Stereospecific synthesis of alkylidenecyclopropanes via sequential cyclopropene carbomagnesation/1,3-carbon shift

Article abstract of DOI:10.1021/jo1002938

Figure presented Alkylidenecyclopropanes can be synthesized from enantiomerically enriched cyclopropene derivatives with >99% stereotransfer and good to excellent yield. The protocol comprises the stereoselective reaction of Grignard reagents with 1-alkoxymethyl-3-hydroxymethylcyclopropenes and a stereospecific [1,3] carbon shift reaction.

Full text of DOI:10.1021/jo1002938

pubs.acs.org/joc
that rapidly build stereochemical complexity through ring
Stereospecific Synthesis of Alkylidenecyclopropanes
via Sequential Cyclopropene Carbomagnesation/1,3-
Carbon Shift
expansion,2 cycloadditions,3 or ring-opening reactions.4
While a number of methods for generating alkylidene-
cyclopropanes5 have been reported, access to enantio-
merically enriched alkylidenecyclopropanes has been
limited.6
Xiaocong Xie, Zhe Yang, and Joseph M. Fox*
An early approach to nonracemic alkylidenecyclopro-
panes utilized the stereospecific, formal [1,3] carbon shift
of Fiest’s ester, a methylenecyclopropane which is readily
available in enantiomerically pure form.7 However, the
preparative utility of such rearrangements of methylenecy-
clopropanes to alkylidenecyclopropanes is typically limited
by the need for pyrolytic conditions.8 Studies by Gardner,9
Creary,10 and Nakamura11 have shown that aryl-10 or alkoxy-
substituted9,11 methylenecyclopropanes rearrange to alkyli-
denecyclopropanes under mild conditions. However, the
stereospecificity of the rearrangements of methylenecyclopro-
panes withstabilizing substitutentshad notbeentested. More-
over, there was no method to access enantiomerically
enriched methylenecyclopropanes with substituents that
facilitate the [1,3]-carbon shift reaction.
Our group had previously demonstrated that enantiomeri-
cally enriched methylenecyclopropanes (e.g., 2) canbeobtained
by addition of Grignard reagents to chiral cyclopropenes
(e.g., 1) with allylic ether leaving groups (Scheme 1).12 Con-
temporaneously, Marek reported Grignard reagent addition
to resolved cyclopropenylcarbinols to form chiral alkylidene-
cyclopropanes.6c-f We anticipated that the aromatic substituents
of methylenecyclopropenes 2 would facilitate the rearrangement
Brown Laboratories, Department of Chemistry and
Biochemistry, University of Delaware, Newark 19716
*jmfox@udel.edu
Received February 20, 2010
Alkylidenecyclopropanes can be synthesized from enantio-
merically enriched cyclopropene derivatives with >99%
stereotransfer and good to excellent yield. The protocol
comprises the stereoselective reaction of Grignard reagents
with 1-alkoxymethyl-3-hydroxymethylcyclopropenes and a
stereospecific [1,3] carbon shift reaction.
Alkylidenecyclopropanes have been the subject of con-
siderable investigation because of their high strain energy
and unique reactivity.1 The utility of chiral alkylidenecyclo-
propanes is exemplified by stereospecific transformations
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DOI: 10.1021/jo1002938
r
Published on Web 05/12/2010
J. Org. Chem. 2010, 75, 3847–3850 3847
2010 American Chemical Society

Xie et al.
JOCNote
SCHEME 1. Stereospecific Synthesis of Chiral Alkylidenecy-
clopropanes (2) from Cyclopropenes with Allylic Leaving Groups
FIGURE 1. Methylenecyclopropanes that do not rearrange effi-
ciently to alkylidenecyclopropanes.
SCHEME 3. Assignment of Absolute Stereochemistry for 2a
SCHEME 2. Synthesis of Alkylidenecyclopropanes from
Methylenecyclopropanes
acee = (product ee/starting material ee) ꢀ 100%. 2a-g and 3a-g were
all measured to be 82% ee ((1% ee).
to alkylidenecyclopropenes 3 under mild conditions. Cyclopro-
penylcarbinols with aromatic substituents (e.g., 1) are readily
available with good levels of enantiomeric excess via Rh2(S-
DOSP)4-catalyzed cyclopropenation.13 Accordingly, we envi-
sioned a general methodology that would produce alkylidene-
cyclopropanes (3) upon sequential treatment of 1 with Grignard
reagents and heat (Scheme 1).
only starting material was recovered (Figure 1). The formal
[1,3] shifts of 5-7 did take place at higher temperature
(toluene, reflux for 10 h). However, significant decomposi-
tion took place, and only low yields of the alkylidenecyclo-
propanes (<10% yield) were detected by 1H NMR.
The rearrangements of methylenecyclopropanes 1 proceed
in THF at reflux temperature (Scheme 2). For all of the
reactions in Scheme 2, small amounts of starting material
were recovered (5-10%). Prolonged heating did not result in
higher conversion. Also, minor amounts of isomeric methy-
lenecyclopropanes (4a-g) were observed. Compounds 4a-g
resulted from epimerization of 2a-g.14 It was possible to
separate 3g and 4g via preparative HPLC. When purified, 3g
was heated to reflux in THF for 16 h, and compound 4g (3%)
and trace 2g (∼1%) were observed along with recovered 3g
(96%). This result demonstrated that the reaction to form 3g
is reversible.
To verify that the methylenecyclopropane to alkylidenecy-
clopropane rearrangement took place with net inversion of
stereochemistry, the absolute configuration of methylenecyclo-
propane 2a and alkylidenecyclopropane 3a were assigned. Thus,
enantiomerically enriched methylenecyclopropane 2a was pre-
pared in 82% ee by the Rh2(S-DOSP)4-catalyzed reaction of
methyl R-diazo-R-phenylacetate with methyl propargyl ether,
followed by DIBAL reduction and reaction with MeMgBr
(Scheme 3). The absolute configuration of intermediate 8 was
assigned by conversion into (4S)-3-[(1S)-phenyl-2-(methoxy-
methyl)cycloprop-2-en-1-oyl]-4-phenyloxazolidinone [(S,S)-9].
The diastereomer (R,S)-9 had been prepared previously,15 and
its absolute configuration has been established through X-ray
crystallography (see the Supporting Information). Thus, Rh2-
(S-DOSP)4 gives cyclopropane 8 with the (S)-configuration and
ultimately provided (R,R)-2a.
As anticipated,10 the aryl substituent on the methylenecy-
clopropane was necessary for reactions to take place under
mild conditions. Thus, compounds 5-7 did not produce the
alkylidenecyclopropanes after refluxing in THF for 16 h;
(13) Davies, H. M. L.; Lee, G. H. Org. Lett. 2004, 6, 1233.
(14) Gajewski, J. J. J. Am. Chem. Soc. 1971, 93, 4450.
(15) Liao, L.-A.; Zhang, F.; Olga, D.; Bach, R. D.; Fox, J. M. J. Am.
Chem. Soc. 2004, 126, 4490.
3848 J. Org. Chem. Vol. 75, No. 11, 2010

Xie et al.
JOCNote
SCHEME 4. Assignment of Absolute Configuration for 2a
SCHEME 5. Substituent Effects on Methylenecyclopropane to
Alkylidenecyclopropane Rearrangementa
FIGURE 2. (a) Diradical mechanism for the methylenecyclopro-
pane to alkylidenecyclopropane rearrangements. (b) For the rear-
rangement of 2j, it is proposed that the o-methyl substituent
hampers aromatic stabilization in a transition state with diradical
character.
after 8 h). The rearrangement of 2i (Ar = p-fluorophenyl)
reached only 36% conversion after 1 h (90% conversion after
8 h). The o-tolyl-substituted methylenecyclopropane 2j
(Ar = o-tolyl) led only to traces (2% yield) of 3j upon pro-
longed heating in THF. At higher temperature (toluene, reflux
5 h) a 12% yield of 3j was observed (Scheme 5).
Excellent levels of chirality transfer [>99% conservation
of enantiomeric excess (cee)] were observed for the transfor-
mations in Scheme 2. In prior studies on rearrangements of
nonracemic methylenecyclopropanes, lower levels of chirality
transfer wereobserved. Feist’s ester was showntorearrangeto
a mixture of (E)- and (Z)-methylcarboxycyclopropylidenea-
cetic acid18a,19 with 93% cee and 47% cee, respectively.19 In
studies on (S,S)-2,3-dimethylmethylenecyclopropane, high
levels of chirality transfer were observed at low conversion
(80% cee ( 20%), but less efficient chirality transfer and
partial racemization of starting material was observed at
higher conversion.8c
These observations are consistent with the accepted diradical
mechanism for the methylenecyclopropane to alkylidenecyclo-
propane rearrangements.10,18-20 Aromatic substituents have a
dramatic stabilizing influence.10 A p-methoxy substituent ac-
celerates the rate of the reaction, and a p-fluoro substituent
decreases the rate of the reaction, but the effect is only minor.
However, the rate of rearrangement for 2j is severly reduced
by the o-methyl substituent, which hampers coplanarity in
a transition state with diradical character and axial chirality
(Figure 2). The observation of isomeric products 4 (Scheme 2)
is also in line with a diradical mechanism, in accord with earlier
observations by Gajewski.8c
aAll reactions were carried out in THF at reflux temperature
The absolute configuration of 3a was assigned by Raney
Ni reduction, which gave separable diastereomers (S,S)-10
and 11. (Scheme 4). The opposite enantiomer of (S,S)-10 was
produced upon reduction of the known compound 12, which
was prepared as described by Davies. Davies had shown that 12
prepared from Rh2(S-DOSP)4 has the (1R,2R)-configuration.16
Thus, (1R,2R)-2a rearranges to give (S)-3a and a net inversion of
stereochemistry at the pivot carbon is observed.17
The effect of varying the aromatic ring of the methylene-
cyclopropane was also studied. An electronically releasing
p-methoxyphenyl group accelerated the rearrangement,
whereas an electron-withdrawing p-fluorophenyl substituent
decreased the reaction rate. Thus, the rearrangement of 2h to
3h (Ar = p-methoxyphenyl) reached 77% conversion after
reflux for 1 h (94% conversion after 4 h). By contrast, only 50%
of 2a to 3a (Ar = Ph) had converted after 1 h (90% conversion
(18) Diradical intermediate mechanistic proposals for the methylenecy-
clopropane rearrangement: (a) Doering, W.; von, E.; Roth, H. D. Tetra-
hedron 1970, 26, 2825. (b) Doering, W.; von, E.; Birladeanu, L. Tetrahedron
1973, 29, 499.
(19) Diradical transition state mechanistic proposal for the methylenecy-
clopropane rearrangement: Buchwalter, S. L. Tetrahedron 1984, 40, 5097.
(20) Concerted mechanistic proposals for the methylenecyclopropane
rearangement: (a) Zimmerman, H. E. Acc. Chem. Res. 1971, 4, 272. (b)
Dewar, M. J. S. Angew. Chem., Int. Ed. 1971, 10, 761. (c) Woodward, R. B.;
Hoffmann, R. Angew. Chem., Int. Ed. 1969, 8, 781. (d) Heilbronner, E.
Tetrahedron Lett. 1964, 5, 1923. (e) Berson, J. A.; Nelson, G. L. J. Am. Chem.
Soc. 1967, 89, 5503. (f) Berson, J. A.; Salem, L. J. Am. Chem. Soc. 1972, 94,
8917.
(16) Davies, H. M. L.; Bruzinski, P. R.; Fall, M. J. Tetrahedron Lett. 1996,
37, 4133.
(17) Ullman, E. F. J. Am. Chem. Soc. 1960, 82, 505.
J. Org. Chem. Vol. 75, No. 11, 2010 3849

Xie et al.
JOCNote
SCHEME 6. One-Pot Reaction to Form Alkylidenecyclopro-
panes
1.37-1.40 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 141.4 (C),
128.4 (CH), 128.2 (C), 128.0 (CH), 126.7 (CH), 114.7 (CH), 68.8
(CH2), 31.0 (C), 16.9 (CH3), 15.6 (CH3); IR (neat, cm-1) 3351,
3083, 3059, 3028, 2957, 2924, 2855, 1602, 1495, 1464, 1416,
1378, 1303, 1222, 1176, 1029, 905, 760, 732, 699, 562, 542;
HRMS-CI (M þ NH4) m/z calcd for C12H18NO 192.1388,
found 192.1380.
Representative Procedure for the One-Pot Grignard Addition/
Rearrangement to Alkylidenecclopropanes: (S,E)-2-Hydroxy-
methyl-2-phenylheptylidenecyclopropane (3c). To a 50 mL round
bottomed flask was added a solution of 3-hydroxymethyl-1-
methoxyethoxymethoxymethyl-3-phenylcyclopropene (63 mg,
0.24 mmol) in THF (5 mL). The mixture was stirred with a
magnetic stir bar, and hexylmagnesium bromide (2.4 mmol,
1.2 mL of a 2.0 M solution in diethyl ether) was slowly added via
syringe. The resulting mixture was allowed to stir at rt for 12 h
and then heated to reflux for 5 h. The reaction was quenched
with saturated NH4Cl. The aqueous layer was extracted with
ethyl acetate (5 mL) three times, and the combined organic
layers were washed with brine and dried over anhydrous
MgSO4. The solvent was removed, and the crude product was
purified by silica gel chromatography (10% ethyl acetate in
hexanes) to give 37 mg (0.15 mmol, 64% yield) of 3c as a pale
yellow oil. A similar experiment that began with 55 mg of 1 gave
3c in 59% yield. Small peaks attributable to 4c (3%) were
detected in the 1H NMR spectrum at 5.73, 5.57, 4.03, and 3.58
ppm. HPLC analysis showed the material to be of 82% ee (using
a chiral OD column, flow rate of 1 mL/min, 1% IPA in hexanes:
Most conveniently, the rearrangement of methylenecyclo-
propanes to alkylidenecyclopropanes can be carried out in
one pot from the cyclopropene precursor 1 (Scheme 6). The
overall yields are comparable with the combined yields of
separate Grignard addition and rearrangement reactions.
In conclusion, a stereospecific method for preparing alky-
lidenecyclopropanes from enantiomerically enriched methy-
lenecyclopropanes has been described. The reaction takes
place under mild conditions and takes place with excellent
transfer of stereochemistry. This reaction can also be carried
out in one pot from enantiomerically enriched cyclopropene
precursors.
[R]20 -47 (c 0.34, CHCl3); 1H NMR (400 MHz, CDCl3) δ
D
7.35-7.40 (m, 2H), 7.28-7.33 (m, 2H), 7.20-7.24 (m, 1H),
6.07-6.12 (m, 1H), 3.88 (dd, J = 11.3, 6.1 Hz, 1H), 3.72 (dd, J =
11.3, 6.8 Hz, 1H), 2.19-2.25 (m, 2H), 1.24-1.56 (m, 11H), 0.88
(t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 141.5 (C),
128.4 (CH), 127.9 (CH), 127.3 (C), 126.6 (CH), 120.2 (CH), 68.8
(CH2), 31.7 (CH2), 31.6 (CH2), 30.4 (C), 29.1 (CH2), 29.0 (CH2),
22.7 (CH2), 16.1 (CH2), 14.1 (CH3); IR (neat, cm-1) 2924, 2854,
2360, 2341, 1494, 1024, 764, 697, 502; HRMS-CI (M þ NH4)
m/z calcd for C17H28NO 262.2171, found 262.2175.
Experimental Section
Representative Procedure for the [1,3] Carbon Shift Reaction:
(S,E)-2-Hydroxymethyl-2-phenylethylidenecyclopropane (3a).
To a 100 mL round bottomed flask was added a solution of 2a
(52 mg, 0.30 mmol) in THF (15 mL). The reaction mixture was
heated to reflux temperature for 16 h. Subsequently, the mixture
was allowed to cool and concentrated under reduced pressure.
Purification by silica gel chromatography (10% ethyl acetate in
hexane) gave 37 mg (0.21 mmol, 71% yield) of 3a as a pale yellow
oil. A similar experiment that began with 46 mg of 2a gave 3a in
70% yield. Small peaks attributable to 4a (7%) were detected in
the 1H NMR spectrum at 5.74, 5.57, 4.00, 3.58, 1.77, and 0.84
ppm and in the 13C NMR at 129.9, 126.9 ppm. HPLC analysis
showed the material to be of 82% ee (using a Chiral OD column,
flow rate of 1 mL/min, 1% IPA in hexanes): [R]20D -76 (c 0.28,
Acknowledgment. For financial support we thank
NIGMS (NIH R01 GM068650). We thank Dr. Lian-an Liao
for growing a crystal of (R,S)-9 and Glenn Yap for determin-
ing the X-ray structure.
1
CHCl3); H NMR (400 MHz, CDCl3) δ 7.37-7.40 (m, 2H),
Supporting Information Available: Full experimental and
1
7.28-7.34 (m, 2H), 7.20-7.25 (m, 1H), 6.09-6.15 (m, 1H), 3.87
(dd, J = 11.3, 6.1 Hz, 1H), 3.72 (dd, J = 11.2, 6.6 Hz, 1H), 1.86
(dt, J = 6.5, 1.7 Hz, 3H), 1.51-1.55 (m, 1H), 1.41-1.45 (m, 1H),
characterization details, H and 13C NMR spectra, and X-ray
data for compound (R,S)-9. This material is available free of
charge via the Internet at http://pubs.acs.org.
3850 J. Org. Chem. Vol. 75, No. 11, 2010