Cyclopentadienones via a Tandem C-Cyclopropylnitrone Cyclization-Cycloreversion Sequence

Article abstract of DOI:10.1002/ejoc.201700915

Aldonitrones derived from spiro[2.4]hepta-4,6-diene-1-carbaldehyde and its benzo analog undergo a tandem uncatalyzed intramolecular cyclopropane–nitrone cyclization-5,6-dihydro-1,2-oxazine cycloreversion to give cyclopentadienones. Similarly, the NH-nitrone generated in situ from spiro[cyclopropane-1,1′-indene]carbaldehyde oxime leads to benzocyclopentadienone (1H-inden-1-one) by the same mechanism. DFT calculations are in favor of a concerted yet highly asynchronous pathway for the cyclizations. Control experiments with the dihydro and tetrahydro derivatives show that the spirocyclopentadiene unit is essential for the success of the reaction, invoking spiroconjugative effects for increased cyclopropane reactivity.

Full text of DOI:10.1002/ejoc.201700915

A Journal of
Accepted Article
Title: Cyclopentadienones via a tandem C-cyclopropylnitrone
cyclization-cycloreversion sequence
Authors: Ihsan Erden, Scott Gronert, Christian Gaertner, Jinxiang Ma,
Gabriel Cabrera, Kate Markham, and Saeed Azimi
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700915
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European Journal of Organic Chemistry
10.1002/ejoc.201700915
FULL PAPER
Cyclopentadienones via a tandem C-cyclopropylnitrone
cyclization-cycloreversion sequence
[
a]
[a]
[a]
[a]
[a]
Ihsan Erden,* Christian Gärtner, Jingxiang Ma, Gabriel Cabrera, Kate Markham, Saeed
[
a]
[b]
Azimi, and Scott Gronert *
Dedicated to Professor Edwin L. Motell on the occasion of his 85th birthday
Abstract: Aldonitrones derived from spiro[2.4]hepta-4,6-diene-1-
carbaldehyde and its benzo analog undergo a tandem uncatalyzed
intramolecular cyclopropane-nitrone cyclization-5,6-dihydro-1,2-
oxazine cycloreversion to give cyclopentadienones. Similarly, the
NH-nitrone generated in situ from spiro[cyclopropane-1,1’-
indene]carbaldehyde oxime leads to benzocyclopentadienone (1H-
inden-1-one) by the same mechanism. DFT calculations are in favor
of a concerted yet highly asynchronous pathway for the cyclizations.
Control experiments with the dihydro and tetrahydro derivatives
show that the spirocyclopentadiene unit is essential for the success
of the reaction, invoking spiroconjugative effects for increased
cyclopropane reactivity.
3
[Yb(OTf) ] catalyzed “homo” (3+2) cycloadditions of nitrones with
activated cyclopropanes -in particular 1,1-cyclopropane diesters-
to give 1,2-oxazinanes.12 In the absence of the Lewis acid, the
reaction is not observed; it is believed that the Lewis acid
coordinates to the ester group, thus further polarizing the
cyclopropane C-C-bond.13 Similar transformations of 1,1-
4 2
cyclopropane diesters in the presence of Ni(ClO ) and chiral
bisoxazoline ligands have been reported.14 Also (3+2)-
cycloadditions of nitrocyclopropane carboxylates with nitrones,
catalyzed by urea derivatives, were shown to give 1,2-oxazinane
derivatives.15
Introduction
Nitrones are reactive dipoles1 that undergo 1,3-dipolar
cycloadditions with alkenes and alkynes to give isoxazolidines or
3
Scheme 1. Yb(OTf) catalyzed intermolecular nitrone-activated cyclopropane
homo [3+2] cycloaddition
2
isoxazolines, respectively. Whereas the combination of nitrones
with electron-deficient alkenes is quite common and is supported
by favorable frontier orbital interactions,3 the corresponding
reactions with electron-rich alkenes are considered as
The situation changes dramatically when a cyclopropyl
group is placed in a bisected antiplanar conformation relative to
a 1,1-divinyl group, as in spiro[2.4]hepta-4,6-diene (5). UV and
NMR spectroscopic studies, theoretical calculations as well as
photoelectron spectroscopy strongly support the existence of
spiroconjugation in this system.16,17
The pseudoconjugation between the Walsh orbitals of
cyclopropane and the LUMO of cyclopentadiene results in
decreased bonding and manifests itself in considerable bond
lengthening of C2-C3 and increased bonding and shortening of
C3-C4 as well as C1-C2 in 5 as compared to dihydro analog
spiro[2.4]hept-4-ene. Of all the spirocyclopropyl systems studied
so far, spiro[2.4]hepta-4,6-diene exhibits the strongest
4
cycloadditions with inverse electron-demand and are enhanced
5
by Lewis acids. Nitrone-alkene cycloadditions are of particular
synthetic value since these can be employed in the synthesis of
6
7
a variety of heterocycles and natural products, in particular the
intramolecular variants. Also the synthetic utility of N-
8
vinylnitrones has been explored. The nucleophilic character of
nitrones has also been exploited in catalytic asymmetric nitrone-
9
aldol reactions. Considerable synthetic and theoretical work has
been done in this area shedding light on the regioselectivity and
stereoselectivity aspects of these important cycloadditions.10
Cyclopropylnitrones have first been reported by Houk et al.,
and they do not exhibit divergent behavior, i.e., the cyclopropyl
group with its -conjugative ability does not engage the adjacent
nitrone C=N in a conceivable intramolecular cyclization, similar
to the cyclopropylimine→2-pyrroline cyclization.11
delocalization of electrons by  and Walsh-orbital interactions
18
(
largest bond ellipticity). Based on these considerations, we
decided to put the -conjugative ability of cyclopropane to test
by placing the cyclopropylnitrone unit onto
a
spiro[2.4]heptadiene framework in hopes of observing an
intramolecular nitrone-cyclopropane cyclization resulting from
this attempt.19
Recently, Kerr et al. reported the first intermolecular Lewis-acid
[
[
a]
b]
Department of Chemistry and Biochemistry, San Francisco State
University, 1600 Holloway Avenue, San Francisco, CA 94132, USA
E-mail: ierden@sfsu.edu
Department of Chemistry, Virginia Commonwealth University, 1001
West Main Street, Richmond, Virginia 23284, USA
E-mail: sgronert@vcu.edu
Figure 1. Spiroconjugative effects in 5
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European Journal of Organic Chemistry
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1
Results and Discussion
the H NMR spectrum of the crude reaction mixture in the case
of 13→14 clearly showed the presence of the fragmentation
product 17.27
The requisite spiro[2.4]hepta-4,6-diene-1-carbaldehyde (6) was
prepared by
a
modified version of
a procedure reported
previously.2
0, 21
Upon treating 6 with N-methylhydroxylamine in
water and extraction of the reaction mixture with EtOAc, a single
product was isolated in 36% yield after purification on silica gel.
It was identified as the endo-Diels-Alder dimer 10 of
cyclopentadienone (8) 22 (Scheme 2). When the reaction was
repeated in the presence of 1,3-cyclopentadiene (9), 8 was
trapped as the corresponding Diels-Alder product 11.23
Scheme 4. Tandem intramolecular nitrone-cyclopropane cycloaddition-
cycloreversion
To our knowledge, these transformations represent the first
intramolecular, uncatalyzed cyclopropane-nitrone cycloadditions.
The ensuing fragmentation of the 5,6-dihydro-1,2-oxazines of
the type 15 (16) is akin to similar fragmentations reported by
Eschenmoser et al.28
The question whether an NH nitrone derived from the
corresponding oximes would exhibit similar reactivity was
addressed by converting the spirocyclopropylcarbaldehydes 6
and 12/12’ to the corresponding stable aldoximes, which were
obtained as mixtures of Z and E isomers, respectively. Since
Scheme 2. Attempted nitrone formation from 6; trapping of cyclopentadienone
8
as Diels-Alder adducts.
o
aldoximes require temperatures in excess of 100 C to undergo
Similarly, the benzo analog of 6 derived from indene (compound
2),24
gave under similar conditions the stable
,2-prototropic shifts to NH nitrones,29, 30 and due to the fact that
1
1
the dimer of cyclopentadienone decomposes near its melting
2
5
benzocyclopentadienone (inden-1-one, 14) in 68% isolated
yield. In neither case could the nitrone intermediate 13 be
detected. (Scheme 3).
o
22a
point (97-98 C), the thermolysis of the Z/E mixture of oximes
8a/18b was not expected to yield isolable quantities of 8.
1
Indeed, thermolysis of the E, Z-oxime mixture 18a and b led to
complete disappearance of the Z isomer via the NH-nitrone 18’a,
leading to an intractable mixture, along with unreacted 18b
(
Scheme 5).
Scheme 3. 1-Indenone formation via N-Methylnitrones 13/13’ derived from
spiro(cyclopropane-1,1’-indene)-2-carbaldehyde (12/12’)
In the remarkable transformations shown in Schemes 2 and
Scheme 5. Attempted generation of cyclopentadienone from 18a
3
, the spirocyclopropanecarboxaldehyde moiety in 6 and 12 is
replaced by a ring carbonyl group in a formal loss of acrolein N-
methylimine (17), resulting in net oxidation of the
On the other hand, of the mixture of the oximes 19a, b+19’a, b,
respectively,only 19a/19a’ (Scheme 6) reacted cleanly under the
a
cyclopentadiene C-5. Compound 10 is obviously a secondary
product formed by spontaneous Diels-Alder dimerization of the
anti-aromatic cyclopentadienone 8, whereas the benzo analog
same conditions and yielded the stable inden-1-one (14). The
1
progress of the reaction was monitored by H NMR (d
8
-toluene),
and it was noted that the thermolysis proceeded cleanly; only
the (Z) isomers were being converted to the product via
20a/20’a, while the E isomers remained intact.31 Upon complete
conversion of the Z isomers to 14, the reaction was interrupted,
the mixture consisting of 14 and the unreacted (E)- oximes
19b/19b‘ separated by flash chromatography, and the products
characterized by spectroscopy.
14 is stable as a monomer. A mechanism for these
transformations consistent with the results shown in the above
Schemes involves initial nitrone formation (acyclic aldonitrones
exist as Z isomers)26 followed by a novel C-cyclopropylnitrone
cyclization to give a 5,6-dihydro-1,2-oxazine 15 or 16 (benzo).
The latter then undergoes a cycloreversion (formally a retro-
Diels-Alder reaction),
a process encouraged by favorable
enthalpy of reaction of -11.5 kcal/mol and a low barrier of 23.0
kcal/mol (M062x/6-311+G** basis set) to give cyclopentadienone
8
(or its benzo analog 14) (Scheme 4). Moreover, inspection of
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European Journal of Organic Chemistry
10.1002/ejoc.201700915
FULL PAPER
removed one or both -bonds in the cyclopentadiene ring via
independent syntheses of the nitrones 25 and 29 (vide infra),
respectively (Schemes 7 and 8).
Scheme 6. 1-Indenone formation via the N-H nitrone (only the Z isomers 20a
and 20’a react).
The process of converting
7
to 15 was explored
3
2
computationally (M062x/6-311+G**). The reaction is concerted,
but involves a very asynchronous path where the cyclopropane
is fully cleaved and the new C-O bond has yet to form in the
transition state (Figure 2).
a: N
2
CHCO
2 2 4
Et, Rh (OAc) , CH
2
Cl
2
, 74%; b: LiAlH /THF, 97%; c: Dess-Martin,
4
66%; d: CH
3
NHOH·HCl, MgSO
4
, NaHCO
3
, CH Cl , 97%
2
2
Scheme 7. Synthesis of nitrone 25, the dihydro analog of 13.
Though the synthesis of 21 was reported previously,33 we
achieved a significant improvement in the yield (93%) of the
+
-
3 3
Wittig reaction by using Ph P CH Br , KOt-Bu as base in
ether,33c instead of n-BuLi (only 36%)33b. It is also noteworthy
that of the two diastereomeric esters that were formed, 22a (1S,
Figure 2. Transition state for transformation of 7 to 15 (M062x/6-311+G**)
2
R) exhibits an ABX
3
system in the 1H NMR spectrum for the
The pathway from reactants to transition state to products
was confirmed with an intrinsic reaction coordinate calculation
diastereotopic ethoxy CH
about the C-C=O group.
2
protons due to hindered rotation
(
IRC). The enthalpy of activation is computed to be 32.1
kcal/mol in the gas phase.
a: LiALH
4 3 4 3
/THF, 87%; c: Swern, 83%; c: CH NHOH·HCl, MgSO , NaHCO ,
CH Cl2, 86%.
2
Scheme 8. Synthesis of nitrone 29, the tetrahydro analog of 7
Nitrone 29 was synthesized starting from the known ester
2634 in an analogous manner. Neither nitrone 25a, b, nor 29
showed any tendency to undergo the intramolecular
Figure 3. Relative enthalpy profile for the conversion of 7 to 8 at the M062x6-
311+G** level. Barriers are posted for transition states. For species 8, the
enthalpy of the associated retro Diels-Alder product is included.
cycloaddition and remained intact even at elevated temperatures
o
(
~60-70 C).
The fact that the spiro[2.4]hepta-4,6-diene unit was essential
for
a
successful
intramolecular
cyclopropane-nitrone
cycloaddition was confirmed by the following experiments: we
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European Journal of Organic Chemistry
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FULL PAPER
Conclusions
(Z)- and (E)-Spiro[2.4]hepta-4,6-diene-1-carbaldehyde oximes (18a
and 18b).
We propose that the concerted intramolecular C-
cyclopropylnitrone cyclization is unique to the cyclopentadienyl
system (or its benzo analog) and is a consequence of the
spiroconjugation effect that lengthens (and weakens) the C1-C3
bond in 7(13) and facilitates the ring opening component of the
reaction pathway.
In addition to the fact that the tandem reaction sequence
described herein represents the first uncatalyzed intramolecular
C-cyclopropylnitrone cyclization, it also provides an excellent
2 3
In a round-bottomed flask, 0.4g (5.3 mmol) of Na CO was added to a
solution of hydroxylamine hydrochloride (0.52 g, 10.3 mmol) in 5 ml of
water. Aldehyde 6, dissolved in 12.5 ml of EtOH was added to the
hydroxylamine solution and the mixture stirred for
1 h at room
temperature. The product was extracted with ethyl acetate, dried over
1
anhydrous MgSO
4
and the solvent rotovapped. According to the H NMR
the product was >95% pure. According to the relative integrals in the 1
H
NMR spectrum of the mixture, the ratio of 18a/18b was 1.3:1.
1H NMR (CDCl
3
, 500 MHz)  8.1 (br s, 1H, NOH, 18b), 7.7 (br s, 1H,
synthetic
entry
into
cyclopentadienones
since
the
NOH, 18a); 7.4 (d, J= 8.5 Hz, 1H, CH=N, 18b); 6.6 (d, J= 8.5 Hz, 1H,
CH=N, 18a); 6.58 (m, 1H, both isomers); 6.54 (m, 1H, both isomers);
6.25 (m, 1H, 18b); 6.22 (m, 1H, 18a); 6.14 (m, 1H, 18b); 6.11 (m, 1H,
18a); 3.49 (q, J= 8.5 Hz, 1H, 14b); 2.84 (q, J= 8.5 Hz, 1H, 18a); 2.1 (dd,
J= 8.5, 5.0 Hz, 1H, 18b); 2.03 (d, J= 8.5 Hz, 2H, 18a); 1.9 (dd, J= 7.0, 5.0,
spirocyclopropylcarbaldehyde precursors are readily available
from the corresponding cyclopentadienes by base-promoted
spiroannulation with epichlorohydrin.
1
1
H, 18b). 13C NMR (CDCl
33.7, 131.7, 131.5, 129.9, 129.7, 43.5, 25.5, 21.1, 17.8, 16.9 ppm.
3
, 175 MHz)  151.4, 151.2, 137.9, 137.7, 134.1,
+
HRMS (ESI) m/z calcd for 136.0757 (M+H) , found 136.0756.
Experimental Section
1
H-Inden-1-one
(14)
from
spiro[cyclopropane-1,1’-indene]-2-
General. 1H and 13C NMR spectra were recorded on a 500 MHz NMR
spectrometer, using CDCl as solvent and TMS as internal standard,
3
carbaldehyde (12/12’) via the N-methylnitrones 13/13’.
unless specified otherwise. Most column chromatographic separations
were carried out on a flash chromatography system using 40-60 mm
silica gel columns using ethyl acetate/n-hexane solvent mixtures. For
preparative TLC, silica gel (grade 60 PF254) was used. All reactions were
conducted under an atmosphere of dry nitrogen or argon. Non-
deuterated solvents were dried and distilled prior to use. Exact masses of
all new products by high resolution mass spectra (HRMS) were
determined at the San Francisco State University Mass Spectrometry
Facility.
The same procedure described above for 6 was implemented for the
nitrone formation from 12/12’. Thus, from 0.95 g (5.6 mmol) of 12/12’,
there were obtained 0.5 g (68%) of bright yellow 14 after chromatography
on silica gel (pet.ether/EtOAc, 1:1). The NMR spectra of the product so
obtained were identical in all respects to those reported in Reference 13.
The crude product spectrum contained both 14 and the other
fragmentation product (E)-allylidenemethanamine (17) (spectral data, see
below).
(
(
E)- and (Z)-spiro[cyclopropane-1,1’-indene]-2-carbaldehyde oximes
19 a and 19 b) from (1S, 2R) aldehyde 12.
Cyclopentadienone dimer 10 from spiro[2.4]hepta-4,6-diene-1-
carbaldehyde (6) via the N-methylnitrone 7.
The mixture of (1S, 2R) and (1S, 2S) aldehydes 12 and 12’, respectively,
was carefully separated by flash chromatography, and the resulting
product was practically pure (1S, 2R) isomer 12 (90%) (see spectral data
below). To a stirred solution of 0.52 g (7.5 mmol) of hydroxylamine
To a solution of N-methylhydroxylamine (0.184 g, 2.2 mmol) and 0.46 g
2
(3.4 mmol) of sodium acetate in 4 ml of H O, a solution of 0.24 g (2
mmol) of 6 in 5 mL of ethanol was added dropwise with rapid stirring at
room temperature. After 5 minutes all starting material was completely
dissolved. Stirring was continued for 2 hours. Then the reaction mixture
was extracted with 4x40 ml of ethyl acetate, the combined extracts dried
hydrochloride, 0.4 g (3.8 mmol) Na
aldehyde 12, dissolved in 12 ml of H
was stirred at room temperature for 1h. Then 10 ml of brine was added
and the mixture extracted with 2x25 ml of CH Cl , the combined extracts
dried over MgSO , the solvent rotovapped and the residue purified by
2 3 2
CO in 5 ml of H 0, 1,2 g (7 mmol) of
2
O was added dropwise. The mixture
2 4
over anhydrous Na SO , and the solvent rotovapped. The residue was
2
2
purified by column chromatography in silica gel eluting with petroleum
ether/ethyl acetate (1:1). Yield: 115 mg (36% yield) of 10. The NMR
spectral data were identical in all respects to those reported in Reference
4
flash chromatography on silica gel, eluting with 40% EtOAc/hexanes to
give a yellow oil to give 1.0 g (78%) of the oximes 19a (Z) and 19b (E) in
a ratio of 1.8:1, and very small amounts of the corresponding oximes
derived from (1S, 2S) aldehyde.
22.
Trapping of cyclopentadienone with cyclopentadiene. Synthesis of
0.
1H NMR (CDCl
3
, 500 MHz):  8.5 (br s, =NOH, 1H, major Z oxime); 8.1
1
(br s, NOH, 1H, minor E oxime); 7.44 (d, J= 7.5 Hz, 1H, CH=N, E
isomer); 7.43 (d, J= 7.0 Hz, 1H, aromatic H, Z isomer); 7.1-7.3 (m, 2H);
6.97-7.05 (two doublets, J= 7. Hz each, 2H); 6.98 (d, J= 5,5 Hz, 1H,
major isomer); 6.96 (d, J= 5.5 Hz, 1H, minor isomer); 6.64 (d, J= 8.5 Hz,
HC=N, Z isomer); 6.33 (d, J= 5.5 Hz, 1H, major Z isomer); 6.31 (d, J= 5.5
Hz, 1H, minor E isomer); 3.4 (dt, J= 8.5, 7.0 Hz, 1H, cyclopropyl CH-
CH=N, major Z isomer); 2.7 (dt, J= 9.0, 7.5 Hz, 1H, cylopropyl CH-CH=N,
4 2 3
In a 25 ml flask, MgSO (0.7 g, 0.01 mol), Na CO (1.5 g, 0.01 mol) and
N-methylhydroxylamine·HCl (1.312 g, 15.75 mmol) were combined, and
o
2
CH Cl
2
(25 ml) was added, the solution was cooled to 0 C, and aldehyde
6
(1.2 g, 0.01 mol) and freshly distilled cyclopentadiene (1 g, 1.5 mmol)
were added. The mixture was allowed to warm up to room temperature
and stirred for 2 h. The mixture was then concentrated, the crude mixture
purified by flash chromatography (EtOAc/hexanes 1:4) to give 10 (0.55 g,
minor isomer); 1.95-2.15 (two sets of multiplets, cylopropyl CH
2
, 2H, for
each isomer). 13C NMR, both isomers, (CDCl
3
, 75 MHz)  151.8, 151.7,
38%). The spectral data of 10 were identical to those reported in
146.9, 143.4, 136.1, 131.9, 131.6, 126.96, 126.90, 125.5, 125.4, 122.3,
Reference 23.
118.4, 118.2, 40.1, 28.4, 24.2, 20.7, 19.6 ppm. HRMS (ESI) m/z
+
calculated for C12H12NO (M+H) 186.0919, found 186.0913.
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European Journal of Organic Chemistry
10.1002/ejoc.201700915
FULL PAPER
Thermolysis of 19a, b and and 19’a, b.
144.4, 141.7, 126.9, 127, 126.9, 125.9, 124.7, 124.2, 123.4, 118.9, 60.6,
6
1
2
0.5, 48.2, 38.1, 37.1, 31.5, 30.73, 30.68, 29.95, 29.69, 24.5, 18.5, 14.6,
4.4 ppm. HRMS (ESI) m/z calculated for C14H O : 216.1150, found
16 2
16.1148.
A 1.8:1 mixture of 0.5g (2.7 mmol) of the oximes 19a,b and 19’a,b,
respectively was dissolved in 4 ml of d -toluene. The solution was placed
8
into a cylindrical pressure vessel with a Teflon bushing and heated with
stirring in an oil bath kept at 110 oC for 2h. The progress of the reaction
was monitored by 1H NMR. After the reaction was complete, the mixture
was subjected to flash chromatography on silica gel, using 40%
EtOAc/hexanes. The bright yellow top fraction was shown to be indenone
((1S, 2R)- and (1S, 2S)-2’,3’-dihydrospiro[cyclopropane-1,1-inden]2-
yl)methanol (23a, b).
A mixture of the esters 22a and 22b (2.55g, 11.81 mmol) was dissolved
in 50 ml of dry THF, and under nitrogen, at 0 oC, 23.6 ml of a 1M THF
(160 mg, 71% based on the relative amount of 19a in the mixture) and a
3
:1 mixture of 19b and the E oxime 19’b derived from the (1S, 2S)
solution of LiALH
addition the mixture was stirred overnight at room temperature. Then it
was cooled in an ice bath, and 50 ml of H O was added dropwise,
followed by 4 ml of 3N NaOHaq. The mixture was extracted with diethyl
ether (3x30 ml), the combined ether extracts washed with H O (30 ml),
brine (30 ml), and dried over anhydrous MgSO . The solvent was
rotovapped and the residue purified by flash chromatography on silica gel
hexane/EtOAc 3:1) to 2g of give a colorless oil (97% yield).
4
(23.6 mmol) was added dropwise. After complete
aldehyde (130 mg, 70% based on the relative amount of 19b in the
mixture). Inden-1-one (14) was identified by comparing its 1H NMR
spectrum with that described in Reference 25.
2
2
(
(
E)-(1S, 2R)-Spiro[cyclopropane-1,1’—indene-2-carbaldehyde oxime
19b).
4
(
1
1H NMR (CDCl
3
H NMR (CDCl , 500 MHz, both isomers)  7.1-7.3 (m, 3H); 6.87 (m, 1H,
3
, 500 MHz)  9.03 (br s, 1H, NOH); 7.4 (d, J= 7.5 Hz, 1H,
major isomer); 6.7 (m, 1H, minor isomer); 3.8, 3.6 and 3.5 (multiplets,
both isomers, 2H); 3.1, 2.9 (two multiplets, 2H); 2.4 and 2.3 (m, 1H); 2.1
and 1.9 (m, 1H); 1.5 (m, 1H); 1.4 (broad s, 1H, OH, minor isomer); 1.1 (m,
HC=N); 7.36 (d, J= 7.0 Hz, 1H); 7.23 (t, J= 7 Hz, 1H); 7.14 (t, J= 7.0 Hz,
1
1

H); 6.92 (d, J= 7.0 Hz, 1H); 6.9 (d, J= 5.5 Hz, 1H); 6.25 (d, J= 5.5 Hz,
H); 2.7 (m, 1H), 1.99 (m, 1H); 1.92 (m, 1H); 13C NMR (CDCl
3
, 125 MHz)
1
H); 1.04, and 0.82 (m, 1H); 1.01 (broad s, 1H, OH, major isomer). 13C
NMR (CDCl , 175 MHz)  148.1, 145.8, 143.81, 143.5, 126.8, 126.4,
26.24, 126.17, 124.9, 124.5, 121.1, 118.6, 64.4, 62.5, 37.8, 32.2, 31.6,
151.2, 135.7, 131.0, 126.4, 125.0, 121.9, 117.8. Signals due to the
minor isomer 19’b visible in the 13C NMR spectrum: 150.1, 139.7, 129.6,
3
1
3
126.4, 124.5, 122.1, 120.8, 25.4, 18.4 ppm.
1.1, 31.0, 30.5, 29.7, 28.6 ppm. HRMS (ESI) m/z calculated for
+
12
C H14O+Na : 197.0937, found 197.0932.
1-Methylene-2,3-dihydro-1H-indene (21).
(
1S, 2R)- and (1S, 2S)-2’,3’-Dihydrospiro[cyclopropane-1,1’-indene]-
In a 250 ml round bottomed flask equipped with a reflux condenser and
+
Br- and 3.50g (30.60
2-carbaldehyde (24a,b).
nitrogen inlet, 10.71g (30.0 mmol) of Ph
3
P CH
3
mmol) of 98% KOt-Bu were placed in 60 ml of anhydrous diethyl ether.
The mixture was refluxed under nitrogen for 2h. I was then cooled in an
ice bath, and a solution of 3.97g (30.0 mmol) of 1-indanone in 4 ml of
ether was added dropwise at 0 oC. Then the ice bath was removed and
the mixture refluxed for 1h. After allowing the mixture to cool to room
temperature, the solid was removed by filtration, the solution washed with
H O (30 ml), brine (30 ml), dried over anhydrous MgSO and the solvent
2 4
rotovapped. The crude product was purified by flash chromatography on
silica gel, eluting with hexane/ethyl acetate (4:1) to give a 3.62g (93%) of
a light yellow oil. The 1H NMR spectrum of 1-methylene-2,3-dihydro-1H-
To a solution of 348 mg (2.0 mmol) of the mixture of alcohols from the
reaction described above in 10 ml of CH
in CH Cl , 2.4 mmol, 1.2 equivs.) of the Dess-Martin periodinane (DMP)
was added dropwise at 0 oC. The the mixture was stirred at room
temperature for 2h. Aqueous Na (10 ml, 0.5M) was added and the
mixture stirred for 10 min, the aqueous layer separated, extracted with
CH Cl (2x10 ml), the combined extracts washed with each 10 ml of
NaHCO and brine and dried over anhydrous MgSO . The solvent was
2 2
Cl , 5.0 ml (0.48 M 15 weight%
2
2
2 2 3
S O
2
2
3
4
rotovapped and the crude product was purified by flash chromatography
on silica gel (hexane/EtOAc 5:1).
indene (21) so obtained was identical to that reported previously (see
Reference 33).
1H NMR (CDCl
, 500 MHz)  9.54 (d, J= 4.5 Hz, 1H, CHO, minor isomer);
.29 (d, J= 5.0 Hz, 1H, CHO, major isomer); 7.15-7.3 (m, 3H, ArH, both
isomers); 7.07 (m, 1H, major isomer); 6.76 (m, 1H, minor isomer); 2.0-3.2
overlapping multiplets, 2H), 2.46 (m, 1H, major isomer); 2.3 (m, 2H,
3
9
(
1S, 2R) and (1S, 2S)-Ethyl 2’3’-dihydrospiro[cyclopropane-1,1’-
(
indene-2-carboxylate (22a,b).
minor isomer); 2.24 (m, 1H, major isomer); 2.19 (t, J= 5.5 Hz, 1H, major
isomer); 1.96 (ddd, J= 13.0, 8.0, 1.5 Hz, 1H, major isomer), 1.91 (t, J=
1
-Methylene-2,3-dihydro-1H-indene (21, 3.60, 27.7 mmol) was dissolved
in 60 ml of CH Cl , 132 (0.30 mmol) mg of Rh (OAc) was added, and a
solution of ethyl diazoacetate (2.91 ml, 27.7 mmol) dissolved in 4 ml of
CH Cl was added dropwise through a syringe at room temperature. The
.0 Hz, 1H, minor isomer); 1.65 (m, 1H, both isomers isomers). 13C NMR
CDCl , 175 MHz) d 199.9, 1997, 145.7, 145.1, 143.9, 141.2, 127.33,
5
(
2
2
2
4
3
127.30, 127.0, 126.2, 124.9, 124.8, 122.3, 118.9, 40.8, 40.3, 39.2, 38.5,
2
2
3
C
7.7, 30.9, 30.7, 29.7, 23.1, 18.7 ppm. HRMS (ESI) m/z calculated for
mixture was stirred overnight and the green catalyst was removed by
filtration through a short pad of silica gel. The solvent was rotovapped
and the crude product was purified by flash chromatography on silica gel
+
13
H13O (M+H ): 173.0962, found 173.0963.
N-Methylnitrones 25a and 25b.
(
hexane/ethyl acetate 6:1) to give 4.80 g (74% yield) of a colorless oil.
1
H NMR (CDCl
3
, 500 MHz, two isomers)  7.1-7.25 (m, aromatic H’s),
4
A mixture of 300 mg (2.5 mmol) of anyhdrous MgSO , 420 mg (5.00
6.72 (m, 1H, aromatic); 4.19 (q, J= 7.0 Hz, 2H, major isomer); 4.04 (dq, A
mmol) of NaHCO
hydrochloride was placed in 10 ml of CH
of aldehydes 24a,b in 2 ml of CH Cl
mixture was stirred overnight at room temperature. Then 20 ml of H
was added, the layers were separated, the aquesous layer was extracted
once with 20 ml of CH Cl . The combined methylene chloride extracts
were washed with 20 ml of brine, dried over MgSO and the solvent
3
,
209 mg (2.5 mmol) of N-methylhydroxylamine
Cl . To this mixture, a solution
was added with stirring. The
part of an ABX
3
system, JAB= 10.5 Hz, JAX= 7.0 Hz, 1H, minor isomer);
system, JAB= 10.5 Hz, JAX= 7.0 Hz, 1H, minor
isomer); 2.85-3.15 (m, 2H, both isomers); 1.92-2.44 (several multiplets,
H, both isomers); 1.89 and 1.68 (2 triplets for each isomer, J= 5 Hz in
2
2
3.97 (dq, B part of an ABX
3
2
2
2
O
3
each, 1H); 1.44 (two overlapping multiplets, 1H, both isomers); 1.3 (t, J=
.0 Hz, 3H, major isomer); 1.14 (t, J= 7.0 Hz, 3H, minor isomer). 13C
2
2
7
NMR (CDCl , 175 MHz, both isomers)  172.07, 170,68, 145.9, 145.8,
3
4
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201700915
FULL PAPER
rotovapped. Due to the sensitivity of nitrones 25a and 25b toward silica
gel, it was not further purified. The product was >98% pure by 1H NMR.
Yield: 195 mg (97%).
and dried over MgSO
4
. After removal of solvent under reduced pressure,
the product was obtained as colorless oil (262 mg, 86%).
1H NMR (CDCl
, 500 MHz)  6.23 (d, J= 8.5 Hz, 1H, CH=N); 3.7 (s, 3H,
NCH ); 2.4 (dt, J= 8.5, 4.5 Hz, 1H); 1.6-1.8 (m, 6H), 1.56 (m, 1H); 1.47
(m, 1H); 1.2 (dd, J= 8.5, 4.5 Hz, 1H); 0.8 (t, 4.5 Hz, 1H). 13C NMR (CDCl
,
3
3
1H NMR (CDCl
.75 (m, 1H, minor isomer), 6.4 (d, J= 8.5 Hz, CH=N, major isomer); 6.34
d, J= 8.5 Hz, CH=N, minor isomer); 3.71 (s, 3H, NMe, major isomer);
.56 (s, NMe, minor isomer); 3.07 (m, 2H, major isomer); 3.042 and 2.92
2 multiplets, 2H, minor isomer), 2.8 (m, 1H, major isomer), 2,7 (m, 1H,
minor isomer); 2.4 (m, 1H. minor isomer); 2.2 (m, 1H, major isomer); 2.1
m, 1H, major isomer); 2.0 (m, 1H, minor isomer); 1.6 (overlapping
multiplets, 1H, both isomers); 1.46 (t, J= 5.5 Hz, 1H, minor isomer); 1.23
t, J= 5.5 Hz, 1H, major isomer). 13C NMR (CDCl
, 175 MHz), major
isomer,  145.7, 143.3, 139.7, 126.9, 126.8, 124.4, 119.2, 52.6, 36.8,
3
, 500 MHz)  7.1-7.2 (m, 3H), 6.8 (m, 1H, major isomer);
3
6
(
3
(
500 MHz)  142.0 (C=N); 52.4 (NMe), 37.4, 36.8, 32.0, 26.6, 25.8, 22.9,
21.8 ppm. HRMS (ESI) m/z calculated for 154.1227 (M+H) , found
154.1226.
+
(
Supporting Information. Supporting information ( H and 13C
NMR spectra of 10, 11, 12, 12’, 14/17, 18a, b, 19/19’, 19b/19’b’,
1
(
3
22a ,b, 23a, b, 24a, b, 25a, b, 27, 28, 29; complete reference 32,
as well as all computational data) associated with this article can
be found in the online version at
35.7, 30.9, 30.8, 24.9, 23.6 ppm; minor isomer, d 146.1, 142.7, 139.5,
1
26.9, 126.2, 125.3, 120.5, 52.6, 33.0, 36.5, 30.9, 25.8, 19.1 ppm. HRMS
+
(ESI) m/z calculated for C13
H16NO (M+H ): 202.1227, found 202.1227.
Spiro[2.4]heptan-1-ylmethanol (27).
Acknowledgements
To a solution of ethyl spiro[2.4]heptane-1-carboxylate2 (2.44 g, 14.5
o
mmol) in THF (50 ml) at 0 C, LiAlH
4
(1.0 M in THF, 29.0 ml, 29.0 mmol)
I. Erden acknowledges financial support of this work by funds
from the National Institutes of Health (Grant No. SC1 GM082340).
S. Gronert acknowledges support from the National Science
Foundation (CHE-1565852). The mass spectrometry work at SFSU
was in part supported by a grant from the National Science
Foundation (CHE-1228656) and is gratefully acknowledged. Mr.
G. Cabrera acknowledges an NIH MS/PhD Bridge fellowship
was added dropwise. The mixture was stirred overnight at room
temperature. After addition of water (50 ml) at 0 C, 3 N NaOHaq (4 ml)
o
was added. The aqeous layer was extracted with diethyl ether (3 x 20 ml),
the combined organic layers were washed with water (50 ml), brine (50
ml), and dried over anhydrous magnesium sulfate. The solvent was
rotovapped and the product was purified by flash chromatography on
silica gel (hexane/EtOAc 3:1) to give 21 as a colorless oil (1.587 g, 12.6
(R25-GM04897). We thank Ms. Lourdes Adame for technical
mmol, 87%).
1
support.
H NMR (CDCl , 500 MHz)  3.6 (dd, J= 11, 6.5 Hz, 1H); 3.5 (dd, J= 11.0,
3
8
1
1
1
1
.0 Hz, 1H); 1.64-1.76 (m, 4H); 1.6 (m, 2H); 1.45 (m, 2H); 1.37 (broad s,
H, OH); 1.09 (m, 1H); 0.64 (dd, J= 8.5, 4.5 Hz, 1H); 0.27 (t, J= 5.0 Hz,
Keywords: spiroconjugation • C-cyclopropylnitrone •
cycloaddition • cyclopentadienone • NH-nitrone
H). 13C NMR (CDCl
8.6 ppm. HRMS (ESI) m/z calcd for C
, 175 MHz)  65.2, 37.4, 30.5, 27.4, 26.7, 26.1, 25.6,
3
+
8
H15O (M+H ) 127.1118, found
27.1119.
[
[
1]
2]
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2 2
To a solution of oxalyl chloride (0.655 ml, 7.5 mmol) in CH Cl (20 ml)
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2010/4, pp. 325-403.
o
15 min at -78 C, a solution of spiro[2.4]heptan-1-ylmethanol (0.63 g, 5.0
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o
mmol) in 4 ml of CH
2
Cl
2
was added. The mixture was stirred at -78 C for
30 min. After the addition of NEt
3
(2.087 ml, 15.0 mmol) at -78 oC, the
o
resulting solution was stirred at -78 C for 30 min, then for 60 min at room
temperature. After adding H
and the aqueous layer extracted with CH
organic extracts were washed with water (20 ml), brine (20 ml), and dried
over anhydrous MgSO . After removal of solvent under reduced pressure
the residue was purified by column chromatography on silica gel (hexane
OEtAc = 6:1) to give 28 as a colourless oil (0.512 mg, 83%).
2
O (20 ml) the organic layer was separated
2
Cl (2 x 20 ml). The combined
2
4
[
[
3]
4]
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H NMR (CDCl
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.0, 5.5 Hz, 1H); 1.81 (m, 1H); 1.63-1.77 (m, 6H), 1.58 (m, 1H); 1.4 (t, J=
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3
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8
H
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To a suspension of MgSO
mmol) and N-methylhydroxylamine hydrochloride (418 mg, 5.0 mmol) in
0 ml of CH Cl , spiro[2.4]heptane-1-carbaldehyde (248 mg, 2.0 mmol)
was added, the resulting mixture stirred overnight at room temperature.
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4 3
(600 mg, 5.0 mmol), NaHCO (840 mg, 10.0
1
2
2
2
2
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201700915
FULL PAPER
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European Journal of Organic Chemistry
10.1002/ejoc.201700915
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Cyclopentadienone synthesis
Ihsan Erden,*[ Christian Gärtner,
a]
[a]
Jingxiang Ma,[ Gabriel Cabrera,[a] Kate
Markham,[a] Saeed Azimi,[a] and Scott
Gronert,*[b]
a]
Page No. – Page No.
C-Cyclopropylnitrones derived from spiro[2.4]hepta-4,6-diene-1-carbaldehyde and
its benzo analog undergo an unprecedented tandem cyclization-retro-Diels-Alder
reaction of the 5,6-dihydro-1,2-oxazine intermediates to give the corresponding
cyclopentadienones. Computational work indicates that the cyclization step is
concerted but highly asynchronous.
Cyclopentadienones via a tandem C-
cyclopropylnitrone cyclization-
cycloreversion process
[
[
a]
b]
Department of Chemistry and Biochemistry, San Francisco S
University, 1600 Holloway Avenue, San Francisco, CA 9413
E-mail: ierden@sfsu.edu
Department of Chemistry, Virginia Commonwealth Universit
West Main Street, Richmond, Virginia 23284, USA
E-mail: sgronert@vcu.edu
Supporting information for this article is given via a link at the
the document.
This article is protected by copyright. All rights reserved.