Convenient access to various 1-cyclopropylcyclopropane derivatives

Article abstract of DOI:10.1002/ejoc.201000209

1-Bromo-1-cyclopropylcyclopropane (1), which is easily accessible in two steps from methyl cyclopropanecarboxylate, does not form a stable Grignard reagent: upon reaction with elemental magnesium, yet it readily undergoes bromine/ lithium exchange without rearrangement upon treatment with tert-butyllithium in diethyl ether/pentane at -78 °C, and the resulting 1-lithio-1-cyclopropylcyclopropane can be trapped with various electrophiles to give the correspondingly 1-substituted bicyclopropyl derivatives 10 in yields ranging from 38 to over 90 % (13 examples). The (1-cyclopropylcyclopropyl) boronate 10m, which is also obtained from the 1-lithio derivative, has been subjected to Suzuki cross couplings with a number of aryl halides to furnish 1-aryl-1,1′bicyclopropyl compounds 11 (4 examples, 14-50% yield), predominantly without rearrangement. Further transformations of 1-cyclopropylcyclopropanecarbaldehyde (10e) have provided 2-(1- cyclopropylcyclopropyl)glycme (16), ethyl 3-(1-cyclopropylcyclopropyl)acrylate (17), and its cycloadducts with the nitrone 18 and cyclopentadiene 19, albeit the latter only in poor yield.

Full text of DOI:10.1002/ejoc.201000209

FULL PAPER
DOI: 10.1002/ejoc.201000209
Convenient Access to Various 1-Cyclopropylcyclopropane Derivatives[‡]
Armin de Meijere,*[a] Alexander F. Khlebnikov,[b] Hans Wolf Sünnemann,[a] Daniel Frank,[a]
Karsten Rauch,[a] and Dmitrii S. Yufit[c]
Dedicated to Professor Wolfgang Lüttke on the occasion of his 90th birthday
Keywords: Cyclopropanes / Organolithium compounds / Electrophilic substitution / Cross coupling / Cycloaddition / Small
ring systems
1-Bromo-1-cyclopropylcyclopropane (1), which is easily ac-
cessible in two steps from methyl cyclopropanecarboxylate,
does not form a stable Grignard reagent upon reaction with
elemental magnesium, yet it readily undergoes bromine/
lithium exchange without rearrangement upon treatment
with tert-butyllithium in diethyl ether/pentane at –78 °C, and
the resulting 1-lithio-1-cyclopropylcyclopropane can be
ylcyclopropyl)boronate 10m, which is also obtained from the
1-lithio derivative, has been subjected to Suzuki cross cou-
plings with a number of aryl halides to furnish 1-aryl-1,1Ј-
bicyclopropyl compounds 11 (4 examples, 14–50% yield),
predominantly without rearrangement. Further transforma-
tions of 1-cyclopropylcyclopropanecarbaldehyde (10e) have
provided 2-(1-cyclopropylcyclopropyl)glycine (16), ethyl 3-
trapped with various electrophiles to give the correspond- (1-cyclopropylcyclopropyl)acrylate (17), and its cycloadducts
ingly 1-substituted bicyclopropyl derivatives 10 in yields with the nitrone 18 and cyclopentadiene 19, albeit the latter
ranging from 38 to over 90% (13 examples). The (1-cycloprop- only in poor yield.
the 1-cyclopropylcyclopropyl substituent onto various func-
tionalities and skeletons, and here we report our first re-
sults.
Introduction
With the appearance of two recent patent applications
claiming particular biological activities for certain 1- and 2-
cyclopropylcyclopropane derivatives[1,2] the interest in the
peculiar 1- and 2-cyclopropylcyclopropyl substituents has
dramatically increased in research groups concerned with
drug and agrochemical discovery and development. Since
1-bromo-1-cyclopropylcyclopropane (1) has been made
available in two simple steps on a reasonably large scale[3]
as the immediate precursor to the versatile cyclopropyl
building block bicyclopropylidene,[4] we set out to probe,
whether 1 would be applicable as a reagent itself to attach
Results and Discussion
Initial attempts to convert 1 under classical Grignard
conditions into (1-cyclopropylcyclopropyl)magnesium bro-
mide (2) in order to trap the latter with a variety of electro-
philes and obtain the corresponding 1-substituted bi-
cyclopropyl derivatives, only gave
a
mixture of
1,1Ј;1Ј,1ЈЈ;1ЈЈ,1ЈЈЈ-quatercyclopropane (4), 1-cyclopropyl-1-
(3-cyclopropylidenepropyl)cyclopropane (5) and 1,6-di-
cyclopropylidenehexane (6) in a ratio of 1:8:20 in 90% yield
(Scheme 1).
Apparently, the initially formed intact Grignard reagent
2, just like (1-cyclopropylcyclopropyl)palladium intermedi-
ates[5] and simple (cyclopropylmethyl)metal derivatives,[6,7]
undergoes a relatively rapid rearrangement to the homoallyl
[‡] Cyclopropyl Building Blocks for Organic Synthesis, 154. Part
153: M. Limbach, A. Lygin, V. S. Korotkov, M. Es-Sayed, A.
de Meijere, Org. Biomol. Chem. 2009, 3338–3342; Part 152:
V. A. Rassadin, A. A. Tomashevskiy, V. V. Sokolov, A. Ringe, J.
Magull, A. de Meijere, Eur. J. Org. Chem. 2009, 2645–2641.
[a] Institut für Organische und Biomolekulare Chemie der Georg- counterpart 3. This must serve as the precursor to 3-cyclo-
August-Universität Göttingen,
propylidenepropyl bromide (8), probably by way of the
Tammannstrasse 2, 37077 Göttingen, Germany
Schlenk equilibrium of 3 with 7 and magnesium bromide.
The bicyclopropylyl bromide 1 does not rearrange to 8
in the presence of magnesium bromide in refluxing diethyl
ether, as was proved by a control experiment. The homo-
allyl bromide 8 can then react with the intact Grignard rea-
gent 2 to give 5, and with the rearranged homoallylmagne-
sium bromide 3 or the bis(homoallyl)magnesium 7 to fur-
Fax: +49-551-399475
E-mail: ameijer1@uni-goettingen.de
[b] Department of Chemistry, Saint Petersburg State University,
Universitetskii Prosp. 26, Petrodvorets, 198504 St. Petersburg,
Russia
[c] Department of Chemistry, University of Durham,
South Rd., Durham DH1 3L, U.K
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000209.
Eur. J. Org. Chem. 2010, 3295–3301
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A. de Meijere et al.
FULL PAPER
Scheme 2. Bromine/lithium exchange on 1-bromobicyclopropyl (1)
and subsequent electrophilic substitution. For details see Table 1.
Table 1. Bromine/lithium exchange on 1-bromobicyclopropyl (1)
and subsequent electrophilic substitution (see Scheme 2).
Scheme 1. Reaction of 1-bromo-1-cyclopropylcyclopropane (1)
with magnesium turnings.
nish 6. The latter can also be formed by reductive elimi-
nation from 7. The quatercyclopropyl 4 must arise by re-
ductive elimination from bis(1-cyclopropylcyclopropyl)-
magnesium (9), which is formed in the Schlenk equilibrium
with 2 and magnesium bromide.
Treatment of 1 in tetrahydrofuran with magnesium turn-
ings in the presence of benzaldehyde, i.e. under conditions
of the so-called Barbier reaction,[8] furnished the same hy-
drocarbons 5 and 6, but none of the tertiary alcohol that
would have resulted from the addition of 2 to benzaldehyde.
The formation of the bicyclopropyl coupling products 4
and 5 indicates that the rearrangement of (bicyclopropyl-1-
yl)magnesium bromide (2) is not extremely rapid even at
35 °C. One would therefore expect that a (bicyclopropyl-1-
yl)metal derivative, when generated at lower temperature,
would survive long enough to be trapped by appropriate
[a] The aldehyde was not completely purified, but further trans-
formed as a 1:1 mixture with Et2O. [b] Isolated as the air-stable
borane complex.
electrophiles before undergoing rearrangement to the corre- clopropylboronates are known,[15] and an analogous cross
sponding (homoallyl)metal species. An attempt to achieve coupling of a (trans-2-cyclopropylcyclopropyl)boronate to
a bromine/magnesium exchange by treatment of 1 with iso- yield (trans-2-cyclopropylcyclopropyl)arenes has previously
propylmagnesium chloride in the presence of lithium chlo- been developed in our laboratory.[16] However, 10m is a ter-
ride (so-called turbo-Grignard) according to Knochel et tiary and at the same time neopentyl-type alkylboronate,
al.,[9] was not successful. An attempted bromine/lithium ex- and couplings of such substrates are unknown. Yet, when
change on 1 with n-butyllithium at –78 °C also failed.
10m and phenyl iodide were subjected to typical Suzuki
However, treatment of 1-bromobicyclopropyl (1) in di- coupling conditions, 1-phenyl-1,1Ј-bicyclopropyl (11n) was
ethyl ether with tert-butyllithium in pentane at –78 °C and obtained in 50% yield (Scheme 3). Analogously, the reac-
subsequent quenching with trimethylsilyl chloride gave 1- tions of 10m with 1-bromo-4-(trifluoromethyl)benzene and
(trimethylsilyl)-1-cyclopropylcyclopropane (10a) in 53% 4-iodoanisol gave the corresponding bicyclopropyl deriva-
yield. Analogously, various 1-substituted bicyclopropyl de- tives 11o and 11p each in 45% yield. 1,4-Dibromobenzene
rivatives 10b–m were obtained in yields ranging from 38 to furnished the twofold coupling product 12 in poor yield
approx. 92% (Scheme 2 and Table 1). Among them are the (14%) along with the monocoupling/monoreduction prod-
(1-cyclopropylcyclopropyl)stannane 10b, the carboxylic uct 11n (25%) and 1-iodo-2,4,6-trimethylbenzene only pro-
acid 10d,[10] the aldehyde 10e, the diphenylphosphanyl de- vided the product 13 with a rearranged C6 unit (17% yield),
rivative 10l as a potentially interesting new ligand for transi- the formation of which is not understood. Attempted cou-
tion metals, and the boronate 10m. This access to 10m is pling of 10m with 1-bromo-2-(trifluoromethyl)benzene, 2-
far superior to a previously published preparation of 2-(bi- bromoaniline, 2-bromo-N-(tert-butoxycarbonyl)aniline as
cyclopropyl-1-yl)-1,3,2-dioxaborinane from bicyclopropyl- well as 3-iodopyridine did not lead to any identifiable prod-
idene.[11]
ucts, and 2-iodopyridine in the presence of 10m only led to
Since the boronate 10m was obtained in higher yield 2,2Ј-bipyridyl (14). Although all the yields in the successful
(71%) than the stannane 10b (61%) and Suzuki cou- couplings of 10m are not very high, it is remarkable that
plings[12] are more popular than Stille couplings,[13,14] the the products 11n–p were obtained without rearrangement
palladium-catalyzed cross coupling of 10m with some aryl (Table 2), as previously developed cross couplings proceed-
halides was tested. Suzuki cross couplings of simple cy- ing via (1-cyclopropylcyclopropyl)palladium intermediates
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Convenient Access to Various 1-Cyclopropylcyclopropane Derivatives
gave rearrangement products only.[5] Attempts to improve (3RS,4SR,5SR), i.e. trans,trans-18 (Figure 1). This is consis-
the yields in the Suzuki couplings of 10m by using the more tent with the interactions 3-H/CH2O, 3-H/5-H, 4-H/o-H(3-
advanced protocol by Buchwald et al.,[17] failed completely. Ph), 4-H/cPr-H, observed in the 2D-NOESY 1H-NMR
Under two types of conditions as reported, only traces of spectrum.
the product 11n could be detected, when bromo- and iodo-
benzene were employed.
Scheme 3. Suzuki cross coupling of (1-cyclopropylcyclopropyl)-
boronate 10m with some aryl halides. For details see Table 2.
Table 2. Suzuki cross coupling of (1-cyclopropylcyclopropyl)-
boronate 10m with some aryl halides (see Scheme 3).
ArX
Time [h]
Product
Yield [%]
Scheme 5. Preparation of ethyl (E)-3-(1-cyclopropylcyclopropyl)-
acrylate (17) and its employment in cycloaddition reactions.
PhI
20
25
25
25
25
20
11n
11o
11p
12
13
14
50
45
4-F3CC6H4Br
4-MeOC6H4Br
4-BrC6H4Br
2,4,6-Me3C6H2I
2-Py-I
45
14[a]
17
67
[a] In addition, 25% of 11n was isolated.
The aldehyde 10e could be converted into the unusual
amino acid 16 via the (1-cyclopropylcyclopropyl)-substi-
tuted hydantoin 15 (Scheme 4) by employing an established
procedure[18] in 21% overall yield (not optimized).
Scheme 4. Preparation of 2-amino-2-(1-cyclopropylcyclopropyl)-
acetic acid (16).
The versatility of 10e was also demonstrated by its con-
version to the 2-(1-cyclopropylcyclopropyl)-substituted
ethyl acrylate 17 and further transformations of the latter
to additional new bicyclopropyl derivatives (Scheme 5).
Wittig–Horner–Emmons alkenation of 10e with ethyl (di-
ethoxyphosphoryl)acetate gave the acrylate 17 in approxi-
mately 61% yield. For a test, this α,β-unsaturated ester 17
was employed in a 1,3-dipolar cycloaddition as well as a
Diels–Alder reaction (Scheme 5). Thus, upon heating of a
mixture of diphenyl nitrone with a twofold excess of 17 at
85 °C for 65 h, a 7:1 mixture of the two diastereomeric cy-
cloadducts trans,trans- and cis,trans-18 was obtained. The
individual diastereomers were isolated in 77 and 10% yield,
Figure 1. Structures of ethyl (3RS,4SR,5SR)-5-(1-cyclopropylcy-
clopropyl)-2,3-diphenylisoxazolidine-4-carboxylate (trans,trans-18)
(top) and 1-cyclopropylcyclopropanecarboxylic acid (10d) (bottom)
in the crystal.[19]
The bicyclopropyl substituent in trans,trans-18 adopts
respectively, by column chromatography, and the structure the same synclinal (gauche) conformation as that in 1-cy-
including the relative configuration of the major isomer was clopropylcyclopropanecarboxylic acid (Figure 1). This is
proven by an X-ray crystal-structure analysis to be typical for 1-substituted bicyclopropyl derivatives,[11]
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A. de Meijere et al.
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0.200 mm, 70–230 mesh ASTM). TLC: Macherey–Nagel, TLC
plates Alugram® Sil G/UV254. Detection under UV light at
254 nm, development with MOPS reagent (10% molybdophos-
phoric acid, solution in ethanol). Melting points: Büchi 540 capil-
lary melting point apparatus, uncorrected values. The elemental
analyses were performed on an HP185B CHN analyzer.
whereas bicyclopropyl itself in the crystal assumes an anti-
periplanar (s-trans) orientation.[20] The carboxy group of the
acid 10d is in a plane bisecting the adjacent three-membered
ring. This conformation as well as the bond-length alter-
ation in the carboxy-substituted cyclopropane ring is typi-
cal for cyclopropanes with an electron-withdrawing substit-
uent.[21] The molecules 10d in the crystal form centrosym-
metrical dimers as is typical for carboxylic acids.[22]
The 2-substituted acrylate 17 turned out to be a poor
dienophile. Heating of a mixture of 17 and cyclopentadiene
at 42 °C for 10 h did not furnish any of the expected cy-
cloadduct. Only under conditions that have been put for-
ward for Diels–Alder reactions to be carried out at low tem-
peratures,[23] i.e. in the presence of AlMe3/AlCl3 in toluene
at 0 °C, could the cycloadducts endo-19 and exo-19 be iso-
lated in 8 and 2% yield, respectively (Scheme 5). The endo –
with respect to the orientation of the methoxycarbonyl
group – configuration of the major diastereomer was as-
signed on the basis of 1D-NOE NMR measurements show-
ing strong interactions between 7-Hsyn and 2-H as well as
between 7-Hsyn and some cyclopropyl protons, but none be-
tween 7-Hsyn and 3-H.
Reaction of 1-Bromobicyclopropyl (1) with Magnesium: A 100 mL
round-bottomed Schlenk flask, fitted with a reflux condenser as
well as a rubber septum and equipped with a magnetic stirring bar,
was charged with magnesium turnings (0.34 g) and anhydrous Et2O
(20 mL). The magnesium was activated by addition of a few drops
of 1,2-dibromoethane from a syringe; then bromide 1 (2.0 g,
12.4 mmol) was added dropwise at room temp. The mixture was
heated under reflux for 2 h, then cooled to 0 °C, and the reaction
was quenched with satd. aq. NaHCO3 solution (14 mL). The aque-
ous phase was extracted with Et2O (3ϫ10 mL), the combined or-
ganic phases were dried (MgSO4) and concentrated in a rotary
evaporator at 0 °C/150 Torr to give 900 mg (90%) of a mixture of
1,1Ј;1Ј,1ЈЈ;1ЈЈ,1ЈЈЈ-quatercyclopropyl (4), 1-cyclopropyl-1-(3-cyclo-
propylidenepropyl)cyclopropane (5) and 1,6-dicyclopropyl-
idenehexane (6) in a ratio of 1:8:20. The isomers were separated
by preparative-scale gas-liquid chromatography on a 3 mϫ0.63 cm
glass column with 15% FFAP on Chromosorb W/AW/DMCS 60–
80 mesh and helium as carrier gas at 150 °C.
Compound 4: Colorless oil. 1H NMR (600 MHz, CDCl3): δ = –0.05
to –0.02 (m, 4 H, cPr-H), 0.01–0.04 (m, 4 H, cPr-H), 0.05–0.08 (m,
4 H, cPr-H), 0.28–0.31 (m, 4 H, cPr-H), 1.28–1.33 (m, 2 H, cPr-H)
ppm. 13C NMR (125.7 MHz, CDCl3, additional DEPT): δ = 2.3
(–, cPr-C), 7.0 (–, cPr-C), 15.1 (+, cPr-C), 25.1 (Cq, cPr-C) ppm.
EI-MS: m/z (%) = 147 (2) [M – 15]+, 134 (22), 119 (27), 105 (19),
93 (18), 91 (55), 84 (27), 79 (46), 67 (24), 55 (24), 53 (20), 41 (100).
DCI: m/z (%) = 180 (18) [M + NH4]+, 163 (100) [M + H]+, 134
(22), 121 (10), 93 (8).
Compound 5: Colorless oil. 1H NMR (600 MHz, CDCl3): δ = –0.09
to –0.06 (m, 2 H, cPr-H), 0.10–0.12 (m, 4 H, cPr-H), 0.26–0.29 (m,
2 H, cPr-H), 0.97–1.01 (m, 4 H, cPr-H), 1.02–1.06 (m, 1 H, cPr-
H), 1.47–1.49 (m, 2 H, CH2), 2.33–2.38 (m, 2 H, CH2), 5.75–5.79
(m, 1 H, =CH) ppm. 13C NMR (125.7 MHz, CDCl3, additional
DEPT): δ = 1.9 (–, cPr-C), 2.1 (–, cPr-C), 2.2 (–, cPr-C), 9.3 (–,
cPr-C), 14.4 (+, cPr-C), 20.3 (Cq, cPr-C), 29.5 (–, CH2), 39.6 (–,
CH2), 118.7 (+, =CH), 120.4 (Cq, =C) ppm. EI-MS: m/z (%) = 147
(3) [M – 15]+, 133 (10), 119 (26), 105 (34), 93 (46), 91 (73), 79 (100),
67 (70), 55 (47), 53 (42), 41 (96). DCI: m/z (%) = 180 (54) [M +
NH4]+, 163 (100) [M + H]+, 134 (22), 121 (43), 107 (36), 95 (46),
93 (32).
Compound 6: Colorless oil. 1H NMR (600 MHz, CDCl3): δ = 0.98–
1.02 (m, 8 H, cPr-H), 1.43–1.47 (m, 4 H, CH2), 2.15–2.20 (m, 4 H,
CH2), 5.72–5.76 (m, 1 H, =CH) ppm. 13C NMR (125.7 MHz,
CDCl3, additional DEPT): δ = 1.9 (–, cPr-C), 2.3 (–, cPr-C), 29.1
(–, CH2), 31.8 (–, CH2), 118.3 (+, =CH), 120.8 (Cq, =C) ppm. EI-
MS: m/z (%) = 161 (0.3) [M – H]+, 147 (3) [M – 15]+, 133 (7), 119
(22), 105 (37), 93 (37), 91 (70), 79 (100), 67 (50), 55 (24), 53 (21),
41 (75). DCI: m/z (%) = 180 (33) [M + NH4]+, 163 (22) [M + H]+,
147 (43), 134 (38), 121 (60), 107 (70), 93 (100).
Conclusions
Bromine/lithium exchange on 1-bromo-1,1-bicyclopropyl
(1) with tert-butyllithium generates an electrophilic reagent
that allows one to attach the 1-cyclopropylcyclopropyl sub-
stituent to various substructures by way of building blocks
like the carboxylic acid 10d, the aldehyde 10e, the boronate
10m, the acrylate 17 and others, that are conveniently ac-
cessible from 1-lithiobicyclopropyl. The interest in the 1-
and 2-cyclopropylcyclopropyl substituents is growing,[1,2]
and this must have to do with the peculiar electronic prop-
erties of cyclopropyl substituents in general[24] and the
added steric features of substituted bicyclopropyl units,
which have a preferred synclinal (gauche) orientation.[11,25]
Experimental Section
General Remarks: All reagents were used as purchased from com-
mercial suppliers without further purification. All reactions in non-
aqueous solvents were carried out by using standard Schlenk tech-
niques under dry nitrogen. Solvents were purified and dried accord-
ing to conventional methods prior to use. 1H and 13C NMR spectra
were recorded with a Bruker AM 250 (250 MHz for 1H and
62.9 MHz for 13C), a Varian UNITY-300 (300 MHz for 1H and
75.5 MHz for 13C) or an Inova-500 (125.7 MHz for 13C) instru-
ment. Chemical shifts δ are given in ppm relative to residual reso-
nances of solvents (1H: δ = 7.26 ppm for CHCl3, 2.50 ppm for [D6]-
DMSO; 13C: δ = 77.0 ppm for CDCl3, 39.52 for [D6]DMSO) or
tetramethylsilane (1H: δ = 0.00 ppm; 13C: δ = 0.0 ppm); coupling
constants J are presented as absolute values in Hz. The multiplicit-
ies of 13C signals were determined by the DEPT or the APT tech-
nique. IR: Bruker IFS 66 (FTIR) spectrometer, measured as KBr
pellets or oils between KBr plates. EI-MS: Finnigan MAT 95,
70 eV. ESI-MS: Finnigan LCQ. High resolution mass spectrometry
(HRMS): APEX IV 7T FTICR, Bruker Daltonic. Chromatog-
raphy: Separations were carried out on Merck Silica 60 (0.063–
General Procedure for the Bromine/Lithium Exchange on 1-Bromo-
1,1Ј-bicyclopropyl (1) and Subsequent Trapping with Electrophiles
(GP1): A solution of tBuLi (1.5–1.7  in pentane or hexane, 1.05–
2.10 equiv.) was added dropwise at –78 °C within 5 min to a solu-
tion of 1-bromobicyclopropyl (1) (1 equiv.) in Et2O (10 mL). After
the given time (1) (see Table 1), the respective electrophile
(1.05 equiv.) was added from a syringe (5 min), and the mixture
was warmed slowly to room temp. over the given time (2) (see
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Convenient Access to Various 1-Cyclopropylcyclopropane Derivatives
1
Table 1). The reaction was quenched with H2O, if not stated other-
wise; the aqueous layer was extracted with diethyl ether (3ϫ20 mL)
and then with pentane (2ϫ10 mL); the combined organic phases
were washed with brine, dried (Na2SO4) and concentrated in a ro-
tary evaporator at 0 °C/80 Torr. The residue was purified by col-
umn chromatography (silica gel, pentane), if not stated otherwise.
ν = 3075 (cPr-H) cm–1. H NMR (250 MHz, CDCl ): δ = –0.19 to
˜
3
–0.13 (m, 2 H, cPr-H), 0.15–0.22 (m, 2 H, cPr-H), 0.48–0.59 (m, 2
H, cPr-H), 0.98–1.07 (m, 2 H, cPr-H), 1.21–1.31 (m, 1 H, cPr-H),
7.39–7.49 (m, 6 H, Ph-H), 7.71–7.78 (m, 4 H, Ph-H) ppm. 13C
NMR (62.9 MHz, CDCl3, additional DEPT): δ = 3.1 (–, d, JCP
3 Hz, cPr-CHP), 7.7 (–,d, JCP = 1.2 Hz, cPr-C), 12.2 (+, d, JCP
=
=
4.2 Hz cPr-C), 13.9 (Cq, d, JCP = 54.8 Hz, cPr-C), 128.3–133.4 (Ph-
1-Cyclopropylcyclopropanecarboxylic Acid (10d):[10] A solution of
tBuLi (1.6  in pentane, 8.16 mL, 13.04 mmol) was added dropwise
at –78 °C within 30 min to a solution of 1-bromobicyclopropyl (1)
(2.00 g, 12.42 mmol) in Et2O (45 mL). After 20 min at –78 °C, an
excess of dry ice was added, and the mixture was warmed slowly
to room temp. over 2 h. The reaction was quenched with 0.2  aq.
Na2CO3 (ca 100 mL), the aqueous layer was washed with diethyl
ether (3ϫ50 mL), and then acidified with concd. HCl under ice
cooling. The resulting mixture was extracted with diethyl ether
(3ϫ50 mL), and then with pentane (2ϫ30 mL); the combined or-
ganic phases were dried with anhydrous Na2SO4 and concentrated
1
C) ppm. 31P NMR (121 MHz, CDCl3): δ = 34.7 (q, JBP = 71 Hz)
1
ppm. 11B NMR (96 MHz, CDCl3): δ = –39.4 (q, J = 55 Hz) ppm.
EI-MS: m/z = 279, 277 [M]+, 265, 266, 267, 251, 183, 108.
C18H22BP (280.15): calcd. C 77.2, H 7.9; found C 76.9, H 7.8.
2-(1-Cyclopropylcyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborol-
ane (10m): 2-Isopropyloxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
was prepared according to a puplished procedure.[27] From a solu-
tion of triisopropyl borate (31.0 g, 0.164 mol) and pinacol (19.4,
0.164 mol) in hexane (230 mL), a 2-propanol/hexane azeotrope was
slowly distilled off at 55–60 °C. The residue was distilled to give
25.0 g (0.134 mol, 82%) of the product, b.p. 52 °C/12 mbar. A solu-
tion of tBuLi (1.5  in pentane, 17.5 mL, 26.3 mmol) was added
dropwise at –78 °C within 30 min to a solution of the bromide 1
(3.62 g, 22.5 mmol) in Et2O (80 mL). After 30 min at –78 °C, iso-
propyloxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was added
dropwise within 10 min, and the mixture was warmed slowly to
room temp. over 6 h. The reaction was quenched with satd. NH4Cl
solution (ca. 20 mL). The resulting mixture was extracted with di-
ethyl ether (3ϫ60 mL), then with pentane (2ϫ20 mL); the com-
bined extracts were dried (Na2SO4), concentrated, and the residue
was purified by flash chromatography (200 mL of silica gel, ether/
pentane, 1:100 Ǟ 1:50) to give compound 10m as a colorless oil
(3.34 g, 16.1 mmol, 71%), which solidified upon standing in the
to give the acid 10d as colorless crystals (1.40 g, 11.10 mmol, 89%),
1
m.p. 51–52 °C. IR (KBr): ν = 3085 (cPr-H), 1688 (C=O) cm–1. H
˜
NMR (250 MHz, CDCl3): δ = –0.05–0.00 (m, 2 H, cPr-H), 0.40–
0.47 (m, 2 H, cPr-H), 0.57–0.61 (m, 2 H, cPr-H), 1.10–1.14 (m, 2
H, cPr-H), 1.40–1.49 (m, 1 H, cPr-H), 12.18 (br. s, 1 H, COOH)
ppm. 13C NMR (62.9 MHz, CDCl3, additional DEPT): δ = 2.5
(–, cPr-C), 10.8 (–, cPr-C), 13.6 (–, cPr-C), 24.4 (Cq, cPr-C), 183.2
(+, C=O) ppm.
1-Cyclopropylcyclopropanecarbaldehyde (10e): A solution of tBuLi
(1.7  in pentane, 3.7 mL, 6.3 mmol) was added dropwise at –78 °C
within 15 min to a solution of 1-bromobicyclopropyl (1) (996 mg,
6 mmol) in Et2O (20 mL). After 45 min at –78 °C, N,N-dimethyl-
formamide (512 mg, 7 mmol) was added from a syringe (5 min),
and the mixture was allowed to slowly warm to room temp. over
1 h. The reaction was quenched by addition of diluted HCl (H2O/
concd. HCl, 50:1; 51 mL), the aqueous layer was extracted with
diethyl ether (3ϫ60 mL), then with pentane (2ϫ20 mL); the com-
bined organic phases were washed with aq. NaHCO3 solution,
brine, dried with anhydrous Na2SO4 and concentrated in a rotary
evaporator at 0 °C/115 Torr to give the aldehyde 10e as a mixture
with diethyl ether (ca. 1:1), corresponding to approximately 610 mg
refrigerator. IR (film): ν = 3078 (cPr-H) cm–1. 1H NMR (250 MHz,
˜
CDCl3): δ = –0.09 to –0.02 (m, 2 H, cPr-H), 0.19–0.29 (m, 4 H,
cPr-H), 0.49–0.52 (m, 2 H, cPr-H), 0.97–1.08 (m, 1 H, cPr-H), 1.20
(s, 12 H, Me) ppm. 13C NMR (62.9 MHz, CDCl3, additional
DEPT): δ = 1.8 (–, cPr-C), 8.7 (–, cPr-C), 12.9 (+, cPr-C), 24.6 (+,
Me), 82.8 (Cq, OC) ppm. EI-MS: m/z = 208 [M+], 193, 180, 165,
151, 107, 101, 84. C12H21BO2 (208.10): calcd. C 69.3, H 10.2; found
C 69.4, H 10.4.
General Procedure for Palladium-Catalyzed Cross-Coupling Reac-
tions of 2-(1-Cyclopropylcyclopropyl)-4,4,5,5-tetramethyl-1,3,2-di-
oxaborolane (10m) (GP2): A 25 mL two-necked flask was charged
with the borolane 10k (1.00 mmol), Pd(PPh2)4 (0.10 mmol, 10 mol-
%), the respective (het)aryl halide (1.00 mmol) and DME (10–
12 mL), and flushed with dry nitrogen. Then degassed KOtBu (1 
in tBuOH, 3.30 mmol) was added, and the mixture was heated in
the sealed flask under nitrogen at 85 °C (bath temperature) for 20–
25 h. After cooling to room temp., the DME was removed in vacuo
in a rotary evaporator, the residue was diluted with diethyl ether/
pentane (5:1, 50 mL) and the solution filtered through a pad of
silica gel. The filtrate was concentrated and the residue purified by
column chromatography.
(5.54 mmol, 92%) of 10e. IR (film): ν = 3084 (cPr-H), 1716, 1687
˜
(C=O) cm–1. 1H NMR (250 MHz, CDCl3): δ = –0.03–0.04 (m, 2
H, cPr-H), 0.45–0.53 (m, 2 H, cPr-H), 0.73–0.78 (m, 2 H, cPr-H),
0.99–1.03 (m, 2 H, cPr-H), 1.34–1.43 (m, 1 H, cPr-H), 8.97 (s, 1 H,
CHO) ppm. 13C NMR (62.9 MHz, CDCl3, additional DEPT): δ =
1.9 (–, cPr-C), 8.9 (–, cPr-C), 11.5 (–, cPr-C), 33.4 (Cq, cPr-C),
202.9 (+, C=O) ppm. The NMR spectra of 8e were identical with
those of the aldehyde obtained in 73% yield by Dess–Martin oxi-
dation of (1-cyclopropylcyclopropyl)methanol (10f).[26]
(1-Cyclopropylcyclopropyl)diphenylphosphane–Borane
Complex
(10l): A solution of tBuLi (1.6  in pentane, 4.08 mL, 6.52 mmol)
was added dropwise at –78 °C within 15 min to a solution of 1-
bromobicyclopropyl (1) (1.00 g, 6.21 mmol) in Et2O (30 mL). After
20 min at –78 °C, a solution of Ph2PCl (1.038 g, 6.21 mmol) in
Et2O (4 mL) was added from a syringe (15 min), and the mixture
was warmed slowly to room temp. over 2 h. Borane–THF complex
(1 , 8 mL, 8 mmol) was added at 0 °C, and the mixture was stirred
for an additional 1 h. The reaction was then quenched by addition
of MeOH (3 mL) and water (20 mL). The aqueous layer was ex-
tracted with diethyl ether (3ϫ60 mL), and the combined organic
phases were washed with brine, dried (Na2SO4) and concentrated
in a rotary evaporator to give 2.04 g of a colorless oil, which crys-
tallized slowly. Recrystallization from methanol afforded 10l as a
colorless solid (1.12 g, 4.00 mmol, 64%), m.p. 98–99 °C. IR (KBr):
1-(1-Cyclopropylcyclopropyl)benzene (11n): From 10m (208 mg,
1.00 mmol) and iodobenzene (204 mg, 1.00 mmol) according to
GP2, the product 11n was obtained as a colorless oil (79 mg,
0.50 mmol, 50%). IR (film): ν = 3079 (cPr-H) cm–1. 1H NMR
˜
(250 MHz, CDCl3): δ = 0.15–0.18 (m, 2 H, cPr-H), 0.41–0.46 (m,
2 H, cPr-H), 0.63–0.68 (m, 2 H, cPr-H), 0.72–0.77 (m, 2 H, cPr-
H), 1.25–1.36 (m, 1 H, cPr-H), 7.17–7.40 (m, 5 H, Ph) ppm. 13C
NMR (62.9 MHz, CDCl3, additional DEPT): δ = 2.8 (–, cPr-C),
11.6 (–, cPr-C), 17.1 (+, cPr-C), 25.0 (Cq, cPr-C), 125.6 (+, Ph-C),
127.7 (+, Ph-C), 128.1 (+, Ph-C), 146.8 (Cq, Ph-C) ppm. EI-MS:
m/z = 158 [M+], 143, 129, 115, 102, 91. C12H14 (158.24): calcd. C
91.1, H 8.9; found C 91.3, H 8.8.
Eur. J. Org. Chem. 2010, 3295–3301
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3299

A. de Meijere et al.
FULL PAPER
5-(1-Cyclopropylcyclopropyl)imidazolidine-2,4-dione (15): A suspen-
sion of 1-cyclopropylcyclopropanecarbaldehyde (10e) (ca. 495 mg,
4.5 mmol), NaCN (700 mg, 14.3 mmol), (NH4)2CO3 (4.0 g,
41.6 mmol) in 50% aq. EtOH (16 mL) was heated at 50 °C with
stirring for 4.5 h and then left overnight. Water (15 mL) was added,
and the reaction mixture then concentrated in a rotary evaporator
under reduced pressure (10 Torr) to half of the original volume.
The residue was acidified with concd. HCl to pH ≈ 1 under cooling
(0 °C), the precipitate was filtered off, washed with ice/water and
dried under reduced pressure (0.01 Torr) to give the hydantoin
(250 mg, 1.39 mmol, 31%; m.p. 173 °C), which was used for the
(62.9 MHz, CDCl3, additional DEPT): δ = 2.2 (–, cPr-C), 12.2 (+,
cPr-C), 13.1 (–, cPr-C), 14.3 (+, Me), 23.7 (Cq, cPr-C), 60.0 (–,
CH2), 117.1 (+, =CH), 157.5 (+, =CH), 167.2 (Cq, C=O) ppm. EI-
MS: m/z = 180 [M+], 152, 124, 107, 91, 79. C11H16O2 (180.24):
calcd. C 73.3, H 9.0; found C 73.1, H 8.8.
Ethyl (3RS,4SR,5SR)- and (3RS,4RS,5RS)-5-(1-Cyclopropylcy-
clopropyl)-2,3-diphenylisoxazolidine-4-carboxylate (trans,trans- and
cis,trans-18): A mixture of diphenyl nitrone (197 mg, 1 mmol) and
the acrylate 17 (360 mg, 2 mmol) was heated in a sealed vial at
85 °C for 65 h. The excess of 17 was removed in vacuo in a Kugel-
rohr apparatus (80 °C/0.05 mbar), and the residue was purified by
column chromatography (60 mL of silica gel, ether/pentane, 1:50
Ǟ 1:25) to give trans,trans-18 as a colorless solid (291 mg,
0.77 mmol, 77%), m.p. 60–61 °C and cis,trans-18 as a colorless so-
lid (39 mg, 0.10 mmol, 10%), m.p. 75–76 °C.
next step without further purification. IR (KBr): ν = 3175 (br.,
˜
1
NH), 3083 (cPr-H), 1779, 1731 (C=O) cm–1. H NMR (250 MHz,
[D6]DMSO): δ = –0.06–0.16 (m, 2 H, cPr-H), 0.17–0.32 (m, 2 H,
cPr-H), 0.46–0.50 (m, 2 H, cPr-H), 1.02–1.12 (m, 2 H, cPr-H), 3.52
(s, 1 H, CH), 7.98 (s, 1 H, NH), 10.55 (s, 1 H, NH) ppm. 13C NMR
(62.9 MHz, [D6]DMSO, additional DEPT): δ = 1.0 (–, cPr-C), 1.6
(–, cPr-C), 6.2 (–, cPr-C), 6.8 (–, cPr-C), 10.2 (+, cPr-C), 21.7 (Cq,
cPr-C), 65.2 (+, CH), 157.5 (Cq, C=O), 174.9 (Cq, C=O) ppm.
1
trans,trans-18: IR (KBr): ν = 3070 (cPr-H), 1730 (C=O) cm–1. H
˜
NMR (250 MHz, CDCl3): δ = –0.09–0.00 (m, 1 H, cPr-H), 0.07–
0.24 (m, 2 H, cPr-H), 0.26–0.41 (m, 3 H, cPr-H), 0.46–0.54 (m, 1
H, cPr-H), 0.58–0.66 (m, 1 H, cPr-H), 1.21 (t, J = 7 Hz, 3 H, Me),
1.24–1.34 (m, 1 H, cPr-H), 3.83 (dd, J = 6.7, 9.1 Hz, 1 H, 4-H),
3.98 (d, J = 9.1 Hz, 1 H, 3-H), 4.12 (q, J = 7 Hz, 2 H, OCH2), 5.15
(d, J = 6.7 Hz, 1 H, 5-H), 6.90–7.01 (m, 3 H, Ph-H), 7.21–7.40 (m,
5 H, Ph-H), 7.54–7.58 (m, 2 H, Ph-H) ppm. 13C NMR (62.9 MHz,
CDCl3, additional DEPT): δ = 0.4 (–, cPr-C), 3.2 (–, cPr-C), 5.6
(–, cPr-C), 9.3 (–, cPr-C), 10.4 (+, cPr-C), 14.1 (+, Me), 20.0 (Cq,
cPr-C), 60.7 (+, C-4), 61.1 (–, OCH2), 74.3 (+, C-3), 88.5 (+, C-5),
113.9 (+, Ph-C), 121.5 (+, Ph-C), 126.3 (+, Ph-C), 127.5 (+, Ph-
C), 128.8 (+, Ph-C), 128.9 (+, Ph-C), 141.8 (Cq, Ph-C), 151.8 (Cq,
Ph-C), 171.1 (Cq, C=O) ppm. EI-MS: m/z = 377 [M+], 262, 198,
181, 91. C24H27NO3 (377.48): calcd. C 76.4, N 3.7, H 7.2; found C
76.6, N 3.7, H 7.4. The relative configuration of this product was
+
HRMS: calcd. for C9H13N2O2 [M + H+] 181.09715; found
181.09713.
2-Amino-2-(1-cyclopropylcyclopropyl)acetic Acid (16): A suspension
of the hydantoin 15 (214 mg, 1.19 mmol) and LiOH (279 mg,
11.66 mmol) in water (5 mL) was heated under reflux for 25 h. The
reaction mixture was cooled, concentrated in a rotary evaporator
under reduced pressure (10 Torr), the residue was acidified with
concd. HCl to pH ≈ 1, and the mixture was filtered. The pH of the
filtrate was adjusted with aq. LiOH to 5.5, and the solution was
concentrated to dryness in a rotary evaporator (10 Torr). The resi-
due was stirred with MeOH (4 mL) for 1 h, the precipitate was
filtered off, washed with cold MeOH and dried under reduced pres-
sure (0.01 Torr) to give the amino acid 16 [125 mg, 0.81 mmol,
1
confirmed by a 2D NOESY H NMR spectrum that disclosed in-
68%; m.p. (decomp.) Ͼ 260 °C] as a colorless solid. IR (KBr): ν =
˜
teractions 3-H/CH2O, 3-H/5-H, 4-H/o-H(3-Ph), 4-H/cPr-H.
3100–2600 (br., NH3+), 1654 (NH3+), 1590 (CO2 ) cm–1. 1H NMR
–
cis,trans-18: IR (KBr): ν = 3075 (cPr-H), 1734 (C=O) cm–1. 1H
˜
(300 MHz, D2O): δ = 0.00–0.17 (m, 2 H, cPr-H), 0.35–0.55 (m, 4
H, cPr-H), 0.59–0.66 (m, 1 H, cPr-H), 0.80–0.87 (m, 1 H, cPr-H),
1.05–1.14 (m, 1 H, cPr-H), 3.26 (s, 1 H, CH), 4.73 (s, 3 H, NH3)
ppm. 13C NMR (75.6 MHz, D2O, additional APT): δ = 0.5 (–, cPr-
C), 1.9 (–, cPr-C), 7.7 (–, cPr-C), 10.0 (+, cPr-C), 10.2 (–, cPr-C),
21.8 (–, cPr-C), 63.8 (+, CH), 173.6 (+, C=O) ppm. HRMS: calcd.
NMR (250 MHz, CDCl3): δ = –0.07–0.10 (m, 2 H, cPr-H), 0.13–
0.20 (m, 1 H, cPr-H), 0.24–0.34 (m, 1 H, cPr-H), 0.38–0.54 (m, 3
H, cPr-H), 0.62–0.70 (m, 1 H, cPr-H), 0.90 (t, J = 7 Hz, 3 H, Me),
1.23–1.34 (m, 1 H, cPr-H), 3.55–3.78 (m, 2 H, OCH2), 3.97 (dd, J
= 9.4, 10.5 Hz, 1 H, 4-H), 4.45 (d, J = 9.4 Hz, 1 H, 3-H), 4.79 (d,
J = 10.5 Hz, 1 H, 5-H) 6.90–6.98 (m, 3 H, Ph-H), 7.15–7.33 (m, 5
H, Ph-H), 7.45–7.49 (m, 2 H, Ph-H) ppm. 13C NMR (62.9 MHz,
CDCl3, additional DEPT): δ = 0.8 (–, cPr-C), 3.0 (–, cPr-C), 5.6
(–, cPr-C), 8.6 (–, cPr-C), 10.9 (+, cPr-C), 13.7 (+, Me), 20.5 (Cq,
cPr-C), 55.7 (+, C-4), 60.5 (–, OCH2), 72.3 (+, C-3), 84.5 (+, C-5),
116.3 (+, Ph-C), 122.2 (+, Ph-C), 128.0 (+, Ph-C), 128.2 (+, Ph-
C), 128.3 (+, Ph-C), 128.5 (+, Ph-C), 137.9 (Cq, Ph-C), 149.7 (Cq,
Ph-C), 169.5 (Cq, C=O) ppm. EI-MS: m/z = 377 [M+], 269, 198,
181, 91. C24H27NO3 (377.48): calcd. C 76.4, N 3.7, H 7.2; found C
76.5, N 3.9, H 7.1.
+
for C8H14NO2 [M + H+] 156.10191; found 156.10196. C8H13NO2
(155.19): calcd. C 61.9, H 8.4, N 9.0; found C 61.8, H 8.5, N 8.9.
Ethyl (E)-3-(1-Cyclopropylcyclopropyl)acrylate (17): A solution of
diethyl (diethoxyphosphoryl)acetate (13.5 g, 60.2 mmol) in THF
(45 mL) was added dropwise at room temp. within 30 min to a
stirred suspension of sodium hydride (60% suspension, 2.41 g,
60.2 mmol) in THF (45 mL), and the mixture was stirred at room
temp. for 1 h. A solution of the aldehyde 10e (ca. 5 g, ca. 46 mmol)
in THF (25 mL) was added in one portion. The mixture was heated
under reflux for 30 min, then stirred at room temp. overnight, be-
fore satd. aq. NH4Cl solution (10 mL) was added. The THF was
evaporated in vacuo, and the residue was then partitioned between
water and diethyl ether. The aqueous layer was extracted with di-
ethyl ether (3ϫ50 mL), and the combined organic extracts were
washed with brine, dried (MgSO4) and concentrated under reduced
pressure. The residue was purified by column chromatography
(150 mL of silica gel, ether/pentane, 1:200 Ǟ 1:50) to give the acryl-
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures for all new compounds as well as 1H
and 13C NMR spectra for compounds 4–6, 10g.
Acknowledgments
This work was supported by the Land Niedersachsen and the
Fonds der Chemische Industrie as well as Chemetall GmbH (chem-
icals).
ate 17 as a colorless oil (5.05 g, 28.02 mmol, 61%). IR (film): ν =
˜
3083 (cPr-H), 1714 (C=O), 1641 (C=C) cm–1. 1H NMR (250 MHz,
CDCl3): δ = –0.01–0.05 (m, 2 H, cPr-H), 0.42–0.50 (m, 2 H, cPr-
H), 0.66–0.70 (m, 4 H, cPr-H), 1.14–1.25 (m, 1 H, cPr-H), 1.29 (t,
J = 7.2 Hz, 3 H, Me), 4.18 (q, J = 7.2 Hz, 2 H, CH2), 6.08 (d, J =
5.6 Hz, 1 H, =CH), 6.56 (d, J = 5.6 Hz, 1 H, =CH) ppm. 13C NMR
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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with anisotropic displacement parameters, hydrogen atoms
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Received: February 16, 2010
Published Online: May 6, 2010
Eur. J. Org. Chem. 2010, 3295–3301
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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