Mechanistic Studies on the Base-Promoted Conversion of Alkoxy-Substituted, Ring-Fused gem-Dihalocyclopropanes into Furans: Evidence for a Process Involving Electrocyclic Ring Closure of a Carbonyl Ylide Intermediate

Article abstract of DOI:10.1021/acs.joc.8b01766

The mechanism associated with the base-promoted conversion of alkoxy-substituted and ring-fused gem-dihalocyclopropanes such as 40 into annulated furans has been explored. Treatment of compound 40 with potassium tert-butoxide affords a mixture of furans 23/27 and 41, an outcome that suggests the intermediacy of the slowly interconverting carbonyl ylides 42 and 43 that undergo rapid [1,5]-electrocyclizations and subsequent dehydrohalogenation to afford the observed products. This proposal is supported by ab initio MO and DFT calculations that also suggest a vinylcarbene insertion pathway is less likely to be operative.

Full text of DOI:10.1021/acs.joc.8b01766

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Article
Mechanistic Studies on the Base-Promoted Conversion of Alkoxy-Substituted,
Ring-Fused gem-Dihalocyclopropanes into Furans: Evidence for a Process
Involving Electrocyclic Ring Closure of a Carbonyl Ylide Intermediate
Phillip P. Sharp, Jiri Mikusek, Junming Ho, Elizabeth H. Krenske,
Martin G Banwell, Michelle L. Coote, Jas S Ward, and Anthony C. Willis
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01766 • Publication Date (Web): 03 Oct 2018
Downloaded from http://pubs.acs.org on October 4, 2018
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Mechanistic Studies on the Base-Promoted Conversion of Alkoxy-Substituted, Ring-Fused
gem-Dihalocyclopropanes into Furans: Evidence for a Process Involving Electrocyclic Ring
Closure of a Carbonyl Ylide Intermediate
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Phillip P. Sharp,a Jiri Mikusek,a Junming Ho,a,b Elizabeth H. Krenske,a Martin G. Banwell,*,a
Michelle L. Coote,a,c Jas S. Ward a and Anthony C. Willisa
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aResearch School of Chemistry, Institute of Advanced Studies
The Australian National University, Canberra, ACT 2601, Australia
bSchool of Chemistry, The University of New South Wales, Sydney, NSW 2052, Australia
cARC Centre of Excellence for Electromaterials Science
Abstract: The mechanism associated with the baseꢀpromoted conversion of alkoxyꢀ
substituted and ringꢀfused gemꢀdihalocyclopropanes such as 40 into annulated furans
has been explored. Treatment of compound 40 with potassium tertꢀbutoxide affords a
mixture of furans 23/27 and 41, an outcome that suggests the intermediacy of the
slowly interconverting carbonyl ylides 42 and 43 that undergo rapid [1,5]ꢀ
electrocyclisations and subsequent dehydrohalogenation to afford the observed
products. This proposal is supported by ab initio MO and DFT calculations that also
suggest a vinylcarbene insertion pathway is less likely to be operative.
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Introduction
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gemꢀDihalocyclopropanes are readily prepared by addition of the relevant dihalocarbene to
the corresponding alkene1 and we have demonstrated that these kinetically stable but distinctly
strained threeꢀmembered carbocycles are useful building blocks in natural products synthesis.2
In one aspect of our activities in this area, we reported that treatment of compound 1 (Figure
1) with potassium tertꢀbutoxide in THF affords the ringꢀcleaved product 2 (56% at 87%
conversion), the structure of which was established by singleꢀcrystal Xꢀray analysis.3 We have
since used this ringꢀcleavage reaction in the assembly of tetracyclic frameworks related to the
gibberellins.4 However, before seeking to apply this rather unusual process more extensively,
we sought to develop an understanding of its mechanism.
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Figure 1: Starting alkoxyꢀsubstituted and ringꢀfused gemꢀdichlorocyclopropane 1 and the
derived, baseꢀinduced elimination product 2
The working hypothesis we established is shown in Scheme 1 and involves an initial baseꢀ
promoted elimination of the elements of HCl from substrate 1 so as to form the ringꢀfused
cyclopropene 3. The regioselectivity associated with this first step may be attributed to a
directed orthoꢀmetallation (DoM) typeꢀprocess5 whereby the methoxy group facilitates
deprotonation and concomitant kaliation at the adjacent cyclopropyl centre. The resulting
anion then engages in the second step of an E1cb process to give cyclopropene 3, related
examples of which3 have been trapped in DielsꢀAlder cycloaddition reactions.6
Rearrangement of compound 3 to the corresponding “vinylcarbene” 4 might be expected7 and
this latter species could then undergo a proton transfer reaction to give the carbonyl ylide 5.
The transformation 4 → 5 accounts for the Eꢀconfiguration about the exocyclic double bond
within the final product (2) that would be formed by a proton transfer within intermediate 5.
This same conversion also suggests that the zwitterionic species 4B is the major contributor to
the associated resonance hybrid.
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Scheme 1: Possible reaction pathway associated with the baseꢀpromoted conversion of the
alkoxyꢀsubstituted and ringꢀfused gemꢀdichlorocyclopropane 1 into diene 2.
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As part of an effort to intercept such proposed carbonyl ylide intermediates, the baseꢀ
promoted reaction of a substrate incapable of engaging in a final proton transfer was
investigated.8 To this end, the dichlorocarbene adduct, 6 (Figure 2), of 1ꢀmethoxyꢀ3,4ꢀ
dihydronaphthalene was treated with potassium tertꢀbutoxide in THF and the annulated furan
7 thus obtained in 72% yield. The ethoxyꢀequivalent, 8, of compound 6 was converted into the
corresponding C2ꢀmethylated furan 9 (88%) under the same conditions. Such conversions
provide a useful method for forming annulated furans and one that we have exploited in the
total synthesis of the racemic modification of the furanosesquiterpene pallescensin A.8
Figure 2: Alkoxyꢀsubstituted and ringꢀfused gemꢀdichlorocyclopropanes 6 and 8 and the
derived, annulated furans 7 and 9
Two reaction pathways can be envisaged to account for the conversions 6 → 7 and 8 → 9.
The first of these (Scheme 2) would involve initial baseꢀpromoted elimination of the elements
of HCl from substrate 6 or 8 and rearrangement of the resulting cyclopropene, 11 and 12
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respectively to the corresponding vinylcarbene 13 or 14. Insertion of the latter species into one
of the CꢀH bonds of the pendant alkoxyꢀgroup would give the chlorodihydrofuran 15 or 16
that then loses the elements of a second equivalent of HCl to afford the observed and fully
aromatic heterocycle 7 or 9. This pathway is closely related to that proposed by Müller and
Pautex9 to account for the baseꢀpromoted conversion of the dichlorocarbene adduct of 9ꢀ
methoxyphenanthrene into phenanthro[9,10ꢀb]furan.
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Scheme 2: The vinylcarbene CꢀH insertion pathway leading from cyclopropanes 6 and 8 to
the annulated furans 7 and 9
An alternate reaction pathway that seems more consistent with the one proposed for the
conversion 1 → 2 is shown in Scheme 3. Thus, as with the pathway proposed immediately
above, this also involves initial formation of cyclopropene 11 or 12 and the subsequent
conversion of these into the corresponding vinylcarbenes 13A and 14A, respectively. These
can each be represented in the corresponding zwitterionic forms 13B and 14B. Now, rather
than participating in a carbene insertion reaction, these latter species undergo intermolecular
proton transfer to give the carbonyl ylides 17 and 18 that then engage in 6πꢀelectron
electrocyclic ring closures {[1,5]ꢀelectrocyclisation}10 to give the chlorodihydrofurans 15 and
16 that lose the elements of HCl to give the observed products 7 and 9, respectively. The
intervention of the electrocyclisation process in the present cases is the consequence of a lack
of a protonꢀtransfer pathway available to ylides 17 and 18 (but which is available to congener
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5 and which is presumably the faster of the two processes in that particular case). When
various 1,3ꢀdipolarophiles (e.g. parent furan) were added to such reaction mixtures no adducts
arising from the trapping of carbonyl ylides were observed, mostly likely because of the
significant kinetic advantage of the available intramolecular reaction pathways.
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Scheme 3: The carbonyl ylide pathway leading from cyclopropanes 6 and 8 to the
corresponding annulated furans 7 and 9
The objective of the present work was to establish the validity or otherwise of the mechanistic
proposals shown in Schemes 2 and 3. These studies were of both a theoretical and
experimental nature. Details are presented in the following section.
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Results and Discussion
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Theoretical Studies
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Highꢀlevel quantum chemical calculations were performed (see Experimental Section for
details) to determine the transition state energies for the carbene insertion (13A → 15), the
proton transfer (13B → 17) and the electrocyclic ring closure steps (17 → 15) shown in
Schemes 2 and 3. In all cases, conventional attempts to locate a transition state for CꢀH
insertion with B3LYP were unsuccessful. Instead, the formation of the dihydrofuran appears
to take place in two steps with initial proton transfer to form 17 followed by an electrocyclic
ringꢀclosure to form dihydrofuran 15. In that portion of the reaction sequence leading from
zwitterion 13B to dihydrofuran 15, the barrier for proton transfer is rateꢀlimiting at 0 °C and
approximately 74 kJ mol–1 (inclusive of tunneling correction ꢀ tunneling lowers the barrier to
proton transfer by approximately 5 kJ mol–1). This barrier translates to a halfꢀlife of
approximately 0.3 mins, consistent with the observed conversions being complete in 2 hours
or less. The overall energy profile for this more favorable pathway is presented in Figure 3.
Clearly, then, such relatively highꢀlevel theoretical studies suggest the pathway shown in
Scheme 3 will be favored over the one shown in Scheme 2.
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Two other noteworthy features of the energetically favored pathway were revealed through
these theoretical studies. A comparison of the geometries (bond lengths and angles) as well as
calculated (NBO) atomic charges of 13A and 13B suggest that the “vinylcarbene” is better
represented in its zwitterionic form (viz. 13B). Further, the potentially competing reaction
pathway wherein ylide 17 cyclizes to form the isomeric spiroꢀepoxide was also considered
(since there is the possibility that the reaction could be “trapped” in a kinetic well as this
spiroꢀepoxide or SE – see SI for structure). The relevant calculations revealed that the barrier
to the formation the spiroꢀepoxide is about 30 kJ mol–1 higher than that associated with the
formation of the dihydrofuran 15 and is, therefore, unlikely to be kinetically competitive.
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Figure 3: Gibbs free energy profile (kJ mol–1) for the conversion of the cyclopropene 11 into
corresponding dihydrofuran 15 in THF at 0 °C (values shown are relative to ringꢀfused
cyclopropene 11). Calculations performed at the G3(MP2)ꢀRADꢀ(+)//B3LYP/6ꢀ31+G(d) level
of theory in conjunction with SMD solvent corrections.
Experimental Studies
The devising of experimental studies that would differentiate between the pathways shown in
Schemes 2 and 3 became the next focus of our efforts. Details of studies that appear to do so
are presented in the following sections.
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C-labeling
1.
Investigations of the Proposed Reaction Pathways Using
Experiments
If compound 1911 (Scheme 4) were available and would engage in the same sort of baseꢀ
promoted reaction that has been observed for congeners 6 and 8 then the two alternate
reaction pathways that might be followed in producing furan 23 are those depicted in Schemes
4 and 5. Thus, the first pathway (Scheme 4) involves the “usual” baseꢀpromoted elimination
of the elements of HCl from the substrate 19 to generate the cyclopropene 20.3,6
Rearrangement of this highly strained species to the corresponding “vinylcarbene” 21 would
then be followed by carbene insertion into one of the methylene CꢀH bonds of the pendant
OEt unit and thus affording chlorodihydrofuran 22. This loses another molecule of HCl to
give the C3ꢀmethylated furan 23. Should such a reaction sequence be carried out on a
substrate carrying a 13Cꢀlabel ( ) at the geminally dichlorinated carbon then this should
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appear, exclusively, at the illustrated (protonated) carbon, C2, of the furan ring in the product.
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Scheme 4: The conversion, via a carbeneꢀinsertion pathway, of 13Cꢀlabelled gemꢀ
dichlorocyclopropane 19 into furan 23.
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On the other hand, if the reaction pathway from substrate 19 to product 23 follows the
alternate pathway shown in Scheme 5 then a different distribution of the 13Cꢀlabel should be
observed. Thus, the carbonyl ylide 24 derived from proton transfer within intermediate 21A/B
is a pseudoꢀsymmetrical species that should be able to isomerize about the ylide subunit to
give compound 25 that only differs from its precursor by virtue of the presence of the 13Cꢀ
label. Each of compounds 24 and 25 could engage in electrocyclic ring closure reactions to
give the chlorodihydrofurans 22 and 26, respectively. This latter pair of compounds would
then lose the elements of HCl to give furans 23 and 27 differing only in the positions of the
13Cꢀlabel ( ) within the molecular framework. Thus, the two possible pathways shown in
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Schemes 4 and 5 could, in principle at least, be distinguished by the nature of the distribution
of the 13Cꢀlabel ( ) within the product furan. In particular, the carbene insertion route would
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lead to a siteꢀspecifically labeled furan whilst the protonꢀtransfer/electrocyclic ringꢀclosure
pathway might be expected to result in scrambling of the same label within the product furan.
Accordingly, the preparation of compound 19 was pursued.
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Scheme 5: The conversion, via ylide 1,5ꢀelectrocyclisation pathways, of 13Cꢀlabelled gemꢀ
dichlorocyclopropane 19 into the isotopomeric furans 23 and 27.
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Syntheses of the nonꢀlabeled form of compound 19 and its methoxyꢀsubstituted counterpart
were established using the route shown in Scheme 6. Thus, cyclohexanone (28) was converted
into 1ꢀethoxycyclohexene (29)12 under standard conditions involving initial formation of the
corresponding diethyl ketal and cracking of this at high (150 °C) temperatures. 1ꢀ
Methoxycyclohexene (30)12 was prepared by analogous means and in similar yield.
Dichlorocarbene, generated from chloroform and sodium hydroxide in the presence of a phase
transfer catalyst,13 was then added to alkenes 29 and 30 thus affording the previously reported
cyclopropanes 3114 and 326 in yields of 54% and 73%, respectively. Independent treatment of
the latter compounds with potassium tertꢀbutoxide, in the same manner as employed for
conversions such as 1 → 2, afforded the expected but rather unstable dienes 33 and 34 in
yields of 91% and 90%, respectively. Compounds 33 and 34 were immediately reacted with
dichlorocarbene and the required cyclopropanes 19 and 35 thus obtained in yields of 70% and
65%, respectively. All the spectral data derived from these materials were in accord with the
assigned structures. Definitive confirmation of these came from single crystal Xꢀray analyses
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of both the ethoxyꢀ and methoxyꢀsubstituted systems 19 and 35, respectively. Relevant data
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are presented in Experimental Section and the Supporting Information (SI).
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Scheme 6: The synthesis of the gemꢀdichlorocyclopropanes 19 and 35 from cyclohexanone
(28)
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With the unlabelled compounds 19 and 35 to hand these were subjected to reaction with
potassium tertꢀbutoxide (Scheme 7) and the expected furans 23/27 and 36 thus obtained as
clear colorless oils in 82% and 35% yields respectively. The spectral data derived from these
rather unstable materials were, once again, in complete accord with the assigned structures. As
a prelude to the foreshadowed isotopeꢀlabeling studies, various COSY and other experiments
were conducted on compound 23/27 in order to fully assign the {1H}13C NMR spectrum
(Figure 4).
Scheme 7: Baseꢀinduced conversion of the alkoxyꢀsubstituted, gemꢀdichlorocyclopropanes 19
and 35 into the corresponding annulated furans and the DielsꢀAlder adduct, 38, and its
aromatic isomer 39 derived from one of these.
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Figure 4: The 75 MHz {1H}13C NMR spectrum of the unlabelled form of compound 23/27
(recorded in C6D6)
In an effort to obtain a crystalline derivative, compound 36 was heated in toluene with an
excess of dimethyl acetylenedicarboxylate (DMAD, 37). Depending on the temperature
employed, then either the adduct, 38, arising from a DielsꢀAlder reaction, or its aromatized
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isomer 39 were obtained albeit in rather modest yields (Scheme 7). Unfortunately, and despite
many attempts, neither compound 38 or 39 could be crystallized. Efforts to effect an
analogous cycloaddition reaction between compound 23/27 and DMAD failed.
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The foregoing results indicated that the proposed 13Cꢀlabelling studies were viable.
Accordingly, the ca. 15% 13Cꢀlabelled form of substrate 19 was prepared by treating the diene
precursor 33 with 15% 13Cꢀlabelled chloroform and aqueous sodium hydroxide in the
presence of TEBAC. A comparison of the 13C NMR spectra of both the labeled and unlabeled
forms of compound 19 (both recorded in C6D6) revealed, in the spectrum of the latter material,
a ca. 13ꢀfold enhancement in the resonance at δ 70.0 which is assigned to the gemꢀ
dichlorocyclopropyl carbon C7. Reaction of the 13Cꢀlabelled substrate 19 with potassium tertꢀ
butoxide under the same conditions as described earlier resulted in the clean conversion of it
into the expected furan. 13C NMR analysis of chromatographically purified samples of this
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material (Figure 5) established that, within the limits of experimental error, the 13Cꢀlabel ( )
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had been incorporated only into that carbon giving rise to the resonance at δ 107.5 and which
had been assigned to C3.
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Figure 5: The 75 MHz {1H}13C NMR spectrum of the ca. 15% 13Cꢀlabelled compound 23
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(recorded in C6D6)
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Accordingly, the product furan is assigned as compound 23 and not an admixture of it with
isotopomer 27. On the face of it, then, this outcome is only consistent with the carbene
insertion pathway presented in Scheme 4. However, a partitioning of the label between C2 and
C9, as would be expected from operation of the pathway shown in Scheme 5, will only be
observed if the interconversion of isotopomers 24 and 25 proceeds at a rate that is competitive
with the electrocyclic ring closure of these ylides. Certainly, the theoretical calculations
detailed above suggest that the latter process has a very small/low activation enthalpy.
Interestingly, DFT calculations reveal that rotation about the ylide bond in the nonꢀlabelled
form of compound 24/25 results in spontaneous cyclization to form 26/22 and involves a free
energy barrier of 47.5 kJ mol–1. This is significantly higher than the barrier for direct
electrocyclization of 24 to form 22 which is only 9.3 kJ mol–1. Accordingly, it is conceivable
that the ylide pathway shown in Scheme 5 is operative but there is no detectable (within
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experimental error) “scrambling” of the 13Cꢀlabel ( ) because of this relatively high barrier to
•
interconversion of isotopomers 24 and 25.
2.
Investigations of the Proposed Reaction Pathway Using Halogen-labeling
Experiments
Given the results and interpretations just described, it became important to devise experiments
that could provide a capacity for more definitive detection of scrambling of label (if this was
indeed occurring). The outcomes of an experiment that does so are presented below.
Subjecting the gemꢀdibrominated analogue, 40 (Figure 6), of compound 19 to reaction with
potassium tertꢀbutoxide could produce at least two possible outcomes. The first of these,
which would be encountered if the carbene insertion pathway (see Scheme 4) were followed,
would involve the exclusive production of the previously observed chloroꢀfuran 23/27.
Figure 6: Substrate 40 and the possible products, 23/27 and 41, of its reaction with base
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In contrast, if the carbonyl ylide pathway (Scheme 8) were followed and if the initially formed
ylide 42 could rearrange to isomer 43, at least to some extent and prior to the
electrocyclisation reaction, then a mixture of chloroꢀfuran 23/27 and its bromoꢀcounterpart 41
might be observed. Even if the chlorinated system still predominated, since these two furans
are distinctly different by virtue of the variation in the nature of the associated halogen then
the presence of even rather small quantities of the brominated system 41 should be detectable
by mass spectrometric methods. DFT calculations reveal that rotation about the ylide bond in
compound 42 (to give 43) involves a free energy barrier of 48.8 kJ mol–1 while that for direct
electrocyclization (of 42) is only 11.9 kJ mol–1.
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Scheme 8: Possible outcomes of the reaction of the gemꢀdibromocyclopropane 40 with base
and involving carbonyl ylide intermediates
The requisite gemꢀdibromocyclopropane 40 was readily prepared, in 51% yield, by selective
addition of dibromocarbene to diene 33 and the structure of the product cyclopropane
confirmed by singleꢀcrystal Xꢀray analysis (see Experimental and SI for details). When
compound 40 was treated with potassium tertꢀbutoxide, under the (by now) standard
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conditions for furan formation, and the reaction mixture obtained on workꢀup subjected to
GCꢀMS analysis then the major product proved to be the expected chlorinated furan 23/27, the
70 eV EI mass spectrum of which is shown in Figure 7a. However, a chromatographically less
mobile reaction component present at the 2ꢀ3% level (relative to the major product) gave a 70
eV EI mass spectrum (Figure 7b) entirely consistent with that expected for the brominated
furan 41.
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Figure 7: (a) top: 70 eV EI mass spectrum of chlorofuran 23/27 isolated by GC from the
reaction of gemꢀdibromocyclopropane 40 with potassium tertꢀbutoxide; (b) bottom: 70 eV EI
mass spectrum of the corresponding and coꢀformed bromofuran 41
In particular, the correct pair of molecular ions is observed at m/z 226 and 228 and, as with the
analogous spectrum of congener 23/27, loss of atomic bromine results in a daughter ion with
m/z 147. The remaining fragment ions observed in the mass spectrum of bromofuran 41
parallel those observed in the equivalent spectrum of the chlorinated system 23/27 and so
strongly supporting the assigned structure. So, whilst we have not been able to isolate
compound 41 from this reaction, including by using HPLC techniques, the data just described
strongly indicate that this material has been coꢀproduced with its chlorinated analogue
(various attempts to establish an independent synthesis of compound 41, including one
involving bromomethylenation of the corresponding ketone, were unsuccessful). We take such
results as indicating that the carbonyl ylide 42 is an intermediate in the conversion 40
→ 23/27 + 41 and that this first species is partially converted into isomer 43 prior to the
electrocyclic ring closure event and thus giving rise to “scrambling” of the halogen label.
An experiment complementary to that just described would be the one shown in Scheme 9 and
wherein the compound 44 was now the substrate to be treated with base. In this case the
carbonyl ylide 43 should be formed preferentially and then undergo electrocyclization and
subsequent elimination to form the brominated furan 41 as the major product. That said, some
isomerization of ylide 43 to congener 42 could occur and thus leading to at least the coꢀ
production of small amounts of the chlorofuran 23/27.
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Scheme 9: Possible outcomes of the reaction of the gemꢀdibromocyclopropane 44 with base.
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Investigating the proposal shown in Scheme 9 necessitated the acquisition of compound 44
and the outcomes of our attempts to do so are shown in Scheme 10. Thus, dibromocarbene
addition to enol ether 29 proceeded as expected to afford the anticipated adduct 4514 (61%).
However, on treating this last compound with potassium tertꢀbutoxide diene 46 failed to form.
Rather, a 2:5 mixture of the βꢀalkoxycycloheptenones 47 and 48 was obtained in 71%
combined yield. As such the reaction pathways postulated in Scheme 9 could not be
investigated. The precise modes of formation of the unexpected products 47 and 48 from
precursor 45 remain unclear at the present time and are the subject of a separate invesitigation,
the results of which will be reported in due course.
Scheme 10: Attempted synthesis of gemꢀdichlorocyclopropane 44 via intermediate 46.
Unanticipated formation of the βꢀalkoxycycloheptenones 47 and 48.
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Conclusions
The foregoing theoretical and experimental studies provide evidence for the involvement of a
hitherto unrecognized reaction pathway associated with the baseꢀpromoted conversion of the
title cyclopropanes into furans. Whether this pathway operates in competition with the
previously proposed carbene insertion mechanism9 remains unclear although the theoretical
studies detailed here would suggest not. The potential utility of this kind of process is
highlighted by our observation that treatment of the dichlorocarbene adducts of certain
enamines with strong base leads to pyrroles,15 presumably by a reaction pathway analogous to
the one defined in Scheme 3.
Experimental Section
General Experimental Procedures
Melting points were measured on a Stanford Research Systems Optimelt – Automated
Melting Point System and are uncorrected. Proton (1H) and carbon (13C) NMR spectra were
recorded on a Bruker 800, 600, 400 or a Varian Gemini 300 NMR spectrometer. Unless
otherwise specified, spectra were acquired at 20°C in deuteroꢀchloroform (CDCl3) or ꢀ
benzene (C6D6) that had been filtered through basic alumina immediately prior to use.
Chemical shifts are recorded as δ values in parts per million (ppm). The signal due to residual
CHCl3 appearing at δH 7.26 and the central resonance of the CDCl3 “triplet” appearing at δC
77.0 were used to reference H and 13C NMR spectra, respectively. Infrared spectra (νmax
)
1
were recorded on a Perkin–Elmer 1800 Series FTIR Spectrometer and samples were analyzed
as KBr disks (for solids) or as thin films on KBr plates (for oils). Low resolution mass spectra
were recorded on a Micromass–Waters LCꢀZMD single quadrupole liquid chromatographꢀMS
or a VG Quattro II triple quadrupole MS instrument under, as specified in the individual cases
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specified below, either electron ionization (EI) or electrospray ionization (ESI) conditions.
High resolution mass spectra were recorded on a magnetic sector instrument under EI
conditions. Dichloromethane (DCM) was distilled from calcium hydride and THF was
distilled, under nitrogen, from sodium benzophenone ketyl or these same solvents were dried
using a purification system based on technology originally described by Grubbs et al.16 Where
necessary, reactions were performed under a nitrogen atmosphere. Flash chromatography was
carried out according to the protocols defined by Still et al.17
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Theoretical Studies
All electronic structure calculations were carried out using Gaussian0918 and Molpro
2009.1.19 The geometries and vibrational frequencies were obtained at the B3LYP/6ꢀ31+G(d)
level of theory. The gas phase electronic energies were obtained at the G3(MP2)ꢀRADꢀ(+)20
level of theory, where (+) signifies that calculations with the 6ꢀ31G(d) basis set has been
replaced with the 6ꢀ31+G(d) basis set so as to allow for an improved description for the
electronic structure of the zwitterionic species. The thermal corrections to the Gibbs free
o
energies were obtained using scaled harmonic frequencies21 at 0 C. The solvation free
energies in THF were computed using the SMD solvent model22 also at the B3LYP/6ꢀ
31+G(d) level of theory. The tunnelling correction to the rate of proton transfer was calculated
using the Eckart method,23 using the vibrationally adiabatic potential energy surface obtained
using the SMD solvent model at the B3LYP/6ꢀ31+G(d) level of theory. NBO atomic charges
were obtained at the B3LYP/6ꢀ311+G(3df,2p) level of theory.
Synthetic Studies
General Procedure for the Formation of gem-Dihalocyclopropanes
A mixture of finely powdered sodium hydroxide (2.40 g, 60.0 mmol) and triethylbenzyl
ammonium chloride (TEBAC) (114 mg, 0.5 mmol) was added to a vigorously stirred solution
of the corresponding alkene (10 mmol) in dichloromethane (2.5 mL) maintained at 0 °C
(ice/water bath). The relevant haloform (30 mmol) was then added, dropwise, to the reaction
mixture then the reaction vessel was fitted with a Liebig condenser and maintained under a
nitrogen atmosphere. The ice/water bath was removed and the reaction mixture thus obtained
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allowed to warm to 22 °C. A vigorous exotherm and associated foaming of the reaction
mixture was often observed after ca. 0.5 to 2 h and the ensuing darkꢀbrown slurry was cooled,
after 3 h, then filtered through a 5 cm deep pad of diatomaceous earth contained in a sintered
glass funnel. The solids thus retained were washed with dichloromethane until the washings
appeared colorless. The combined filtrates were concentrated under reduced pressure to give a
darkꢀbrown oil that was subjected to flash chromatography.
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General Procedure for the Reaction of gem-Dihalocyclopropanes with t-BuOK
A solution of commercially obtained potassium tertꢀbutoxide (2.24 g, 20.0 mmol) in THF (10
mL) was added, dropwise, to a magnetically stirred solution of the corresponding gemꢀ
dihalocyclopropane (10.0 mmol) in THF (5 mL) maintained under a nitrogen atmosphere at 0
°C (ice/water bath). After 0.25 h the reaction mixture was quenched with NaHCO3 (15 mL of
a saturated aqueous solution) and the resulting mixture partitioned between diethyl ether (30
mL) and water (10 mL). The separated aqueous phase was extracted with diethyl ether (3 × 20
mL) and the organic extracts combined, dried (Na2SO4) and then filtered through a No. 3
porosity sintered glass funnel. The filtrate was concentrated under reduced pressure and the
resulting oil subjected to flash chromatography.
E-7,7-Dichloro-2-(chloromethylene)-1-ethoxybicyclo[4.1.0]heptane (19)
The title compound 19 was prepared from (6E)ꢀ6ꢀchloromethyleneꢀ1ꢀethoxycyclohexene (33)
(500 mg, 2.90 mmol) using the general method for the formation of gemꢀdihalocyclopropanes
as described above. The darkꢀbrown oil obtained after workꢀup was subjected to flash
chromatography (silica, 99:1 → 98:2 v/v hexane/ethyl acetate gradient elution) and
concentration of the appropriate fractions (Rf = 0.5 in 9:1 v/v hexane/ethyl acetate) then
afforded Eꢀ7,7ꢀdichloroꢀ2ꢀ(chloromethylene)ꢀ1ꢀethoxybicyclo[4.1.0]heptane (19) (520 mg,
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70%) as a white, crystalline solid, m.p. = 47–50 °C (recrystallized from CH2Cl2/hexane). H
NMR (400 MHz, CDCl3) δ 6.57 (s, 1H), 3.58 (m, 1H), 3.37 (m, 1H), 2.61 (m 1H), 2.27–2.16
(complex m, 1H), 2.01–1.88 (complex m, 2H), 1.71–1.56 (complex m, 2H), 1.31–1.18
(complex m, 4H); 1H NMR (300 MHz, C6D6) δ 6.47 (s, 1H), 3.10 (m, 1H), 2.81 (m, 1H), 2.31
(m, 1H), 1.77 (m, 1H), 1.47 (m, 2H), 1.17 (m, 2H), 0.91 (t, J = 7.0 Hz, 3H), 0.72 (m, 1H); 13C
NMR (100 MHz, CDCl3) δ 132.5, 120.4, 69.2, 65.9, 63.6, 35.0, 25.8, 20.8, 20.1, 15.1; 13C
NMR (75 MHz, C6D6) δ 133.2, 120.9, 70.0, 66.2, 63.6, 35.3, 26.3, 21.2, 20.3, 15.4; IR υmax
2978, 2942, 1616, 1445, 1111, 1052, 833, 781 cm–1; MS m/z (EI, 70 eV) 221 and 219 [(Mꢀ
Cl•)+, 88 and 99%], 193 and 191 (98 and 100), 163 (54), 155 (98), 125 (80), 109 (93), 91 (94);
HRMS (EI, 70 eV) (MꢀCl•)+ Calcd for C10H1335Cl2O 219.0343; Found 219.0341.
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The ca. 15% C7 13Cꢀlabeled form of compound 19 was obtained using the same procedure as
defined above but using ca. 15% 13Cꢀlabeled chloroform in place of natural abundance
material. Comparison of the 13C NMR spectra of the unlabeled and labeled materials indicated
a ca. 15 fold enhancement of the signal at δC (75 MHz, C6D6) 70.0 in the latter case.
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E-7-(Chloromethylene)-4,5,6,7-tetrahydro-2-methylbenzofuran (23/27)
The title compound (23/27) was prepared from Eꢀ7,7ꢀdichloroꢀ2ꢀ(chloromethylene)ꢀ1ꢀ
ethoxybicyclo[4.1.0]heptane (19) (195 mg, 0.76 mmol) using the general method for treating
of gemꢀdihalocyclopropanes with tꢀBuOK described above. The darkꢀbrown oil obtained after
workꢀup was subjected to flash chromatography (silica, 99:0 → 98:2 v/v hexane/ethyl acetate
gradient elution) and concentration of the appropriate fractions (Rf = 0.6 in 9:1 v/v
hexane/ethyl
acetate)
then
afforded
Eꢀ7ꢀ(chloromethylene)ꢀ4,5,6,7,ꢀtetrahydroꢀ2ꢀ
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methylbenzofuran (23/27) (114 mg, 82%) as a clear, colorless oil. H NMR (400 MHz,
CDCl3) δ 6.25 (s, 1H), 5.86 (s, 1H), 2.59–2.52 (complex m, 2H), 2.47 (t, J = 6.1 Hz, 2H), 2.27
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(s, 3H), 1.86–1.78 (complex m, 2H); H NMR (300 MHz C6D6) δ 6.40 (s, 1H), 5.58 (s, 1H),
2.41 (tm, J = 7.0 Hz, 2H), 2.13 (t, J = 6.0 Hz, 2H), 1.94 (s, 3H), 1.54 (dq, J = 7.0 and 6.0 Hz,
2H); 13C NMR (100 MHz, CDCl3) δ 151.9, 146.4, 128.9, 122.7, 107.3, 106.9, 25.8, 23.1,
22.5, 13.7; 13C NMR (75 MHz, C6D6) δ 151.9 (C2), 146.8 (C7a), 129.4 (C7), 122.9 (C3a),
107.5 (C3), 107.3 (C8), 26.0 (C5), 23.2 (C4), 22.5 (C6), 13.4 (CꢀMe); IR υmax 3080, 2939,
2847, 1550, 1254, 1138, 898, 799 cm–1; MS m/z (EI, 70 eV) 184 and 182 (M+•, 36 and 100%),
147 (24), 119 (25), 91 (25), 43 (40); HRMS (EI, 70 eV) M+• Calcd for C10H1135ClO 182.0498;
Found 182.0498. The ca. 15% C7 13Cꢀlabeled formed of compound 23/27 was obtained using
the same procedure as defined above but using ca. 15% 13Cꢀlabeled precursor 19 in place of
unlabelled material. Comparison of the 13C NMR spectra of the unlabeled and labeled
materials indicated a ca. 15 fold enhancement of the signal at δC (75 MHz, C6D6) 107.5 (C3)
in the latter case.
1-Ethoxycyclohexene (29)
1ꢀEthoxycyclohexene (29) was prepared in the manner described by Wohl12. Thus, a
magnetically stirred solution of cyclohexanone (28) (10 mL, 9.5 g, 97 mmol) and triethyl
orthoformate (17.7 g, 120 mmol) maintained at 0 °C (ice/water bath) was treated with pꢀ
toluenesulfonic acid (190 mg, 1.0 mmol) in three roughly equal portions over 3 min. The
ensuing mixture was warmed to 22 °C, maintained at this temperature for 18 h then heated to
150 °C for 18 h in an apparatus that allowed the ethanol, ethyl formate and triethyl
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orthoformate to be distilled from the reaction mixture. Distillation of the ensuing lightꢀorange
oil and collection of the fraction boiling in the range 150ꢀ160 °C at 760 mm Hg gave variable
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mixtures, as judged by H NMR analysis, of 1ꢀethoxycyclohexene (29)12 and cyclohexanone
diethyl ketal (quantitative yield). This material was used, without purification, in the next step
of the reaction sequence.
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1-Methoxycyclohexene (30)
1ꢀMethoxycyclohexene (30) was prepared in the same manner as described above for the
formation of 1ꢀethoxycyclohexene (29) save for the use of trimethyl orthoformate in place of
triethyl orthoformate and using a heating temperature and time of 110 °C and 2 h,
respectively. Distillation of the ensuing lightꢀorange oil and collection of the fraction boiling
in the range 138ꢀ140 °C at 760 mm Hg gave a ca. 3:2 mixture, as judged by 1H NMR analysis,
of 1ꢀmethoxycyclohexene (30)12 and cyclohexanone dimethyl ketal (quantitative yield). This
material was used, without purification, in the next step of the reaction sequence.
7,7-Dichloro-1-ethoxybicyclo[4.1.0]heptane (31)
The title compound 31 was prepared from 1ꢀethoxycyclohexene (29) (8.47 g, 67.0 mmol)
using the general method for the formation of gemꢀdihalocyclopropanes as described above.
The darkꢀbrown oil obtained after workꢀup was subjected to flash chromatography (silica,
99:1 → 98:2 v/v hexane/ethyl acetate gradient elution). Concentration of the appropriate
fractions (Rf = 0.4 in 9:1 v/v hexane/ethyl acetate) then afforded 7,7ꢀdichloroꢀ1ꢀ
ethoxybicyclo[4.1.0]heptane (31)14 (7.48 g, 54%) as lightꢀyellow oil. H NMR (400 MHz,
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CDCl3) δ 3.69 (m, 2H), 2.20–1.97 (complex m, 3H), 1.76 (dd, J = 9.5 and 2.4 Hz, 1H), 1.65–
1.52 (complex m, 1H), 1.50–1.34 (complex m, 3H), 1.24 (m, 4H); 13C NMR (100 MHz,
CDCl3) δ 69.3, 64.1, 62.4, 33.6, 23.8, 21.1, 20.2, 19.2, 15.2; IR υmax 2977, 2941, 2878, 1444,
1380, 1202, 1117, 1073, 1045, 916, 904, 815 cm–1; MS m/z (EI, 70 eV) 175 and 173 [(Mꢀ
Cl•)+, 30 and 89%), 147 and 145 (34 and 100), 111 and 109 (28 and 61), 81 (10); HRMS (EI,
70 eV) (MꢀCl•)+ Calcd for C9H1435ClO 173.0733; Found 173.0736.
7,7-Dichloro-1-methoxybicyclo[4.1.0]heptane (32)
The title compound 32 was prepared from 1ꢀmethoxycyclohexene (30) (6.00 g, 53.5 mmol)
using the general method for the formation of gemꢀdihalocyclopropanes as described above.
The darkꢀbrown oil obtained after workꢀup was subjected to flash chromatography (silica,
99:1 → 98:2 v/v hexane/ethyl acetate gradient elution) and concentration of the appropriate
fractions (Rf = 0.4 in 9:1 v/v hexane/ethyl acetate) then afforded 7,7ꢀdichloroꢀ1ꢀ
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methoxybicyclo[4.1.0]heptane (32)6 (7.62 g, 73%) as a clear, paleꢀyellow oil. H NMR (400
MHz, CDCl3) δ 3.45 (s, 3H), 2.18–1.98 (complex m, 3H), 1.74 (dd, J = 9.4 and 2.4 Hz, 1H),
1.66–1.55 (complex m, 1H), 1.50–1.35 (complex m, 3H), 1.26 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 69.2, 64.8, 54.3, 33.3, 23.0, 21.1, 20.2, 19.2; IR υmax 2940, 2859, 1446, 1381, 1334,
1258, 1208, 1110, 1073, 917, 816 cm–1; MS m/z (EI, 70 eV) 161 and 159 [(MꢀCl•)+, 33 and
100%), 123 (23), 91 (31); HRMS (EI, 70 eV) (MꢀCl•)+ Calcd for C8H1235ClO 159.0577;
Found 159.0573.
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(6E)-6-Chloromethylene-1-ethoxycyclohexene (33)
The title compound, 33, was prepared from 7,7ꢀdichloroꢀ1ꢀethoxybicyclo[4.1.0]heptane (31)
(2.00 g, 9.6 mmol) using the general method for treating of gemꢀdihalocyclopropanes with tꢀ
BuOK as described above. The lightꢀyellow oil obtained after workꢀup was subjected to flash
chromatography (silica, 98.5:1:0.5 v/v/v hexane/ethyl acetate/triethylamine elution).
Concentration of the appropriate fractions (Rf = 0.8 in 9:1 v/v hexane/ethyl acetate) then
afforded the title diene 33 (1.50 g, 91%) as a clear, colorless oil. 1H NMR (400 MHz, CDCl3)
δ 6.46 (s, 1H), 4.93 (t, J = 4.5 Hz, 1H), 3.74 (q, J = 7.0 Hz, 2H), 2.52–2.47 (complex m, 2H),
2.21–2.15 (complex m, 2H), 1.69–1.61 (complex m, 2H), 1.30 (t, J = 7.0 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 150.5, 133.3, 113.5, 100.3, 62.3, 26.1, 24.2, 22.1, 14.6; IR υmax 2978,
2932, 2878, 1637, 1375, 1236, 1180, 1123, 1046, 872, 805 cm–1; MS m/z (EI, 70 eV) 174 and
172 (M+•, 27 and 80%), 144 (26), 137 (34), 109 (100), 79 (50). The unstable nature of this
material precluded the acquisition of HRMS data.
(6E)-6-Chloromethylene-1-methoxycyclohexene (34)
The title compound 34 was prepared from 7,7ꢀdichloroꢀ1ꢀmethoxybicyclo[4.1.0]heptane (32)
(1.00 g, 5.12 mmol) using the general method for treating gemꢀdihalocyclopropanes with tꢀ
BuOK as described above. The darkꢀbrown oil obtained after workꢀup was subjected to flash
chromatography (silica, 98.5:1:0.5 v/v/v hexane/ethyl acetate/triethylamine elution) and
concentration of the appropriate fractions (Rf = 0.6 in 9:1 v/v hexane/ethyl acetate) then
1
afforded the title diene 34 (733 mg, 90%) as a clear, colorless oil. H NMR (400 MHz,
CDCl3) δ 6.42 (s, 1H), 4.94 (t, J = 4.5 Hz, 1H), 3.56 (s, 3H), 2.55–2.45 (complex m, 2H),
2.23–2.16 (complex m, 2H), 1.71–1.59 (complex m, 2H); 13C NMR (100 MHz, CDCl3) δ
151.3, 133.2, 113.5, 99.5, 54.2, 26.1, 24.1, 22.1; IR υmax 2938, 2836, 1640, 1378, 1238, 1204,
1171, 1027, 890, 809 cm–1; MS m/z (EI, 70 eV) 160 and 158 (M+•, 24 and 63%), 123 (100), 93
(31), 91 (93), 81 (40), 79 (93); HRMS (EI, 70 eV) M+• Calcd for C8H1135ClO 158.0498; Found
158.0498.
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E-7,7-Dichloro-2-(chloromethylene)-1-methoxybicyclo[4.1.0]heptane (35)
5
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8
The title compound 35 was prepared from (6E)ꢀ6ꢀchloromethyleneꢀ1ꢀmethoxycyclohexene
(34) (700 mg, 4.41 mmol) using the general method for the formation of gemꢀ
dihalocyclopropanes as described above. The darkꢀbrown oil obtained after workꢀup was
subjected to flash chromatography (silica, 99:1 → 98:2 v/v hexane/ethyl acetate gradient
elution) and concentration of the appropriate fractions (Rf = 0.4 in 9:1 v/v hexane/ethyl
acetate) then afforded Eꢀ7,7ꢀdichloroꢀ2ꢀ(chloromethylene)ꢀ1ꢀmethoxybicyclo[4.1.0]heptane
(35) (692 mg, 65%) as a white, crystalline solid, m.p. = 69 °C (recrystallized from
CH2Cl2/hexane). 1H NMR (400 MHz, CDCl3) δ 6.56 (s, 1H), 3.30 (s, 3H), 2.62 (dm, J = 16.9
Hz, 1H), 2.22 (m, 1H), 2.00–1.86 (complex m, 2H), 1.73–1.54 (complex m, 2H), 1.25 (m,
1H); 13C NMR (100 MHz, CDCl3) δ 131.6, 120.6, 69.2, 66.8, 55.2, 34.8, 25.8, 20.9, 20.1; IR
υmax 2887, 1616, 1448, 1111, 1051, 834 cm–1; MS m/z (EI, 70 eV) 242 and 240 (M+•, 2 and
3%), 209, 207 and 205 [(MꢀCl•)+, 13, 64 and 100%], 179 and 177 (14 and 21); HRMS (EI, 70
eV) (MꢀCl•)+ Calcd for C9H1135Cl2O 205.0187; Found 205.0184.
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E-7-(Chloromethylene)-5,6,7,8-tetrahydrobenzofuran (36)
The title compound 36 was prepared from Eꢀ7,7ꢀdichloroꢀ2ꢀ(chloromethylene)ꢀ1ꢀ
methoxybicyclo[4.1.0]heptane (35) (600 mg, 2.48 mmol) using the general method for the
treatment of gemꢀdihalocyclopropanes with tꢀBuOK as described above. The darkꢀbrown oil
obtained after workꢀup was subjected to flash chromatography (silica, 99:1 → 98:2 v/v
hexane/ethyl acetate gradient elution) and concentration of the appropriate fractions (Rf = 0.6
in 9:1 v/v hexane/ethyl acetate) then afforded Eꢀ7ꢀ(chloromethylene)ꢀ4,5,6,7ꢀ
1
tetrahydrobenzofuran (36) (146 mg, 35%) as a clear, colorless oil. H NMR (400 MHz,
CDCl3) δ 7.26 (d, J = 1.8 Hz, 1H), 6.35 (s, 1H), 6.26 (d, J = 1.8 Hz, 1H), 2.62–2.57 (complex
m, 2H), 2.54 (t, J = 6.1 Hz, 2H), 1.89–1.81 (complex m, 2H); 13C NMR (100 MHz, CDCl3) δ
148.0, 141.7, 129.0, 121.5, 111.0, 108.5, 25.8, 23.1, 22.5; IR υmax 2931, 2847, 1490, 1146,
1104, 894, 789, 691 cm–1; MS m/z (EI, 70 eV) 170 and 168 (M+•, 33 and 100%), 133 (30), 105
(59), 77 (30); HRMS (EI, 70 eV) M+• Calcd for C9H935ClO 168.0342; Found 168.0346.
Formation of the Diels-Alder Adduct 38 [Dimethyl (E)-5-(Chloromethylene)-5,6,7,8-
tetrahydro-2H-2,4a-epoxynaphthalene-3,4-dicarboxylate]
A magnetically stirred solution of furan 36 (60 mg, 0.36 mmol) in toluene (1.0 mL) maintained
under nitrogen was treated with DMAD (37) (73 ꢀL, 84 mg, 0.59 mmol) and the ensuing solution
heated in a sealed tube at 50 °C for 16 h. The resulting grey solution was cooled and then
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concentrated under reduced pressure to afford a brown oil. Subjection of this material to flash
chromatography (silica, 95:5 v/v hexane/ethyl acetate elution) gave two fractions, A and B.
Concentration of fraction A (Rf = 0.6 in 9:1 v/v hexane/ethyl acetate) gave compound 36
(25 mg, 42% recovery) as clear, colorless oil.
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9
Concentration of fraction B (Rf = 0.1 in 9:1 v/v hexane/ethyl acetate) gave compound 38
(13 mg, 20% based on recovered starting material) as clear, lightꢀyellow oil. 1H NMR (400 MHz,
CDCl3) δ 6.60 (m, 1H), 6.30 (d, J = 2.0 Hz, 1H), 5.60 (d, J = 2.0 Hz, 1H), 3.82 (s, 3H), 3.78 (s,
3H), 3.11 (dm, J = 15.8 Hz, 1H), 2.74 (dm, J = 15.8 Hz, 1H), 2.35 (m, 1H), 2.24 (m, 1H), 2.00
(m, 1H), 1.58–1.42 (complex m, 1H); 13C NMR (100 MHz, CDCl3) δ 164.8, 162.7, 156.8, 155.9,
150.4, 134.8, 132.1, 117.9, 93.5, 82.4, 52.4, 52.3, 26.6, 26.1, 23.0; IR υmax 2952, 1716, 1647,
1435, 1267, 1228, 1112, 1042, 932 cm–1; MS m/z (EI, 70 eV) 312 and 310 (M+•, 5 and 14%), 275
(43), 215 (18), 170 (44), 168 (100), 105 (19); HRMS (EI, 70 eV) M+• Calcd for C15H1535ClO5
310.0608; Found 310.0603.
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Dimethyl (E)-8-(Chloromethylene)-3-hydroxy-5,6,7,8-tetrahydronaphthalene-1,2-dicarboxy
-late (39)
A magnetically stirred solution of furan 36 (90 mg, 0.53 mmol) in toluene (4.0 mL) maintained
under nitrogen was treated with DMAD (37) (66 ꢀL, 76 mg, 0.53 mmol) and the ensuing solution
heated under reflux for 28 h. The resulting grey solution was cooled and then concentrated under
reduced pressure to give brown oil. Subjection of this material to flash chromatography (silica,
95:5 v/v hexane/ethyl acetate elution) gave, after concentration of the appropriate fractions (Rf =
1
0.1 in 9:1 v/v hexane/ethyl acetate), compound 39 (32 mg, 28%) as clear, yellow oil. H NMR
(400 MHz, CDCl3) δ 10.98 (s, 1H), 6.85 (s, 1H), 6.31 (m, 1H), 3.91 (s, 3H), 3.86 (s, 3H), 2.64
(td, J = 7.2 and 2.1 Hz, 2H), 2.58 (m, 2H), 1.77 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 169.3,
169.2, 161.0, 149.3, 135.4, 132.7, 125.3, 117.5, 116.5, 107.9, 53.0, 52.5, 30.8, 26.5, 21.1; IR υmax
2951, 1733, 1674, 1445, 1349, 1228, 1207, 1097, 1016 cm–1; MS m/z (ESI) 335 and 333
(M+Na+, 31 and 100%), 313 (4), 301 (3); HRMS (EI, 70 eV) (M+H)+ Calcd for C15H1635ClO5
311.0686; Found 311.0687.
E-2-(Chloromethylene)- 7,7-dibromo-1-ethoxybicyclo[4.1.0]heptane (40)
The title compound 40 was prepared from (6E)ꢀ6ꢀchloromethyleneꢀ1ꢀethoxycyclohexene (33)
(374 mg, 2.16 mmol) using the general method for the formation of gemꢀdihalocyclopropanes as
described above. The darkꢀbrown oil obtained after workꢀup was subjected to flash
chromatography (silica, 99:1 → 98:2 v/v hexane/ethyl acetate gradient elution) and concentration
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of the appropriate fractions (Rf = 0.4 in 9:1 v/v hexane/ethyl acetate) then afforded Eꢀ2ꢀ
(chloromethylene)ꢀ7,7ꢀdibromoꢀ1ꢀethoxybicycloꢀ[4.1.0]heptane (40) (377 mg, 51%) as a lightꢀ
1
yellow, crystalline solid, m.p. = 59–63 °C (recrystallized from CH2Cl2/hexane). H NMR (400
MHz, CDCl3) δ 6.60 (s, 1H), 3.59 (m, 1H), 3.37 (m, 1H), 2.59 (dm, J = 16.8 Hz, 1H), 2.35–2.23
(complex m, 1H), 2.05–1.93 (complex m, 2H), 1.75–1.65 (complex m, 1H), 1.55–1.42 (complex
m, 1H), 1.34–1.16 (complex m, 4H); 13C NMR (100 MHz, CDCl3) δ 133.2, 120.7, 65.1, 63.6,
43.8, 36.4, 26.0, 22.5, 20.7, 15.1; IR υmax 2939, 1612, 1444, 1216, 1108, 1050, 815, 767 cm–1;
MS m/z (EI, 70 eV) 311 and 309 [(MꢀCl•)+, 33 and 64%], 307 (34), 265 (41), 273 (89), 199 (38),
103 (45), 91 (100); HRMS (EI, 70 eV) (M–Cl•)+ Calcd for C10H1379Br2O 306.9333; Found
306.9338.
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Treatment of Compound 40 with Potassium tert-Butoxide. GC-MS Detection of Compounds
23/27 and 41
Compound 40 was treated with potassium tertꢀbutoxide in THF in the same manner as congener
19. The reaction mixture thus obtained was worked up in the prescribed manner and the ensuing
lightꢀyellow oil subjected to GCꢀMS analysis on an Agilent 5073 GCꢀMS Instrument fitted with a
HPꢀ5ms capillary column [20 m × 0.18 mm (ID)] using helium as the carrier gas and a column
temperature of 50 °C. The major peak (ca. 95%) was observed after 13.42 min. and a minor one
(ca. 2ꢀ3%) after 14.32 min. The derived EI mass spectra are shown in Figure 7a and 7b,
respectively.
7,7-Dibromo-1-ethoxybicyclo[4.1.0]heptane (45)
The title compound 45 was prepared from 1ꢀethoxycyclohexene (29) (3.00 g, 23.8 mmol) using
the general method for the formation of gemꢀdihalocyclopropanes described above. The darkꢀ
brown oil obtained after workꢀup was subjected to flash chromatography (silica, 99:1 → 98:2 v/v
hexane/ethyl acetate gradient elution). Concentration of the appropriate fractions (Rf = 0.4 in 9:1
v/v hexane/ethyl acetate) then afforded 7,7ꢀdibromoꢀ1ꢀethoxybicyclo[4.1.0]heptane (45)14 (6.03
1
g, 61%) as clear, lightꢀbrown oil. H NMR (400 MHz, CDCl3) δ 3.72 (m, 2H), 2.22–2.03
(complex m, 3H), 1.90 (dd, J = 9.7 and 2.3 Hz, 1H), 1.52–1.39 (complex m, 4H), 1.30–1.21
(complex m, 4H); 13C NMR (100 MHz, CDCl3) δ 63.5, 61.8, 45.0, 35.3, 24.8, 21.3, 21.2, 20.2,
15.2; IR υmax 2938, 1443, 1374, 1187, 1115, 1070, 1042, 896, 764 cm–1; MS m/z (EI, 70 eV) 219
and 217 [(MꢀBr•)+, 53 and 69%], 191 and 189 (93 and 72), 173 (33), 145 (60), 109 (57), 81
(100); HRMS (EI, 70 eV) (M–Br•)+ Calcd for C9H1479BrO 217.0228; Found 217.0228.
3-Ethoxycyclohept-2-en-1-one (47) and 3-(tert-Butoxy)cyclohept-2-en-1-one (48)
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The title compounds were formed upon treating 7,7ꢀdibromoꢀ1ꢀethoxybicyclo[4.1.0]heptane (45)
(1.00 g, 3.36 mmol) with tꢀBuOK using the general method described above. The brown oil
obtained after workꢀup was subjected to flash chromatography (silica, 9:1 → 1:1 v/v hexane/ethyl
acetate gradient elution). Concentration of the appropriate fractions (Rf = 0.1 in 9:1 v/v
hexane/ethyl acetate) then afforded a ca. 2:5 mixture of compounds 4724 and 48 (943 mg, 71%)
as a clear, lightꢀbrown oil. Resubjection of a small fraction of this material to further flash
chromatographic purification under the same conditions and concentration of a few early or late
fractions allowed for the isolation of spectroscopically pure samples of each of compounds 47
and 48.
Compound 47: 1H NMR (400 MHz, CDCl3) δ 5.34 (s, 1H), 3.76 (q, J = 7.0 Hz, 2H), 2.60–2.48
(complex m, 4H), 1.86–1.71 (complex m, 4H), 1.31 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 202.3, 176.2, 105.7, 64.1, 41.6, 32.9, 23.4, 21.2, 14.1; IR υmax 2941, 1644, 1604, 1377,
1180 cm–1; MS m/z (ESI) 177 (M+Na+, 100%), 155 (5); HRMS (EI, 70 eV) (M+H)+ Calcd for
C9H15O2 155.1072; Found 155.1066.
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Compound 48: H NMR (400 MHz, CDCl3) δ 5.52 (s, 1H), 2.53 (m, 2H), 2.45 (m, 2H), 1.82–
1.70 (complex m, 4H), 1.41 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 202.7, 174.2, 109.3, 80.4,
41.3, 34.2, 28.2, 23.4, 21.0; IR υmax 2938, 1638, 1595, 1368, 1245, 1156, 1138, 884 cm–1; MS
m/z (ESI, +ve) 205 (M+Na+, 100%), 149 (7), 127 (6); HRMS (EI, 70 eV) (M+H)+ Calcd for
C11H19O2 183.1385; Found 183.1381.
Crystallographic Studies on Compounds 19, 35 and 40
Crystal data
Compound 19: C10H13Cl3O, M = 255.55, T = 150 K, triclinic, space group Pꢀ1, Z = 2, a =
7.3031(6), b = 8.9170(7), c = 9.1413(8) Å; α = 81.507(7) °, β = 85.452(7) °, γ = 80.354(7) °;
V = 579.54(8) Å3, Dx = 1.464 g.cmꢀ3, 2712 unique data (2θmax = 60.2°), 2141 with I > 2σ(I); R
= 0.041, Rw = 0.091, S = 1.06.
Compound 35: C9H11Cl3O, M = 241.54, T = 200 K, orthorhombic, space group Pna21, Z = 4,
a = 8.4239(4), b = 16.5510(7), c = 7.5180(3) Å; V = 1048.19(8) Å3, Dx = 1.531 g.cmꢀ3, 2366
unique data (2θmax = 55°), 2096 with I > 3σ(I); R = 0.0218, Rw = 0.0263, S = 1.1034.
Compound 40: C10H13Br2ClO, M = 344.47, T = 150 K, triclinic, space group Pꢀ1, Z = 2, a =
7.4888(5), b = 8.8924(6), c = 9.2043(6) Å; α = 83.085(6) °, β = 86.309(6) °, γ = 81.870(6) °;
V = 601.67(7) Å3, Dx = 1.901 g.cm–3, 2828 unique data (2θmax = 60.2°), 2142 with I > 2σ(I); R
= 0.040, Rw = 0.098, S = 1.06.
Structure Determination
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Images for compound 35 were measured on a Nonius Kappa CCD diffractometer (MoKα,
graphite monochromator, λ = 0.71073 Å) and the data extracted using the Denzo/Scaleꢀ
pack package. Images for congeners 19 and 40 were measured on a Rigaku Xcalibur CCD
diffractometer (MoKα, graphite monochromator, λ = 0.71073 Å) and the data extracted using
CrysAlisPro.25 The structure of compound 35 was solved with SIR9226 and refined using
CRYSTALS27 while compounds 19 and 40 were solved with ShelXT28 and refined using
ShelXL29 in OLEX2.30 Atomic coordinates, bond lengths and angles, and displacement
parameters have been deposited at the Cambridge Crystallographic Data Centre (CCDC no.
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1852815–1852817).
These
data
can
be
obtained
freeꢀofꢀcharge
via
www.ccdc.cam.ac.uk/data_request/cif, by emailing data_request@ccdc.cam.ac.uk, or by
contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033.
ASSOCIATED CONTENT
Supporting Information
Table of theoretically derived G3(MP2)ꢀRAD electronic energies, thermal corrections to the
Gibbs free energies (including ZPVE), SMD solvation free energies. Optimized geometries
for 6, 11, 11 → 13 transition state (TS), 13B, 17, 17 → SE transition state, SE, 11 → 13
transition state, 17 → 15 transition state, and 15. Cif and anisotropic displacement ellipsoid
plots from the singleꢀcrystal Xꢀray analyses of compounds 19, 35 and 40. 1H and/or 13C NMR
spectra of compounds 19, 23/27, 29ꢀ36, 38, 39, 40, 45, 47 and 48. This material is available
freeꢀofꢀcharge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Tel: +61ꢀ2ꢀ6125ꢀ8202. Fax: +61ꢀ2ꢀ6125ꢀ8114. Eꢀmail: Martin.Banwell@anu.edu.au
ORCID
Martin G. Banwell: 0000ꢀ0002ꢀ0582ꢀ475X
Author Contributions
The manuscript was written through contributions from all of the authors. All of the authors
have given approval to the final version of the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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The authors thank the Australian Research Council, the Institute of Advanced Studies at the
Australian National University for financial support.
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REFERENCES
1.
For a discussion of the methods available for the generation of dihalocarbenes see: (a)
Banwell, M. G.; Reum, M. E. gemꢀDihalocyclopropanes in Chemical Synthesis, in
Advances in Strain in Organic Chemistry (ed. B. Halton), JAI Press, London, 1991, 1,
19ꢀ64; (b) Fedorynski, M. Syntheses of gemꢀDihalocyclopropanes and Their Use in
Organic Synthesis, Chem. Rev., 2003, 103, 1099ꢀ1132; (c) Halton, B.; Harvey, J.
Electrocyclic RingꢀOpening Reactions of gemꢀDibromocyclopropanes in the Synthesis
of natural products and Related Compounds, Synlett. 2006, 1975ꢀ2000.
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35
36
37
38
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45
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48
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2.
(a) Banwell, M. G.; Beck, D. A. S.; Stanislawski, P. C.; Sydnes, M. O.; Taylor, R. M.
Pyrroles and gemꢀDihalocyclopropanes as Building Blocks for Alkaloid Synthesis
Curr. Org. Chem., 2005, 9, 1589ꢀ1600 and references cited therein; (b) Stanislawski,
P. C.; Willis, A. C. ; Banwell, M. G. gemꢀDihalocyclopropanes as Building Blocks in
NaturalꢀProduct Synthesis: Enantioselective Total Syntheses of entꢀErythramine and
3ꢀepiꢀErythramine Chem. Asian J., 2007, 2, 1127ꢀ1136.
3.
4.
5.
Banwell, M. G.; Gable, R. W.; Halton, B.; Phyland, J. R. Dehydrohalogenation of the
Bisꢀdihalocarbene Adducts of Some Methoxycyclohexaꢀ1,4ꢀdienes: Revision of
Product Structures. Aust. J. Chem., 1994, 47, 1879ꢀ1884.
Banwell, M. G.; Phillis, A. T.; Willis, A. C. Exploitation of Cyclopropane
Ringꢀcleavage Reactions for the Rapid Assembly of Tetracyclic Frameworks Related
to Gibberellins. Org. Lett., 2006, 8, 5341ꢀ5344.
For a useful point of entry into the literature on this topic see Blanchet, J.; Macklin, T.;
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