hz, 1H). 13C NMR (101 MHz,
4.2.3. Bicyclo[2.2.1]hept-5-ene-2-carbonyl chloride (55a). A solu-
tion of 2.57 g (17 mmol) endo 5-norbornene-2-carboxylic acid in
20 mL of thionyl chloride was stirred at 60 ꢀC for 1 h. After removal
of excess thionyl chloride under reduced pressure, the crude
product was obtained in 85% yield and was used for next reaction
without further purification.
CDCl3)
d 205.8, 168.2, 127.1, 125.4, 125.3, 52.7, 47.5, 47.2, 26.9, 25.2,
24.9, 24.7. IR: nmax (neat)/cmꢁ1 (KBr) 3052, 2952, 2850, 1749, 1716,
1650, 1627, 1436, 1405, 1322, 1241, 1153, 1006. ESI (LRMS): MþNa:
205.17.
4.3.4. Methyl-3-(3-methylcyclohex-3-enyl)-3-oxopropanoate (56d).
4.2.4. Bicyclo[2.2.2]oct-5-ene-2-carbonyl chloride (55b). To the 1.3 g
(17 mmol) of cyclohexadiene were added 0.5 g (5.6 mmol) of
acryloyl chloride and catalytic amount of propylene oxide and re-
action mixture was stirred at room temperature for 24 h in dark.
Excess cyclohexadiene was removed under reduced pressure. The
crude 1H NMR showed quantitative conversion with endo isomer as
major product. Separation of endo and exo-isomer was done using
The crude b-ketoester was purified using flash column chroma-
tography using 2:8 EtOAc/hexanes mixture to yield 0.81 g of col-
orless oil (71.2% over two steps). 1H NMR (500 MHz, CDCl3)
d
5.47e5.33 (m,1H), 3.75 (s, 3H), 3.55 (s, 2H), 2.67 (dddd, J¼11.2, 8.7,
6.4, 2.5 Hz, 1H), 2.29e2.15 (m, 2H), 2.12e1.92 (m, 3H), 1.73e1.52 (m,
4H). 13C NMR (126 MHz, CDCl3)
205.9, 168.2, 134.3, 119.3, 52.7,
47.6, 47.2, 29.7, 27.3, 25.1, 23.7. IR: nmax (neat)/cmꢁ1 (KBr) 3044,
d

R.M. Moriarty et al. / Tetrahedron 66 (2010) 5801e5810
5809
2927, 2838, 1749, 1710, 1652, 1623, 1438, 1322, 1234, 1155, 1022. ESI
(LRMS): MþNa: 219.17.
(500 MHz, CDCl3)
d
7.75 (dt, J¼3.0, 1.7 Hz, 2H), 7.55e7.49 (m, 1H),
7.42e7.35 (m, 2H), 5.76e5.70 (m, 1H), 5.70e5.65 (m, 1H), 3.93 (tdd,
J¼11.5, 5.0, 2.7 Hz, 1H), 3.65 (s, 3H), 2.34e2.25 (m, 1H), 2.24e2.05
(m, 2H), 1.94e1.86 (m, 1H), 1.68 (ddd, J¼24.0, 11.5, 5.5 Hz, 1H). 13C
4.3.5. Methyl-3-(3,4-dimethylcyclohex-3-enyl)-3-oxopropanoate
(56e). The crude
chromatography using 1:9 EtOAc/hexanes mixture to yield .65 g of
colorless oil (80% over two steps). 1H NMR (500 MHz, CDCl3)
3.76
b
-ketoester was purified using flash column
NMR (126 MHz, CDCl3) d 192.7, 132.8, 131.4, 131.2, 126.6, 126.4,
109.6, 51.6, 40.6, 28.8, 26.9, 25.6. IR: nmax (neat)/cmꢁ1 (KBr) 2982,
2933, 1648, 1567, 1542, 1461, 1423, 1368, 1316, 1280, 1174, 1089,
1024. FAB (LRMS): MþH: 385.12.
d
(s, 3H), 3.55 (s, 2H), 2.71 (dddd, J¼11.4, 10.3, 5.3, 2.9 Hz, 1H),
2.28e2.14 (m, 1H), 2.13e2.00 (m, 3H), 2.00e1.92 (m, 1H), 1.65 (s,
3H), 1.60 (s, 3H), 1.61e1.51 (m, 1H). 13C NMR (126 MHz, CDCl3)
4.4.4. Methyl-3-(3-methylcyclohex-3-enyl)-2-phenyliodonio-3-ox-
d
205.8, 168.2,125.8, 124.1, 52.7, 48.2, 47.6, 33.2, 31.4, 25.5, 19.4, 19.2.
opropanoate (51d). Pale yellow solid (75%). Mp 96e97. 1H NMR
IR: nmax (neat)/cmꢁ1 (KBr) 3052, 2952, 2850, 1749, 1716, 1650, 1627,
1436, 1405, 1322, 1241, 1153, 1006. ESI (LRMS): MþNa: 233.24.
(400 MHz, CDCl3)
d
7.81e7.71 (m, 2H), 7.53 (t, J¼7.4 Hz, 1H),
7.47e7.36 (m, 2H), 5.43 (s, 1H), 3.86 (tdd, J¼19.3, 9.6, 7.1 Hz, 1H),
3.66 (s, 3H), 2.31e2.20 (m, 1H), 2.19e2.07 (m, 2H), 2.06e1.86 (m,
2H), 1.79e1.70 (m, 2H), 1.66 (s, 3H). 13C NMR (101 MHz, CDCl3)
4.3.6. Methyl-4-(cyclopent-2-enyl)-3-oxobutanoate
crude -ketoester was purified using flash column chromatography
using 1:9 EtOAc/hexanes mixture to yield 0.65 g of colorless oil
(60% over two steps). 1H NMR (400 MHz, CDCl3)
(56f). The
b
d 193.5, 165.3, 133.8, 133.2, 131.9, 131.6, 121.0, 112.8, 52.1, 41.1, 30.9,
29.5, 27.7, 24.0. IR: nmax (neat)/cmꢁ1 (KBr) 2942, 2913, 1658, 1563,
1548, 1469, 1432, 1375, 1336, 1284, 1182, 1079, 1054. FAB (LRMS):
MþH: 399.24.
d
5.74 (ddd, J¼5.5,
4.4, 2.2 Hz, 1H), 5.62 (dq, J¼5.6, 2.1 Hz, 1H), 3.72 (s, 3H), 3.44 (s, 2H),
3.09 (dtdd, J¼8.4, 6.5, 4.3, 2.1 Hz, 1H), 2.58 (qd, J¼17.1, 7.2 Hz, 2H),
2.37e2.24 (m, 2H), 2.19e2.06 (m, 1H), 1.36 (ddt, J¼12.8, 8.8, 6.3 Hz,
4.4.5. Methyl-3-(3,4-dimethylcyclohex-3-enyl)-2-phenyliodonio-3-
1H). 13C NMR (101 MHz, CDCl3)
d
202.6, 168.0, 133.9, 131.9, 89.8,
oxopropanoate (51e). Unstable yellow gummy solid (60%). 1H NMR
52.7, 49.7, 49.5, 41.0, 32.2, 30.1. IR: nmax (neat)/cmꢁ1 (KBr) 3052,
2952, 2850, 1749, 1716, 1650, 1627, 1436, 1405, 1322, 1241, 1153,
1006. ESI (LRMS): MþNa: 205.22.
(500 MHz, CDCl3)
d
7.76 (d, J¼7.6 Hz, 1H), 7.52 (t, J¼7.4 Hz, 1H), 7.38
(t, J¼7.8 Hz, 1H), 3.89 (tdd, J¼11.5, 5.0, 2.7 Hz, 1H), 3.64 (s, 2H),
2.34e2.20 (m, 1H), 2.17 (s, 1H), 1.98 (dd, J¼37.5, 14.4 Hz, 2H), 1.85
(dd, J¼7.5, 5.1 Hz,1H),1.70e1.55 (m, 5H). 13C NMR (126 MHz, CDCl3)
4.4. Preparation of phenyliodonium ylides
d 168.2, 135.8, 131.4, 131.1, 130.5, 125.0, 119.9, 74.7, 51.5, 43.5, 35.1,
32.1, 31.5, 27.7, 22.6, 19.0, 18.8. IR: nmax (neat)/cmꢁ1 (KBr) 2917,
Phenyliodonium ylides were prepared by using modified
schank’s procedure. To the solution of 1.2 g (21 mmol) in 15 mL of
2854, 1658, 1548, 1471, 1432, 1373, 1340, 1288, 1182, 1054, 1012.
methanol was added a solution of
b
-ketoester 1.17 g (7 mmol) in
4.4.6. Methyl-4-(cyclopent-2-enyl)-2-phenyliodonio-3-oxobutanoate
5 mL of dry methanol at ꢁ10 ꢀC at a rate so that internal temper-
ature did not rise above 0 ꢀC. The turbid reaction mixture was
stirred at same temperature for 20 min before addition of 1.94 g
(7 mmol) solid IBD in one portion. The reaction mixture was stirred
for 2 h at 0 ꢀC in dark. A white solid precipitated from the yellow
mother liquor. The reaction was quenched with ice/water mixture
(Sometimes precipitation occurs after addition of ice/water mix-
ture.). The solid was filtered and dried in dark and crystallized using
DCM/hexanes mixture.
(43)28. White solid (93%). Mp 119e120 ꢀC (dec). 1H NMR (500 MHz,
CDCl3)
d
7.77 (dt, J¼2.9,1.7 Hz,1H), 7.56e7.48 (m,1H), 7.45e7.33 (m,
1H), 5.76e5.66 (m, 1H), 3.65 (s, 2H), 3.24e3.14 (m, 1H), 3.06 (d,
J¼7.3 Hz,1H), 2.36 (dddd, J¼16.6, 9.0, 5.0, 2.7 Hz, 1H), 2.31e2.20 (m,
1H), 2.13e1.98 (m, 1H). 13C NMR (126 MHz, CDCl3)
d 188.8, 165.2,
135.2, 132.8, 131.4, 131.2, 130.2, 112.5, 51.6, 43.5, 43.2, 31.8, 29.7. IR:
nmax (neat)/cmꢁ1 (KBr) 2977, 2854, 1662, 1554, 1484, 1432, 1377,
1363, 1279, 1172, 1066. FAB (LRMS): MþH: 385.06.
4.5. Intramolecular metal-free cyclopropanation of
unsaturated phenyliodonium ylides
4.4.1. Methyl-3-(bicyclo[2.2.1]hept-5-en-2-yl)-2-phenyliodonio-3-
oxopropanoate (51a)28. White solid (80%). Mp 98e100 ꢀC (dec). 1H
NMR (400 MHz, CDCl3)
d
7.79e7.70 (m, 2H), 7.57e7.48 (m, 1H),
Intramolecular metal-free cyclopropnation was achieved by
using following general procedure: 50 mg of phenyliodonium ylide
was dissolved in 3 mL dry DCM under argon to obtain a dark yellow
color solution. The reaction mixture was stirred at room tempera-
ture till the solution became colorless (3 h). Solvent was evaporated
and product was purified using flash column chromatography
25:75 (EtOAc/hexanes).
7.44e7.35 (m, 2H), 6.20 (dd, J¼5.6, 3.1 Hz, 1H), 5.80 (dd, J¼5.6,
2.8 Hz, 1H), 4.25e4.15 (m, 1H), 3.69 (s, 3H), 3.30 (s, 1H), 2.89 (s, 1H),
1.89 (ddd, J¼11.4, 9.1, 3.7 Hz, 1H), 1.69e1.52 (m, 1H), 1.47e1.32 (m,
1H). 13C NMR (101 MHz, CDCl3)
d 165.4, 137.5, 133.1, 132.5, 131.8,
131.5, 51.9, 50.5, 47.7, 45.7, 43.5, 30.5, 25.6. IR: nmax (neat)/cmꢁ1
(KBr) 3054, 2966, 2863, 1641, 1563, 1471, 1430, 1363, 1336, 1299,
1270, 1182, 1064, 1041. FAB (LRMS): MþH: 397.22.
4.5.1. 1,3-Methanocyclopropa-pentalene-2
hexahydro-2-oxo-, methyl ester (46a)29. Oil (95%). 1H NMR
(500 MHz, CDCl3)
a(2H)-carboxylic
acid,
4.4.2. Methyl-3-(bicyclo[2.2.2]oct-5-en-2-yl)-2-phenyliodonio-3-ox-
opropanoate (51b). Highly unstable pale yellow gummy solid im-
mediately started decomposing at room temperature to give oil
d
3.74 (s, 3H), 3.10 (dd, J¼7.5, 4.2 Hz, 1H),
2.86e2.77 (m, 2H), 2.64 (s, 1H), 2.46 (dd, J¼8.5, 5.0 Hz, 1H), 2.06 (d,
(69%). 1H NMR (500 MHz, CDCl3)
d
7.72 (d, J¼7.3 Hz, 1H), 7.51 (t,
J¼9.1 Hz, 1H), 1.90e1.70 (m, 1H), 1.60e1.51 (m, 1H). 13C NMR
J¼6.8 Hz, 1H), 7.38 (t, J¼7.6 Hz, 1H), 6.30 (t, J¼7.3 Hz, 1H), 6.16 (t,
J¼7.0 Hz, 1H), 4.00e3.89 (m, 1H), 3.65 (s, 2H), 2.79 (s, 1H), 2.57 (s,
1H), 1.84 (t, J¼11.0 Hz, 1H), 1.74 (d, J¼10.9 Hz, 1H), 1.67 (s, 1H),
(126 MHz, CDCl3) d 167.3, 52.6, 50.3, 47.5, 46.3, 46.0, 44.5, 42.6, 37.7,
36.7. IR: nmax (neat)/cmꢁ1 (KBr) 2933, 2821, 1760, 1732, 1654, 1431,
1342, 1259, 1222, 1080. ESI (LRMS): MþNa: 215.23.
1.59e1.50 (m, 1H), 1.26 (s, 2H). 13C NMR (126 MHz, CDCl3)
d 164.8,
133.9, 132.7, 132.2, 131.3, 131.0, 51.4, 44.2, 34.4, 31.8, 30.1, 26.5, 24.2.
IR: nmax (neat)/cmꢁ1 (KBr) 2993, 2974, 1659, 1556, 1532, 1456, 1416,
1357, 1305, 1269, 1147, 1079, 1031.
4.5.2. 1,3-Methanocyclopropa-hexalene-2
hexahydro-2-oxo-, methyl ester (46b). Oil (55%). 1H NMR (500 MHz,
CDCl3) 3.78 (s, 3H), 2.74e2.66 (m, 2H), 2.53e2.38 (m, 1H),
2.32e2.20 (m, 2H), 1.88 (ddd, J¼13.4, 6.1, 1.9 Hz, 1H), 1.80e1.61 (m,
5H). 13C NMR (126 MHz, CDCl3)
206.1, 169.1, 52.6, 45.7, 40.8, 37.5,
36.7, 34.9, 27.3, 27.1, 23.1, 18.2. IR: nmax (neat)/cmꢁ1 (KBr) 2933,
a
(2H)-carboxylic
acid,
d
4.4.3. Methyl-3-(cyclohex-3-enyl)-2-phenyliodonio-3-ox-
d
opropanoate (51c). Pale yellow solid (83%). Mp 115e116 ꢀC. 1H NMR

5810
R.M. Moriarty et al. / Tetrahedron 66 (2010) 5801e5810
2. Salaun, J. The Chemistry of the Cyclopropyl Group; Wiley: New York, NY, 1987;
Vol. 2; p 809.
3. Gerwick, W. H.; Proteau, P. J.; Nagle, D. G.; Hamel, E.; Blokhin, A.; Slate, D. L.
2821, 1760, 1732, 1654, 1431, 1342, 1259, 1222, 1080. ESI (LRMS):
MþNa: 229.10.
J. Org. Chem. 1994, 59, 1243e1245.
4. Ito, H.; Imai, N.; Tanikawa, S.; Kobayashi, S. Tetrahedron Lett. 1996, 37,
1795e1798.
4.5.3. 1,3-Methanocyclopropa-2
a
(2H)-carboxylic acid, hexahydro-2-
oxo-, methyl ester (46c). Oil (80%). 1H NMR (500 MHz, CDCl3)
d
3.76
5. Graham, D. W.; Wallace, T.; Barash, L.; Brown, J. E.; Brown, R. D.; Canning, L. F.;
Chen, A.; Springer, J. P.; Rogers, E. F. J. Med. Chem. 1987, 30, 1074e1090.
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3664e3669.
(s, 3H), 2.83 (dd, J¼7.8, 3.7 Hz, 1H), 2.63 (d, J¼7.9 Hz, 2H), 2.32e2.21
(m, 2H), 2.16e2.06 (m, 2H), 2.05e1.83 (m, 2H). 13C NMR (126 MHz,
CDCl3)
d 208.1, 168.8, 53.4, 52.2, 42.9, 39.6, 37.4, 29.8, 26.3, 16.3. IR:
nmax (neat)/cmꢁ1 (KBr) 2948, 2871, 1756, 1733, 1716, 1436, 1348,
1257, 1213, 1078. ESI (LRMS): MþNa: 203.10.
8. Seo, Y.; Cho, K. W.; Rho, J.-R.; Shin, J.; Kwon, B. M.; Bok, S.-H.; Song, J.-I. Tet-
rahedron 1996, 52, 10583e10596.
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10. Staudinger, H.; Ruzicka, L. Helv. Chim. Acta 1924, 7, 177e235.
11. Yang, S. F.; Hoffman, N. E. Annu. Rev. Plant Physiol. 1984, 35, 155e189.
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4.5.4. 1,3-Methanocyclopropa-1-Methyl-2
hexahydro-2-oxo-, methyl ester (46d). Oil (68%). 1H NMR (500 MHz,
CDCl3)
a
(2H)-carboxylic
acid,
d
3.81 (s, 3H), 2.67 (d, J¼3.9 Hz, 1H), 2.36e2.24 (m, 1H),
13. Wenkert, E. Heterocycles 1980, 14, 1703e1708.
2.12e2.03 (m, 1H), 1.98 (dddd, J¼12.9, 10.4, 5.6, 3.0 Hz, 1H),
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1.94e1.82 (m, 2H), 1.65 (t, J¼12.8 Hz, 2H), 1.24 (s, 3H). 13C NMR
(126 MHz, CDCl3)
d 52.6, 46.5, 42.1, 38.6, 29.7, 28.7, 27.4, 24.2, 20.8.
IR: nmax (neat)/cmꢁ1 (KBr) 2940, 2868, 1749, 1737, 1709, 1432, 1353,
1249, 1231, 1070. ESI (LRMS): MþNa: 217.21.
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CDCl3) 3.77 (s, 3H), 2.27e2.20 (m, 1H), 2.18e2.06 (m, 1H),
2.03e1.89 (m, 3H), 1.89e1.79 (m, 2H), 1.44 (s, 3H), 1.20 (s, 3H). 13C
a(2H)-carboxylic acid,
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17.5, 15.4. IR: nmax (neat)/cmꢁ1 (KBr) 2944, 2869, 1758, 1735, 1436,
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4.5.6. Cyclopropa-pentalene-2
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3.72 (s, 1H), 3.21e3.14 (m, 1H), 2.96e2.87 (m, 1H), 2.78e2.62 (m,
a(2H)-carboxylic acid, hexahydro-2-
d
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1.54 (dd, J¼11.9, 6.4 Hz, 1H). 13C NMR (126 MHz, CDCl3)
d 167.90,
94.32, 52.28, 49.41, 46.95, 45.78, 40.68, 40.05, 36.01, 24.76. IR: nmax
(neat)/cmꢁ1 (KBr) 2960, 2841, 1754, 1738, 1435, 1349, 1259, 1231,
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Acknowledgements
We thank KYTHERA Biopharmaceuticals, Inc. Calabasas, Cal-
ifornia, for the support of this work. We also thank Professor
Daesung Lee of this department for insightful discussions.
41. Camacho, M. B.; Clark, A. E.; Liebrecht, T. A.; DeLuca, J. P. J. Am. Chem. Soc. 2000,
122, 5210e5211.
Supplementary data
42. Gallos, J. K.; Koftis, T. V.; Massen, Z. S.; Dellios, C. C.; Mourtzinos, I. T.; Coutouli-
Argyropoulou, E.; Koumbis, A. E. Tetrahedron 2002, 58, 8043e8054.
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Structural proofs and spectral data for all new compounds are
provided. Supplementary data associated with this article can be
found in the online version, at doi:10.1016/j.tet.2010.05.005. These
data include MOL files and InChIKeys of the most important com-
pounds described in this article.
References and notes
1. De Meijere, A. Angew. Chem., Int. Ed. Engl. 1979, 18, 809e826.