Functionalized α-bromocyclopropylmagnesium bromides: Generation and some reactions

Article abstract of DOI:10.1134/S1070428013110043

Functional derivatives of gem-dibromocyclopropanes (ethers and esters of gemdibromocyclopropylmethanol, 2,2-dibromocyclopropanecarboxylic acids and their esters) undergo partial hydrodebromination at the treatment with isopropyl magnesium bromide (3-6 mol-equiv) in THF and then in methanol at -60°C affording the corresponding monobromides in 64-95% yields. The addition of nonsolvated magnesium bromide to the reaction mixture results in the considerable reduction of the amount of the Grignard reagent (from 6 to 3 mol-equiv). This allows achieving the partial hydrodebromination of 2,2-dibromocyclopropanecarboxylic acids. Pleiades Publishing, Ltd., 2013.

Full text of DOI:10.1134/S1070428013110043

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2013, Vol. 49, No. 11, pp. 1580−1593. © Pleiades Publishing, Ltd., 2013.
Original English Text © I.G. Bolesov, V.A. Solov’eva, M.S. Baird, 2013, published in Zhurnal Organicheskoi Khimii, 2013, Vol. 49, No. 11, pp. 1604−1616.
Functionalized α-Bromocyclopropylmagnesium Bromides:
Generation and Some Reactions
a
a
b
I. G. Bolesov , V. A. Solov’eva , and M. S. Baird
aLomonosov Moscow State University, Moscow, 119992 Russia
e-mail: dr.vera.solovyeva@gmail.ru
Department of Chemistry, University of Wales Bangor, LL 57 2 UW Gwynedd, UK
b
Received December 29, 2012
Abstract—Functional derivatives of gem-dibromocyclopropanes (ethers and esters of gem-
dibromocyclopropylmethanol, 2,2-dibromocyclopropanecarboxylic acids and their esters) undergo partial
hydrodebromination at the treatment with isopropylmagnesium bromide (3–6 mol-equiv) inTHF and then in methanol
at –60°С affording the corresponding monobromides in 64–95% yields. The addition of nonsolvated magnesium
bromide to the reaction mixture results in the considerable reduction of the amount of the Grignard reagent (from 6
to 3 mol-equiv). This allows achieving the partial hydrodebromination of 2,2-dibromocyclopropanecarboxylic acids.
DOI: 10.1134/S1070428013110043
High synthetic potential of gem-dihalocyclopropanes
provides a possibility to utilize them as initial compounds
for the efficient and selective preparation of diverse
compounds: derivatives of monohalocyclopropane,
cyclopropene, benzocyclopropene, bicyclobutane,
allene, cumulene, cyclopentane, cyclopentadiene, and
many other hydrocarbon systems, both unsubstituted and
containing functional groups [1]. The synthesis of gem-
dihalocyclopropanes is underlain by the application of
available initial compounds: alkenes, dienes, unsaturated
ethers and esters, and haloforms [2].
[6]. The hydrodebromination of chiral 2,2-dibromo-
cyclopropanecarboxylic acids under the methyllithium
treatment results in the formation of the second optical
center and affords monobromo-substituted acids of
the optical purity up to 98% [7]. In such selective
transformations often just the polar functional groups
govern the diastereoselectivity of the metallation of gem-
dihalocyclopropanes.
Unlike the α-halocyclopropyllithium derivatives
the α-halocyclopropylmagnesium halides are far less
studied. In early publications the conditions of the gen-
eration of α-bromocyclopropylmagnesium bromides
without functional groups were described: The treatment
of 1,1-dibromo-2-methyl-2-phenylcyclopropane with
Grignard reagents in THF at –60°С [8] of the reaction
of 7,7-dibromobicyclo[4.1.0]heptane with isopropyl-
magnesium bromide (2.4 mol-equiv) [9]. The corre-
sponding α-chlorocyclopropylmagnesium chlorides can
be effectively obtained by the exchange reactions from
α-halo-cyclopropyl sulfoxides with the aid of alkylmag-
nesium chlorides [10].
The transformations of cyclopropylidene derivatives
that can br easily generated from the corresponding
gem-dihalocyclopropanes are attractive because of
the opportunities to perform efficient and selective
conversions with the help of simple organometallic
reagents [3]. The versatile synthetic routes were found
in the reactions of lithium and magnesium cyclopropane
derivatives containing polar functional groups. The
cyclopropylidenelithium derivatives enter into reactions
of intra- and intermolecular [1+2]-cycloaddition [4], 1,3-,
1
,4-, and 1,5-С–Н-insertion, and insertion into the Н–
In keeping with [11–13] the intermolecular reactions
of alkyl- and aryl-gem-dibromocyclopropanes with Gri-
gnard reagents (3–4 mol-equiv) in THF at –60°С followed
by quenching of the reaction mixtures with electrophiles
heteroatom bonds [5]. The intramolecular acyl transfer in
the functional derivatives of gem-dibromocyclopropane
occurs with a high diastereo- and enantioselectivity
1
580

FUNCTIONALIZED α-BROMOCYCLOPROPYLMAGNESIUM BROMIDES
1581
are efficient for the preparation of the products of the
halogen substitution by the corresponding electrophile.
Therewith the cis- and trans-isomers were commonly
obtained in the ~1 : 1 ratio.
Ethers IV, V were obtained by alkylation of sodium
alcoholates of alcohol I with methyl iodide or allyl
bromide or via Williamson reaction in DMSO as solvent
(Scheme 2). Acetate VI was prepared by treating the
initial compound I with acetic anhydride in the presence
of pyridine. The reaction products as a rule were isolated
by vacuum distillation or by column chromatography
on silica gel. The structure of compounds I–VI was
1
In this study we investigated the features of hydro-
debromination reactions of gem-dibromocyclopropane
functional derivatives under the treatment with organo-
lithium and organomagnesium reagents. The selected
objects of the research are readily available analogs of
already known biologically active compounds or precur-
sors [15, 16].
1
3
1
confirmed by IR, С and Н NMR spectra.
2,2-Dibromo-3,3-dimethylcyclopropanecarboxylic
acid (VII) and trans-2,2-dibromo-3-phenylcyclopro-
panecarboxylic acid (VIII) were obtained by oxidation
of 2,2-dibromo-3,3-dimethylcyclopropylmethanol and
trans-2,2-dibromo-3-phenylcyclopropanecarbaldehyde
with chromic anhydride in glacial acetic acid. Salts IX,
X were prepared by neutralization of cyclopropanecar-
boxylic acid VII with potassium or lithium carbonates
at boiling in methanol (Scheme 3).
The protection of the hydroxy group and the
cyclopropanation of acetaldehyde diprenyl acetal as
well as methyl methacrylate and also the subsequent
hydrolysis of the cyclopropanation products were
carried out by the following established techniques [7,
1
7, 18] (Scheme 1). The obtained 2,2-dibromo-3,3-
dimethylcyclopropylmethanol (I), methyl 1-methyl-2,2-
dibromocyclopropanecarboxylate (II), and 1-methyl-2,2-
dibromocyclopropanecarboxylic acid (III) were purified
by vacuum distillation, recrystallization, or by silica gel
column chromatography.
Compounds II, IV–VI were treated with the solution
of isopropylmagnesium bromide (1.1–3 mol-equiv) in
THF at –60°С in an argon atmosphere, the reaction mix-
tures were quenched with methanol at the same tempera-
Scheme 1.
(
1) CHBr , 50%-ный NaOH,
3
CH CHO
Me
Me
3
[
PhCH NEt ]Cl
2 3
Me
Me
Br
CaCl2
(
2) hydrolysis
Me
Me
CH O CHCH
3
2
2
CH OH
2
CH OH
2
Me
Me
(
CH CO) O
pyridine
Br
I, 64%
3
2
CH OAc
2
Me
Br
Br
H
H
Br
Br
H
H
NaOH, H O
Me
2
EtOH, H O
Me
2
CHBr3,
NaOH
COOMe
[
PhCH NEt ]Cl
2
3
COOMe
II, 47%
COOH
III, 70%
Scheme 2.
_
(
1) NaOH, ДМСО H O
2
Br
Br
Me
Me
Br
Br
Me
Me
Br
Br
Me
Py, AcOAc
H
(2) RHlg
H
H
Me
CH OAc
CH OR
CH OH
2
2
2
IV, V
VI, 72%
I
R = Me (77%, IV), All (82%, V).
_
1
___________
For preliminary communication, see [14].
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 11 2013

1582
BOLESOV et al.
Scheme 3.
The compounds having J 7–8 Hz were assigned to the
cis-series, with J 4–5 Hz, to the trans-series [19].
Br
Br
Ph
Me
Me
Br
Br
Me
Me
CrO , AcOH
H
3
H
The performed experiments demonstrated that the
partial low-temperature hydrodеbromination of ethers and
esters of 2,2-dibromo-3,3-dimethylcyclopropylcarbinol
in tetrahydrofuran at the treatment with alkylmagnesium
halide and methanol made it possible to obtain the
corresponding derivatives of monobromocyclopropane
in 64–95% yields at the stereoisomers ratio 1.2 : 1.7.
5
25°C
CH OH
I
COOH
2
VII, 98%
Ph
CrO , AcOH
Br
Br
3
Br
5
25°C
CH=O
COOH
Br
VIII, 41%
The majority of the stereoisomeric reaction products
were easily separated by the preparative chromatography
on silica gel. However we failed to separate in this way
stereoisomers XVIIа, XVIIb.
Br
Br
Me
Me
Br
Br
Me
H
M
2
CO
3
H
MeOH
Me
COOM
IX, X
COOH
VII
The complete hydrodebromination of compound II
under the described conditions (THF, –60°С, 30 min)
was achieved already at the use of 1.1 mol-equiv of
isopropylmagnesium bromide, whereas compound XII
was not completely metallated even with 2.5 mol-equiv of
the Grignard reagent. The total conversion of compound
XII was attained at the action of no less than 3 equiv of
i-PrMgBr.
M = K (85%, IX), Li (89%, X).
1
ture. The analysis of the Н NMR spectra of the reaction
mixtures showed that as a result of the reaction stereo-
isomeric products of the partial hydrodebromination are
formed in the ratio 1.2–1.7 (Table 1, Scheme 4). The ratio
of the stereoisomeric monobromides was estimated from
the integral intensities of the proton signals of the CHBr
groups in the region 3.0–3.7 ppm, and the configuration
of the formed cis- and trans-monobromo ethers was
determined from the spin-spin coupling constants of the
The treatment of acid VII with 1.5–2.5 mol-equiv
of the Grignard reagent at –60°С and with hydrochloric
acid at room temperature led only to the initial com-
1
pound. In the Н NMR spectra of these reaction mix-
protons in groups CHBr and CHCH OR of the small ring.
tures even traces of hydrodebromination product XVIII
2
Table 1. Low-temperature (–60°С) hydrodebromination of functional derivatives of gem-dibromocyclopropanes in THF with
the use of i-PrMgBr and proton donors
No. of initial com-
pound
Quantity of
i-PrMgBr, equiv
Reaction products
(cis-/trans-, %)
Time, min
Proton donorа
Yield, %
II
1.1
6
30
30
40
30
30
30
30
30
30
30
30
MeOH
MeOH, HCl
MeOH
XIII (55/45)
XIV (75/25)
XV (47/53)
72
85
64
79
95
90
83b
83b
88
86
64
III
IV
3
V
3
MeOH
XVI (37/63)
XVII (45/55)
XVIII (78/22)
XX (75/25)
VI
3
MeOH
VII
VII
VII
VIIIс
XI
6
MeOH, HCl
(CD ) CO, HCl
6
2
3
6
MeOD, HCl
MeOH, HCl
MeOH, HCl
MeOH
XX (75/25)
7
XIX (90/10)
XVIII (74/26)
XXI (47/53)
6
XII
3
а
1
mL, 10 min.
b
Products of deuterodebromination were formed, XXа, XXb.
с
The reaction was carried out at –70°С, the workup with methanol, at ≤ –65°С.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 11 2013

FUNCTIONALIZED α-BROMOCYCLOPROPYLMAGNESIUM BROMIDES
1583
Scheme 4.
Br
R1
R2
(1) Electrophile
(D)H
Br
R1
R2
Br
R1
R2
Br
Br
R1
R3
R3
_
R3
R3
(2) H O HCl
i-PrMgBr, THF
Ar, cooling
2
+
R2
BrMg
(D)H
R4
R4
R4
R4
_
II XII
_
_
A
XIIIa XXIa
XIIIb XXIb
1
2
3
4
1
2
3
4
R = R = H, R = Me, R = COOMe (II, XIII), COOH (III, XIV); R = R = Me, R = H, R = CH OMе (IV, XV), CH OAl (V, XVI),
2
2
4
1
2
3
4
1
2
3
CH OAc (VI, XVII), COOH (VII, XVIII); R = Ph, R = R = H, R = COOH (VIII, XIX); R = R = Me, R = H, R = COOD (XI),
COOH (XX, D); R = Me, R = Ph, R = R = H (XII, XXI).
2
1
2
3
4
were not detected. Apparently under these conditions
the α-bromocyclopropylmagnesium bromides А did not
form, and the only reaction product was the bromomag-
nesium salt of gem-dibromocyclopropanecarboxylic acid
tion mixtures with methanol and HCl resulted in stereo-
isomeric 2-bromocyclopropanecarboxylic acids with
cis-form prevailing.
We also examined the behavior of gem-dibromo-
cyclopropyl carboxylates of the other metals under the
described conditions. To this end we treated potassium
and lithium derivatives IX, X with isopropylmagnesium
bromide (3 equiv) at –60°С in THF for 30 min, then
with methanol at the same temperature and with hy-
drochloric acid at 20°С. The analysis of NMR spectra
of the reaction mixtures showed that the conversion of
lithium salt X reached 90% and of potassium salt IX,
100%. A complex mixture of substances was obtained
in the reaction where 2-bromocyclopropanecarboxylic
acid XVIIIа, XVIIIb prevailed. The ratio of cis- and
trans-isomers depended on the nature of the cation of
(VII). The stereoisomeric monobromo-substituted acids
XVIIIа, XVIIIb were found among the reaction prod-
ucts only at applying more than 3 equiv of the Grignard
reagent.After the treatment of acid VII with 6 mol-equiv
of the organomagnesium compound quantitative metal-
lation of the gem-dibromocyclopropane fragment of the
bromomagnesium salt of the carboxylic acid occurred
quantitatively.
Taking into consideration the experimental results
(Table 1) the quenching of magnesium carboxylates of
α-bromocyclopropylmagnesium bromides with acetone
or methanol led to the predominant formation of the cis-
products of hydrodebromination. The ratio of stereoiso-
meric cis- and trans-monobromocyclopropanecarboxylic
acids XIVа, XIVb and XVIIIа, XVIIIb was ~3 : 1. The
analogous treatment of trans-3-phenyl-2,2-dibromo-
cyclopropanecarboxylic acid (VIII) with the solution
of isopropylmagnesium bromide in THF, further with
methanol at –60°С and hydrochloric acid at room tem-
perature afforded the mixture of monobromo-substituted
acids XIXа, XIXb in the ratio 9 : 1.
2
the cyclopropanecarboxylic acid salt. The treatment of
lithium derivative X with isopropylmagnesium bromide
followed by the quenching of the reaction mixture with
methanol and HCl led to the formation of the mixture
of cis- and trans-2-bromocyclopropanecarboxylic acids
XVIIIа, XVIIIb in the ratio 3 : 1. Potassium derivative
IX reacted more actively and less selectively giving a
mixture of equal amounts of cis- and trans-monoоbromo
derivatives XVIII (Scheme 5).
Probably the formed in the course of the reaction
magnesium (or bromomagnesium) salts of the cyclopro-
panecarboxylic acids possess a complex structure which
also may contain also isopropylmagnesium bromide.
Presumably the bulky complex cation of the magnesium
salt of cyclopropanecarboxylic acid hinders the attack
of isopropylmagnesium bromide on the bromine atom
in the cis-position with respect to the carboxy group,
whereas the more remote bromine atom located in the
trans-position may be more available for the reaction
with the Grignard reagent. The treatment of these reac-
To clear the origin of the proton substituting the halo-
gen atom we carried out experiments using methanol-d1
and acetone-d for quenching the reaction mixtures gen-
6
erated from acid VII and isopropylmagnesium bromide.
In each of these cases products of deuterodebromination
XXa, XXb were isolated as showed the appearance of
singlet signals of СН group linked to the carboxy group at
_
___________
2
The diastereoselectivity of magnesium debromination of gem-dibro-
mocyclopropanecarboxylic acid esters and nitriles with Grignard
reagents depends on solvent. In ether the diastereomeric excess of
cis-2-bromocyclopropane derivatives is up to 96–99% [12].
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 11 2013

1584
BOLESOV et al.
Scheme 5.
(
1) 3 equiv i-PrMgBr, THF,
_
o
6
0 C, 30 min, Ar
H
Me
Me
COOH
XVIIIa
Br
Br
Br
Me
Me
COOM
IX, X
Me
Me
H
_
o
H
H
(
(
2) MeOH, 60 C
_
+
3) H O HCl
2
Br
H
_
COOH
6
7.5 71%
XVIIIb
M = K (IX), Li (X).
1
.79 and 1.82 ppm, respectively. The treatment of the deu-
debromination of gem-dibromocyclopropanecarboxylic
acids at low temperature. This event turned our attention
to the structure of the Grignard reagent in THF.
terated 2,2-dibromo-3,3-dimethylcyclopropanecarboxylic
acid-d (XI) with isopylmagnesium bromide with the sub-
1
sequent quenching of the reaction mixture with methanol
afforded compounds XVIIIа, XVIIIb lacking deuterium.
Consequently in the reactions of dibromocyclopropan-
ecarboxylic acids with isopropylmagnesium bromide in
THF the Grignard reagent primarily attacks the carboxy
The analysis of some structures of Grignard reagents
А–C [22–24] available from the database of the Cam-
bridge Crystallographic Data Center showed that the
magnesium included in the organomagnesium compounds
prepared in THF possessed the coordination number of
4 or 6 and frequently formed oligomeric, e.g., tetrameric
structures where the carbanion sites of the Grignard re-
agents might be spatially blocked (see the figure, B, C ).
function and only afterwards the CBr fragment of the
2
small ring. The α-bromocyclopropylmagnesium bromides
thus generated are further stabilized by the intermolecular
transfer of a proton from the donor used for the quenching
of the reaction mixture.
In the solutions of alkylmagnesium halides in THF
the Schlenk equilibrium is shifted to the side of species
R Mg and MgBr [25, 26].
The features of the reaction mechanism of gem-di-
bromocyclopropanecarboxylic acids with methyllithium
should be mentioned [3, 20]. The latter first attacks the
bromine atom located in the cis-position with respect to
the carboxy group; the intermediate thus generated [20]
is stabilized due to the intramolecular transfer of a proton
from the carboxy function to the carbanion center.
2
2
Assuming that the addition of nonsolvated magnesium
bromide to the solution of the Grignard reagent in THF
would shift the Schlenk equilibrium to the side of the
formation of RMgBr species, probably, more active with
respect to gem-dibromocyclopropanes. The introduction
of the nonsolvated magnesium bromide may affect the
solvate shell of the alkylmagnesium halide: The more po-
At the use of the hexadeuteroacetone for quenching
the reaction mixture containing magnesium or bromo-
magnesium salts of α-bromocyclopropylmagnesium
carboxylates the only reaction products isolated in the
overall yield of 86% were the stereoisomeric deuterated
lar species of MgBr should be more efficiently solvated
2
with THF molecules, and consequently the carbanion
centers of the isopropylmagnesium bromide may become
more accessible to the attack of the nucleophilic centers
of the gem-dibromocyclopropane derivatives. In struc-
tures А and B (see the figure) the carbanion centers of
methyl- and ethylmagnesium chloride in the presence of
magnesium chloride are bound to a single THF molecule,
whereas in the structure C, free of salt additives, the carb-
anion center is surrounded with three solvent molecules.
3
acids XXа, XXb. Even traces of addition products of
α-bromocyclopropyl anionic intermediates to the car-
bonyl group of hexadeuteroacetone were not detected in
1
the Н NMR spectrum of the reaction mixture.
Another fact that came for us as a surprise was a ne-
cessity to apply 6 equiv of isopropylmagnesium bromide
for attaining the 100% conversion in the partial hydro-
If the suggested hypothesis is valid, the addition of
magnesium bromide to the solution of the Grignard re-
agent in THF would make it possible to reduce the amount
of the isopropylmagnesium bromide necessary for the
preparation of monobromocyclopropanecarboxylic acids.
_
____________
3
It was shown in [17, 21] that in the reaction with acetone of
α-bromocyclopropylmagnesium bromide generated from 1,1-di-
bromo-2,2-diphenylcyclopropane is formed 1-bromo-2,2-diphen-
ylcyclopropane. The second compound isolated from the reaction
mixture in 80% yield was the product of acetone condensation,
We carried out a series of experiments where acid VII
was treated with the solution of isopropylmagnesium
4
-hydroxy-4-methylpentan-2-one.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 11 2013

FUNCTIONALIZED α-BROMOCYCLOPROPYLMAGNESIUM BROMIDES
1585
The structure of Grignard reagents in crystals obtained from solutions in tetrahydrofuran.
А
B
C
[22]
[23]
[24]
Et
Mg
Cl
O
Mg
O
O
O
O
O
Cl
Cl
O
O
O
Mg
Mg
O
O
N
O
Cl
Cl
Mg
Cl
Cl
Mg
O
Cl
Cl
H C
3
O
Br
O
Cl
O Mg
O
Mg
Cl
Et
bromide in THF containing 1–3 mol-equiv of magnesium
bromide. The subsequent quenching of the reaction mix-
tures with methanol at –60°С followed by treating with
hydrochloric acid at room temperature resulted in the
formation of the corresponding stereoisomeric mono-
bromocyclopropanecarboxylic acids. The ratio of the
reaction products XVIIIa, XVIIIb remained unchanged.
The results of the experiments (Table 2, Scheme 6)
demonstrated that the addition to the reaction mixture of
nonsolvated magnesium bromide significantly reduced
the quantity of the Grignard reagent (from 6 to 3 mol-
equiv) required for the partial hydrodebromination of
dibromocyclopropanecarboxylic acid with methyllithium
in ether (1.5 mol-equiv) at 0°С in an argon atmosphere
is known to furnish exclusively the product of the
trans-hydrodebromination [18, 20, 27]. The reaction of
2,2-dibromo-3,3-dimethylcyclopropanecarboxylic acid
(VII) with methyllithium under the above conditions led
to a mixture of trans-2-bromocyclopropanecarboxylic
acid (XVIIIb) and the corresponding allene XXII in
3 : 1 ratio. The main reaction product was isolated by
absorption chromatograpgy on silica gel. The variation
of the reaction temperature from –50 to 25°С showed
that the yield of allene XXII from 27 to 35%. The ratio
of the reaction products insignificantly varied with tem-
perature. The reaction of trans-2,2-dibromo-3-phenyl-
2
,2-dibromocyclopropanecarboxylic acids.
The reaction of 2,2-dibromo- and 1-methyl-2,2-
Scheme 6.
_
(
1) i-PrMgBr MgBr ,
2
_
o
Br
Br
H
Me
Me
THF, 60 С, Ar, 30 min
2) 1 mL MeOH, 60 С
Me
Me
Br
H
Me
Me
Me
Me
H
H
H
_
o
(
(
_
3) H O HCl
Br
COOH
2
COOH
VII
COOH
XVIIIа
COOH
XVIIIb
XXII
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 11 2013

1586
BOLESOV et al.
Table 2. Reactions of cyclopropanecarboxylic acid VII with isopropylmagnesium bromide in the presence of 1–3 mol-equiv of
MgBr at –60°С
2
Ratio of reaction products, %
Quantity of
Overall yield, %
i-PrMgBr–MgBr , mol-equiv
2
XVIIIa
XVIIIb
XXII
4
3
3
:2
: 1
: 3
80
80
58
20
20
27
–
86
65
73
Traces
Traces
cyclopropanecarboxylic acid (VIII) with methyllithium
in ether at 0°С afforded acid XIX in 85% yield without
the formation of side products (Scheme 7).
intermediates with methanol or acetone and further with
mineral acids leads to the formation of stereoisomeric
2-bromocyclopropanecarboxylic acids.
Hence the partial low-temperature hydrodebromina-
tion of functional derivatives of gem-dibromocyclopro-
pane with isopropylmagnesium bromide in THF can be
used for the preparative synthesis of ethers and esters of
EXPERIMENTAL
1Н NMR spectra of compounds synthesized were
registered on a spectrometer Varian VXR 400 (400 MHz),
2-bromocyclopropylmethanol, 2-bromocyclopropanecar-
1
3
internal reference TMS. С NMR spectra were obtained
on a spectrometer Varian VXR 400 (100 MHz), solvent
and internal reference deuterochloroform. IR spectra were
recorded on a spectrophotometer UR-20 from thin film of
pure oily substances, from mulls in mineral oil of crystal-
line compounds. GC-MS measurements were carried out
on a GLC instrument Carlo Erba/Kratos Fractovap Series
boxylic acids, and their esters.
Unlike methyllithium which provides with a high
diastereoselectivity the trans-2-bromocyclopropane-
carboxylic acids from the corresponding 2,2-dibromo-
substituted acids, the isopropylmagnesium bromide uti-
lized in this study fulfills the partial hydrodebromination
of gem-dibromocyclopropanecarboxylic acid with the
prevailing formation of cis-isomers. The greatest selec-
tivity of the partial hydrodebromination was observed
in the case of trans-2,2-dibromo-3-phenylcyclopropane-
carboxylic acid (VIII).
4
200, column HPUltra-1, 25 m × 0.2 mm, stationary phase
thickness 0.33 μm, carrier gas helium (1 mL/min), split
ratio 1 : 10, vaporizer temperature 280°С, ramp from
50 to 280°С, heating rqate 5 deg/min). Mass spectral
detector ITD-700 (Finnigan MAT), EI, 70 eV, mass range
1
Based on the findings obtained we suggested the
scheme of the mechanism of hydrodebromination
of gem-dibromocyclopropanecarboxylic acids with
isopropylmagnesium bromide. The main steps of the
mechanism are as follows: (а) The formation of magne-
sium salts of initial carboxylic acids; (b) metallation of
the latter with isopropylmagnesium bromide resulting
predominantly in the generation of the corresponding
α-bromocyclopropylmagnesium bromides of bromomag-
nesium carboxylate with the trans-oriented substituents
BrMg and COOMgBr; (c) treatment of the obtained
m/z 45–400.
The thin layer chromatography was performed on
Silica gel plates on aluminium 20 Aldrich. The prepara-
tive separation and purification was carried out on silica
gel Li-Chroprep Si 60 (25–40 μm) Merck, staining with
the alcoholic solution of phosphomolybdic acid.
The syntheses with the use of Grignard reagents and
methyllithium, and also all distillations applied to the
separation and purification of obtained substances were
performed under an atmosphere of argon of the “special
Scheme 7.
HOOC
+
Br
Br
Ph
H
1.5equiv MeLi,
EtOEt
Br
P
h
Br
Br
Me
Me
Br
Me
Me
H
H
H
H
1
.5 equiv MeLi, EtOEt
o
Ar, 0 C
o
Ar, 0 C
H
H
COOH
H
COOH
COOH
COOH
Me
Me
XXII
VIII
XIXb, 85%
VII
XVIIIb, 68%
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 11 2013

FUNCTIONALIZED α-BROMOCYCLOPROPYLMAGNESIUM BROMIDES
1587
purity” grade.
the solution of 4.7 mL (6.16 g, 50 mmol) of isopropyl
bromide in 4 mL of THF. After 3–5 min the reaction
mixture strongly self-heated. As the reaction mixture
cooled the remaining solution of isopropyl bromide was
added to the flask with the rate preventing the boiling
of the reaction mixture. The stirring was continued for
Reagents of the grades “chemically pure”, “pure”, and
“
pure for analysis” of Khimmed Co (hydrochloric acid,
acetic acid, ethyl acetate, dichloromethane, benzene,
toluene, chloroform, hexane, petroleum ether 40/70,
potassium hydroxide and carbonate), and also reagents
of Aldrich [methanol, bromoофорm, sodium hydroxide,
nonsolvated magnesium bromide (purity 98%), magne-
sium (purity 98%), triethylbenzylаmmonium chloride
1
h, and the reaction mixture was left overnight. Then a
sample of the Grignard reagent (1 mL) was poured into
0 mLof 0.1 m solution of hydrochloric acid followed by
2
titration with 0.1 m solution of sodium hydroxide in the
presence of methyl orange indicator. The concentration
of obtained solutions varied in the range 0.80–1.03 mol
(
purity 99%)] and of Fluka [hexadecyltrimethylammo-
nium bromide (purity 98%)] were used without additional
purification.
−
1
L
(80–103%). The solution of isopropylmagnesium
Anhydrous ethyl ether was prepared by boiling with
alkali (granulated KOH or NaOH) followed by distilla-
tion, then boiling with sodium in the presence of benzo-
phenone and the subsequent distillation (procedure [28]),
or by boiling with lithium aluminum hydride followed by
distillation. Anhydrous pyridine was obtained by boiling
with sodium followed by distillation [28]. Anhydrous
tetrahydrofuran was prepared by boiling with sodium
with subsequent addition of Grignard reagent with low
concentration (0.6–0.8 M) stored more three days from
the moment of preparation, followed by distillation; then
boiling with sodium in the presence of benzophenone till
the solution became of deep blue-violet color, and finally
it was subjected to distillation [28].
bromide was used in reactions within 3 days after the
preparation [14, 17, 25].
Ethylmagnesium bromide. Into a dried flask heated
with dry air (to no less than 200°С) was charged 1.54 g
(63 mmol) of magnesium turnings and 43.7 mL of THF
was added with a syringe. At stirring 1/6 part of the so-
lution of 3.7 mL (5.45 g, 50 mmol) of ethyl bromide in
6
.3 mL of THF was added. After 1–3 min the reaction
mixture strongly self-heated. As the reaction mixture
cooled the remaining solution of ethyl bromide was added
to the flask with the rate preventing the boiling of the
reaction mixture. The stirring was continued for 1 h, then
a sample of the Grignard reagent (1 ml) using a syringe
was poured into 20 mL of 0.1 m solution of hydrochloric
acid followed by titration with 0.1 m solution of sodium
hydroxide in the presence of methyl orange indicator.
The concentration of obtained solution was 0.95 mol
L−1 (95%). The solution of ethylmagnesium bromide
was used within 3 days after the preparation [14, 17, 25].
Reagents of the grades “chemically pure”, “pure”,
and “pure for analysis” (acetic anhydride, ethyl bromide,
isopropyl bromide, allyl bromide) used in the preparation
of organometallic and initial compounds were distilled
prior to use.
Elemental analyses were carried out in the microanaly-
sis laboratory of the Chair of Organic Chemistry of the
Chemical Department of Lomonosov Moscow State Uni-
versity and in the microanalysis laboratories of Institute
of Organic Chemistary and Institute of Organoelemental
Compounds of the Russian Academy of Sciences.
Methyllithium. Into a dried flask heated with dry air
(to no less than 200°С) was charged 1.22 g (0.174 mol)
of lithium cut into small pieces, and 50 mL of ethyl ether
was added with a syringe. At stirring into the flask was
gradually added with a syringe by 2–3 mL portions of
solution of methyl iodide (5.5 mL, 0.09 mol, 12.54 g)
in 38 mL of ether maintaining the rate of addition so
that the boiling of the ether was not too vigorous. On
the completion of the addition the reaction mixture was
heated to boiling for 1 h on a water bath. On cooling the
reaction mixture to room temperature the flask was sealed
from the air access with paraffin wax. The concentration
of the methyllithium solutions in ether was measured
directly before the use along procedure [18, 30]. The
Initial compounds (acetaldehyde diprenyl acetal,
trans-2,2-dibromo-3-phenylcyclopropylcarbaldehyde)
were synthesized from commercially available reagents:
prenyl alcohol, methyl methacrylate, and cinnamic al-
dehyde, according to published procedures [7, 16–18,
2
9]. The compounds were purified by distillation or by
preparative column chromatography.
Isopropylmagnesium bromide. Into a dried flask
heated with dry air (to no less than 200°С) was charged
−
1
concentration of solutions was 0.8–1.04 mol l .
,2-Dibromo-3,3-dimethylcyclopropylmethanol
1
.54 g (63 mmol) of magnesium turnings, 46 mL of
2
THF, and gradually was added at stirring 1/6 part of
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 11 2013

1588
BOLESOV et al.
(
I) [16, 17, 31]. To a solution of 12.9 g (65 mmol)
II in 15 mL of ethanol, the mixture was stirred for 18 h
at room temperature. The mixture was evaporated, the
residue in the flask was dissolved in 70 mL of water,
nonpolar impurities were extracted with dichloromethane
(3 × 15 mL), the water layer was acidified with conc. HCl
to рН 1, the reaction product was extracted into chloro-
form (4 × 15 mL). The combined extracts were washed
with water and dried with magnesium sulfate. The solvent
was distilled off, the precipitated yellowish crystals were
recrystallized from a mixture hexane–benzene, 2 : 1, and
dried in Fischer’s drying pistol. Yield 16.68 g (70%). Col-
orless crystalline powder, mp 112.5–114°С. IR spectrum,
of acetaldehyde diprenyl acetal and 2.4 g (10 mol%)
of hexadecyltrimethylammonium bromide in 36 mL
of dichloromethane and 23 mL (65.8 g, 0.26 mol)
bromoform was added 32.4 g (0.81 mol) of 50% aqueous
solution of sodium hydroxide at 10°С. The formed
mixture was vigorously stirred for 5 h at room temperature
and poured into 150 mL of water, the reaction products
were extracted into dichloromethane (3 × 30 ml), the
extract was dried with magnesium sulfate. The solvent
and bromoform excess were distilled off in a vacuum,
the residue was filtered through a bed of silica gel, the
sorbent was washed with petroleum ether, the solvent
was distilled off. The obtained yellowish oily substance
was dissolved in 20 mL of THF and at cooling to 10°С
with a water bath this solution was added to a solution
of 0.6 g (2.8 mmol, 10 mol%) of p-toluenesulfonic acid
hydrate in 15 mLof water and 30 mLof THF. The reaction
mixture was stirred for 2.5 h at 50°С and poured into
–
1
cm : 3070 m, 2970 s, 2870 s, 1910 w, 1715 s, 1470 s,
1450 s, 1380 m, 1359 w, 1305 w, 1250 s, 1225 m, 1120 s,
1030 w, 980 m, 945 m, 930 m, 840 w, 825 m, 750 w,
1
697 s. Н NMR spectrum (CDCl3), δ, ppm: 1.63 d (1Н,
J 7.9 Hz), 1.64 s (3Н), 2.43 d (1Н, J 7.9 Hz), 7.20 s (1Н).
1
,1-Dibromo-2,2-dimethyl-3-methoxymethylcy-
clopropane (IV). To a solution of 1.5 g (5.8 mmol) of
alcohol I in 12 mL of dimethyl sulfoxide was added a
solution of 0.53 g (13.3 mol) of sodium hydroxide in 1
mL of water, the mixture was stirred for 30 min at 20°С,
then a solution was added of 0.66 mL (1.5 g, 10.2 mmol)
of methyl iodide in 1 mL of DMSO at 20°С. After 3 h
the mixture was poured into 50 mL of water, the reaction
product was extracted into ether (3×15 ml), the extract
was dried with magnesium sulfate. After the purifica-
tion by preparative absorption chromatography ether
IV was isolated as colorless fluid. Yield 1.3 g (77%),
1
00 mLof water, the reaction products were extracted into
dichloromethane (3×30 mL), the extract was washed with
0% water solution of potassium carbonate (3 × 20 mL),
1
with water, and dried with magnesium sulfate. The solvent
was removed in a vacuum, the residue was distilled in a
vacuum. Yield 25.1 g (64%), bp 79–81°С (1 mm Hg). At
storage in the argon atmosphere in a refrigerator at 3°С the
oily substance crystallized into colorless crystals. R 0.29
(
3
1
1
f
–
1
hexane–ether, 4 : 1). IR spectrum, cm : 3600–3100 s,
000 s, 2970 s, 2945 s, 2880 s, 1730 w, 1630 w, 1465 s,
405 s, 1380 s, 1330 w, 1285 w, 1250 w, 1210 w, 1150,
R 0.45 (petroleum ether–ethyl acetate, 20:1). IR spec-
f
120 w, 1080 s, 1045 s, 1050 s, 1000 m, 920 w, 830 w,
–1
trum, cm : 3500–3250 s, 3000 s, 2970 s, 2940, 2910,
1
7
80 s, 760 s, 730 w. H NMR spectrum (CDCl ), δ,
3
2890, 2840 s, 1715 w, 1460 s, 1410 m, 1390 m, 1380 m,
ppm:1.28 s (3Н), 1.43 s (3Н), 1.61 t (1Н, J 7.3 Hz), 1.66 s
(
1290 w, 1255 w, 1230 w, 1200 m, 1160 m, 1120 s, 1115 s,
1Н), 3.76 d (2Н, J 7.3 Hz).
1
080 m, 1050 m, 1005 m, 1005 m, 980 w, 970 w, 930 w,
1
Methyl 1-methyl-2,2-dibromocyclopropanecar-
910 w, 825 w, 780 m, 760 m. Н NMR spectrum (CDCl ),
3
boxylate (II) [18, 29] was obtained from 21.2 mL (20 g,
.2 mol) of methyl methacrylate, 100 mL of dichlo-
romethane, 35 mL of bromoform, 3.64 g (5 mol%) of
hexadecyltriethylammonium bromide, and 120 mL(80 g,
δ, ppm: 1.24 s (3Н), 1.42 s (3Н), 1.56 t (1Н, J 6.7 Hz),
3.39 s (3Н), 3.42 d.d (1Н, J 10.9, 6.7 Hz), 3.57 d.d (1Н,
0
J 10.9, 6.7 Hz). 13С NMR spectrum (CDCl ), δ, ppm:
3
19.42, 27.13, 38.17, 44.49, 58.52, 71.55, 111.56. Found,
2
mol) of 50% aqueous solution of sodium hydroxide.
%: С 31.16; Н 4.58. C H Br O. Calculated, %: С 30.91;
7
12
2
After distillation yield 25.6 g (47%). Colorless fluid,
Н 4.44.
1
bp 100–103°С (10 mm Hg). Н NMR spectrum (CDCl ),
3
1-(Allyloxymethyl)-2,2-dibromo-3,3-dimethyl-
cyclopropane (V) [17]. To a solution of 2 g (7.75 mmol)
of compound I in 20 mLof anhydrous DMSO at 10–15°С
was added a solution of 0.87 g of NaOH in 1.2 mL of
water, the mixture was stirred for 20 min at 20°С, and a
solution was added of 1.8 mL(16 mmol) of allyl bromide
in 1.5 mL of DMSO. After keeping the mixture for 2.5 h
δ, ppm: 1.55 s (3Н), 1.67 d (1Н, J 7.1 Hz), 2.33 d (1Н,
J 7.1 Hz), 3.75 s (3Н).
1
-Methyl-2,2-dibromocyclopropanecarboxylic
acid (III) [18, 29]. To a solution of 4.88 g (0.122 mol)
of sodium hydroxide in 45 mL of ethanol and 15 mL of
water was added a solution of 25 g (92 mmol) of ester
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 11 2013

FUNCTIONALIZED α-BROMOCYCLOPROPYLMAGNESIUM BROMIDES
1589
at 20°С it was poured into 50 mL of water, the reaction
product was extracted into ether (3×15 mL), the extract
was dried with magnesium sulfate. Ether V was isolated
by distillation. Yield 1.45 g (82%). Colorlessая fluid, bp
acidified with conc. НСl to рН 1, acid VII was extracted
with dichloromethane (4×20 mL). The extract was dried
with magnesium sulfate. The drying agent was separated,
the solvent was distilled off to give 4.49 g of crude acid
VII. Ater recrystallization from a mixture heptane–tolu-
ene, 4 : 1, and drying in Fischer’s drying pistol yield
4.16 g (98%). Colorless needle crystals, mp 146–147°С.
1
21–123°С (12 mm Hg), R 0.92 (petroleum ether–ethyl
f
–
1
acetate, 4 : 1). IR spectrum, cm : 3500–3200 s, 3090 w,
3
1
1
8
000 m, 2970 m, 2940 s, 2880 s, 2870 s, 1710 w, 1650 w,
535 w, 1460 s, 1410 m, 1380 s, 1350 w, 1295 w, 1270 w,
260 w, 1230 w, 1145 s, 1105 s, 1090 s, 1000 s, 930 s,
–
1
IR spectrum, cm : 3075 w, 2980–2850 s, 1715 s, 1685 s,
1470 s, 1380 s, 1355 m, 1305 m, 1250 s, 1225 s, 1120 s,
1110 m, 1030 m, 990 m, 955 m, 930 m, 840 w, 760 w,
1
25 m, 780 s, 765 s, 730 w. Н NMR spectrum (CDCl ),
3
1
δ, ppm: 1.25 s (3Н), 1.43 s (3Н), 1.59 d.d (1Н, J 6.8,
.6 Hz), 3.45 d.d (1Н, J 6.8, 10.85 Hz), 3.63 d.d (1Н,
J 6.6, 10.85 Hz), 3.99 d.d (1Н, J 5.6, 12.8 Hz), 5.19 d
1Н, J 10.4 Hz), 5.29 (1Н, J 17.2 Hz), 5.91 d.d.t (1Н,
710 s. Н NMR spectrum (CDCl ), δ, ppm: 1.51 s (3Н),
3
1
3
6
1.54 s (3Н), 2.26 s (1Н), 14.0 s (1Н). С NMR spectrum
(CDCl ), δ, ppm: 19.50, 27.34, 34.44, 38.90, 40.39,
3
(
173.25. Found, %: С 26.67; Н 2.96. С H Br O . Calcu-
6
8
2
2
1
3
J 17.2, 10.4, 5.6 Hz). С NMR spectrum (CDCl ), δ,
lated, %: С 26.50; Н 2.96.
3
ppm: 19.47, 27.14, 28.33, 38.31, 44.58, 68.50, 71.75,
trans-3-Phenyl-2,2-dibromocyclopropanecarbox-
ylic acid (VIII) [33]. To a solution of 10 g (0.1 mmol) of
chromic anhydride in 52 mL(55 g, 0.9 mol) of acetic acid
and 8 mL of water at vigorous stirring and cooling to 0°С
by an ice bath was added a solution of 12 g (40 mmol)
of trans-2,2-dibromo-3-phenylcyclopropylcarbaldehyde
in 10 mL of acetic acid. The mixture was stirred for 20 h
at room temperature After the standard workup of the
reaction mixture and the recrystallization of the product
from a mixture toluene–petroleum ether, 1 : 1, yield 3.9 g
(31%). Colorless crystals, mp 142–143°С. IR spectrum,
1
17.28, 134.55. Found, %: С 35.90; Н 4.97. С H Br O.
9
14
2
Calculated, %: С 36.27; H 4.73.
2
,2-Dibromo-3,3-dimethylcyclopropan-1-yl-
methyl acetate (VI) [14, 16, 32]. To a solution of
.43 g (5.5 mmol) of compound I in 0.9 mL (0.9 g,
1.2 mmol) of pyridine was added 0.85 mL (0.92 g,
.4 mmol) of acetic anhydride. The formed mixture was
1
1
8
stirred for 3 h at room temperature. Acetate VI was iso-
lated by preparative chromatography on silica gel (eluent
hexane–ethyl acetate, 4 : 1, R 0.35) as a colorless fluid.
f
–
1
Yield 1.2 g (72%), bp 101–102°С (3 mm Hg). IR spec-
cm : 3070 w, 2950 s, 2870 s, 1715 s, 1690 s, 1500 w,
1470 s, 1460 s, 1380 s, 1340 m, 1330 m, 1315 m, 1300,
1240 m, 1215 m, 1175 m, 1110 w, 1085, m, 1050 m,
1035 w, 980 m, 950 m, 910 m, 870 m, 850 w, 780 w,
–1
trum, cm : 3470 w, 3000 s, 2970 s, 2940 s, 2910, 2880 s,
745 s, 1650 w, 1465 s, 1390 m, 1375 s, 1280 s, 1240 s,
1
1
160 s, 1120 w, 1090 m, 1045 s, 1010 m, 980 w, 905 w,
1
1
8
1
2
55 w, 820 w, 780 s. H NMR spectrum (CDCl ), δ, ppm:
765 m, 730 w, 715 m, 700 s. Н NMR spectrum (CDCl ),
3
3
.26 s (3Н), 1.41 s (3Н), 1.64 d.d (1Н, J 7.7, 7.4 Hz),
.10 s (3Н), 4.19 d.d (1Н, J 7.7, 11.9 Hz), 4.14 d.d (1Н,
δ, ppm: 2.94 d (1Н, J 8.4 Hz), 3.46 d (1Н, J 8.4 Hz),
7.26–7.41 m (5Н).
1
3
J 7.4, 11.9 Hz). С NMR spectrum (CDCl ), δ, ppm:
3
Potassium 2,2-dibromo-3,3-dimethylcyclopropan-
ecarboxylate (IX). To a solution of 1.99 g (7.32 mmol)
of acid VII in 17 mL of methanol was added 1.04 g
(1.02 equiv, 7.46 mmol) of powdered potassium carbon-
ate, the mixture was boiled on a water bath for 4 h and then
it was stirred for 4 h at room temperature. The precipitate
was filtered off, washed with methanol (4×20 mL). To
the residue 10 mL of toluene was added, the solvent was
distilled off in a vacuum on a rotary evaporator, and this
procedurewas repeated 4 times.After drying the residue in
Fischer’s pistol for 8 h at 60°С over calcium chloride and
1
9.48, 20.82, 27.01, 28.74, 36.84, 43.29, 63.24, 170.73.
2,2-Dibromo-3,3-dimethylcyclopropanecarboxylic
acid (VII) [16, 31]. To a solution of 6.84 g (6.84 mmol)
of chromic anhydride in a mixture of 57.2 mL (60 g) of
acetic acid and 6.8 mL of water at vigorous stirring and
cooling to 0°С by an ice bath was added a solution of
4
.5 g (20 mmol) of alcohol I in 5.7 mL (5.98 g, 0.1 mol)
of acetic acid. The mixture was stirred for 24 h at room
temperature and then poured into 100 mL of water. The
separated oxidation products were extracted with di-
chloromethane (4×30 mL), the combined extracts were
washed with water (2×15 mL), then with the saturated
K CO solution (3×30 mL). The combined alkaline ex-
paraffin wax the yield was 1.93 g (85%). Colorless pow-
1
der. Н NMR spectrum (DMSO-d ), δ, ppm: 1.27 s (3Н),
6
13
1
.32 s (3Н), 2.98 s (1Н). С NMR spectrum (DMSO-d ),
6
2
3
δ, ppm: 20.17, 25.62, 27.49, 28.17, 49.62, 167.47.
tracts were washed with dichloromethane (1×20 mL),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 11 2013

1590
BOLESOV et al.
Lithium 2,2-dibromo-3,3-dimethylcyclopropane-
carboxylate (X). To a solution of 1.97 g (7.25 mmol)
of acid VII in 17 mL of methanol was added 0.55 g
extracted with petroleum ether, the combined organic
extracts were washed with water and dried with magne-
sium sulfate. The solvent was distilled off in a vacuum,
the mixture was filtered through 1.5 g of silica gel, the
sorbent was washed with petroleum ether, then the solvent
was distilled off and the corresponding cis- and trans-
derivatives of monobromocyclopropane were isolated.
(
1.02 equiv, 7.40 mmol) of lithium carbonate. The mixture
was boiled on a water bath for 4 h and then it was stirred
for 4 h at room temperature. The precipitate was filtered
off, washed with methanol (4×20 mL). To the residue
1
0 mL of toluene was added, the solvent was distilled off
Isolation of acids. To the reaction mixture 20 mL of
chloroform was poured, the organic layer was washed
with a solution of 10 mL of conc. HCl in 50 mL of water,
from the water layer the acids were extracted with chlo-
roform, the combined organic extracts were treated with
the saturated solution of potassium carbonate, the water
fraction was washed with chloroform and acidified with
conc. HCl to рН 1. The obtained acid was extracted from
the water phase with chloroform, and the extract was dried
with magnesium sulfate. After the solvent was distilled
off the corresponding cis- and trans-monobromocyclo-
propanecarboxylic acid were isolated.
in a vacuum on a rotary evaporator, and this procedure
was repeated 4 times.After drying the residue in Fischer’s
pistol for 8 h at 60°С over calcium chloride and paraffin
wax the yield was 2.0 g (89%), colorless powder. Н NMR
spectrum (DMSO-d ), δ, ppm: 1.32 s (3Н), 1.38 s (3Н),
1
6
3
2
.01 s (1Н). 13С NMR spectrum (DMSO-d ), δ, ppm:
6
0.07, 20.85, 25.93, 27.30, 50.51, 168.29.
2,2-Dibromo-3,3-dimethylcyclopropanecarboxylic
acid-d (XI). Acid VII (1 g, 3.7 mmol) was boiled with
1
distilled off on a rotary evaporator. The procedure was
1
mL of methanol-d for 1 h, the residue of solvent was
1
repeated thrice.After removal of the solvent yield 0.998 g
Methyl cis-2-bromo-1-methylcyclopropanecarbox-
ylate (XIIIa) [29, 34]. Colorless oily substance. H NMR
1
(
98%). Colorless crystals. Н NMR spectrum (CCl ), δ,
1
4
1
3
ppm: 1.50 s (3Н), 1.51 s (3Н), 2.26 s (1Н). С NMR
spectrum (CCl ), δ, ppm: 19.5, 27.34, 34.44, 38.90,
spectrum (CDCl ), δ, ppm: 1.02 t (1Н, J 5.5 Hz), 1.48 s
3
4
(3Н), 1.84 d.d (1Н, J 8.4, 5.5 Hz), 3.52 d.d (1Н, J 5.5,
8.4 Hz), 3.76 s (3Н).
4
0.39, 73.25. Found, %: С 26.68; Н 2.87. C H Br DO .
6 7 2 2
Calculated, %: C 26.40; H 3.31.
Methyl trans-2-bromo-1-methylcyclopropane-
carboxylate (XIIIb) [29, 34]. Colorless oily substance.
Functionalized α-bromocyclopropylmagnesium
bromides. In a dry three-neck flask filled with argon was
charged 1–3 mmol of dibromocyclopropane II–XII, and 9
mLof THF was charged with a syringe. The solution was
cooled to the temperature in the range from –65 to –80°С
1
H NMR spectrum (CDCl ), δ, ppm: 1.24 d.d (1Н, J 7.7,
3
6
(
.4 Hz), 1.38 s (3Н), 1.80 d.d (1Н, J 5.4, 6.4 Hz), 2.94 d.d
1Н, J 5.4, 6.4 Hz), 3.68 s (3Н).
cis-2-Bromo-1-methylcyclopropanecarboxylic acid
(
with a mixture alcohol–liquid nitrogen). At vigorous
1
(
(
(
XIVa) [18, 29]. Colorless crystals. H NMR spectrum
stirring with a magnetic stirrer to the cooled solution
was added dropwise 1.1–7 mol-equiv of a solution
of isopropylmagnesium bromide or ethylmagnesium
bromide in THF. The rate of addition was chosen so that
the temperature of the reaction mixture did not exceed
from–60 to –75°С. The stirring at this temperature
continued for 30–45 min, then the mixture was cooled to
CDCl ), δ, ppm: 1.32 d.d (1Н, J 7.6, 6.7 Hz), 1.41 s
3
3Н), 1.81 d.d (1Н, J 6.7, 5.8 Hz), 3.02 d.d (1Н, J 7.6,
.8 Hz), 10.6 s (1Н).
5
trans-2-Bromo-1-methylcyclopropanecarboxylic
1
acid (XIVb) [18, 29, 35]. Colorless crystals. H NMR
spectrum (CDCl ), δ, ppm: 1.09 d.d (1Н, J 5.5, 5.8 Hz),
3
1
.63 s (3Н), 1.92 d.d (1Н, J 8.2, 5.8 Hz), 3.57 d.d (1Н,
J 5.5, 8.2 Hz), 10.6 s (1Н).
–
70°С and 1 mL of hydrogen donor (Table 1) was added
dropwise maintaining the temperature between –75 and
60°С. After warming the mixture to 0°С 1 mL of water
cis-1-Bromo-2,2-dimethyl-3-methoxymethylcyclo-
–
1
propane (XVa). Colorless oily substance. H NMR spec-
was added and the reaction mixture was left to warm to
room temperature.
trum (CDCl ), δ, ppm: 1.15 s (3Н), 1.16 s (3Н), 1.21 m
3
(
3
1Н, J 7.9, 6.9 Hz), 2.99 d (1Н, J 7.9 Hz), 3.37 s (3Н),
.45–3.55 m (2Н, J 6.9, 10.4 Hz). Found, %: С 43.72;
Н 6.92. C H BrO. Calculated, %: C 43.56; H 6.78.
Isolation of compounds without a carboxy group.
To the reaction mixture obtained as above described was
added 20 mL of petroleum ether, the organic layer was
decanted, the water slurry of magnesium salts was dis-
solved in 4 M solution of HCl, the reaction products were
7
13
trans-1-Bromo-2,2-dimethyl-3-(methoxymethyl)
1
cyclopropane (XVb). Colorless oily substance. H
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 11 2013

FUNCTIONALIZED α-BROMOCYCLOPROPYLMAGNESIUM BROMIDES
1591
(
CDCl ), δ, ppm: 1.15 s (3Н), 1.21 m (1Н, J 4.2, 6.2 Hz),
19.55, 20.85, 24.27, 26.74, 31.97, 33.22, 63.40, 170.88.
3
1
3
.29 s (3Н), 2.71 d (1Н, J 4.2 Hz), 3.34 s (3Н), 3.45–
.55 m (2Н, J 6.2, 10.6 Hz). Found, %: С 43.57; Н 6.90.
–1
Mixture of XVIIа, XVIIb. IR spectrum, cm : 2965 s,
2
935 s, 2880 m, 2745 w, 1740 s, 1460 m, 1380 s, 1240 s,
1150 w, 1125 w, 1050 s, 1000 w, 990 w, 930–920 w,
C H BrO. Calculated, %: C 43.56; H 6.78.
7
13
cis-1-(Allyloxymethyl)-2-bromo-3,3-dimethylcy-
905 w, 850 w, 810 w, 710 w, 695 w. Mass spectrum, m/z
+
+
clopropane (XVIa) [17]. Colorlessое oily substance. IR
(I , %): [M] 222, 220 (0.02), [M – C H O ] 163, 161
rel 2 3 2
–1
(0.11), [M – C H O ]+ 147, 149 (2.7), [M – Br]+ 141 (10).
3 5 2
spectrum, cm : 3090 w, 3000 m, 2965 s, 2935 s, 2865 s,
1
1
1
730 w, 1650 w, 1470 m, 1450 m, 1420 m, 1380 m,
350 w, 1275 m, 1210 w, 1160–1140 m, 1100 m, 1030 w,
Found, %: С 43.47; Н 6.14. C8H13BrO2. Calculated, %:
C 43.46; H 5.92.
1
000 w, 930 m, 680 m. H NMR spectrum (CDCl ), δ,
cis-2-Bromo-3,3-dimethylcyclopropanecar-
3
1
ppm: 1.07 d.d (1Н, J 6.8, 7.1 Hz), 1.14 s (3Н), 1.16 s
3Н), 2.99 d (1Н, J 7.5 Hz), 3.5 d.d (1Н, J 6.8, 10.6 Hz),
boxylic acid (XVIIIa). Colorless crystals. H NMR
(
spectrum (CDCl ), δ, ppm: 1.27 s (3Н), 1.38 s
3
3
1
1
.54 d.d (1Н, J 10.6, 7.1 Hz), 4.0 m (2Н, J 1.5, 5.8, 17.2,
(3Н), 1.79 d (1Н, J 7.9 Hz), 3.22 d (1Н, J 7.9 Hz).
Found, %: С 37.30; Н 4.54. C H BrO . Calculated, %:
C 37.33; H 4.69.
0.4 Hz), 5.18 d.q (1Н, J 1.5, 10.4 Hz), 5.29 d.q (1Н, J 1.5,
6
9
2
1
3
7.2 Hz), 5.93 m (1Н, J 10.4, 5.8, 17.2 Hz). С NMR
spectrum (CDCl ), δ, ppm: 17.14, 26.19, 26.86, 29.67,
3
trans-2-Bromo-3,3-dimethylcyclopropanecarbox-
ylic acid (XVIIIb). Colorless crystals. H NMR spectrum
3
4.99, 68.31, 71.79, 117.05, 134.89. Mass spectrum, m/z
1
+
+
(I , %): [M] 218, 220 (0.016), [M – C H ] 175, 177
rel. 3 7
(CDCl ), δ, ppm: 1.32 s (3Н), 1.38 s (3Н), 1.82 d (1Н,
3
+
+
(0.11), [M – C H O] 161, 163 (1.7), [M – C H O] 147,
3
5
4
7
J 4.2 Hz), 3.22 d (1Н, J 4.2 Hz). Found, %: С 37.35;
Н 4.53. C H BrO . Calculated, %: C 37.33; H 4.69.
+
1
49 (5), [M – Br] 139 (9.6). Found, %: С 49.47; Н 6.95.
6
9
2
C H BrO. Calculated, %: C 49.33; H 6.89.
9
15
cis-2-Bromo-3-phenylcyclopropanecarboxylic acid
trans-1-(Allyloxymethyl)-2-bromo-3,3-dimethyl-
1
(
XIXa). Colorless crystals. H NMR spectrum (CDCl ),
3
cyclopropane (XVIb) [17]. Colorless oily substance. IR
spectrum, cm : 3085 w, 2985 m, 2965 s, 2930 s, 2870 s,
δ, ppm: 2.42 d.d (1Н, J 6.0, 8.4 Hz), 3.06 d.d (1Н, J 6.0,
.5 Hz), 3.49 d.d (1Н, J 8.4, 5.5 Hz), 7.25–7.5 m (5Н).
–1
5
13
1
1
9
740 m, 1650 w, 1460 m, 1420 m, 1380 m, 1300 w,
С NMR spectrum (CDCl ), δ, ppm: 25.33, 29.01,
3
270 m, 1250 m, 1205 m, 1145 m, 1100 s, 1090 s, 1000 m,
33.70, 126.38, 127.53, 128.81, 136.63, 174.61. Found,
1
35 m, 820 w, 680 m. H NMR spectrum (CDCl ), δ,
%: С 50.13; Н 3.90. C H BrO . Calculated, %: C 49.82;
3
10
9
2
ppm: 1.14 s (3Н), 1.28 s (3Н), 1.25 m (1Н, J 4.3 Hz),
H 3.76.
2
3
5
1
.71 d (1Н, J 4.3 Hz), 3.36 d.d (1Н, J 8.1, 10.9 Hz),
.58 d.d (1Н, J 5.9, 10.9 Hz), 3.98 m (2Н, J 1.5, 5.8,
.5 Hz), 5.19 d.d (1Н, J 1.5, 10.5 Hz), 5.28 d.d (1Н, J 1.5,
trans-2-Bromo-3-phenylcyclopropanecarboxylic
acid (XIXb). Colorless crystals. IR spectrum, cm–1:
3
1
000 w, 2970, 2935 s, 2860 s, 1680 m, 1610 w, 1500 w,
13
7.2 Hz), 5.91 m (1Н, J 10.5, 17.2, 5.8, 5.5 Hz). С NMR
450 m, 1380 w, 1270 w, 1205 w, 1090 w, 1040 w, 1050 w,
spectrum (CDCl ), δ, ppm: 19.43, 21.81, 24.45, 33.15,
1
3
960 w, 765 w, 730 w, 710 w. H NMR spectrum (CDCl ),
3
3
3.71, 68.52, 71.46, 117.08, 134.73. Found, %: С 49.51;
δ, ppm: 2.44 d.d (1Н, J 5.9, 3.8 Hz), 2.96 d.d (1Н, J 5.9,
8.3 Hz), 3.72 d.d (1Н, J 3.8, 8.3 Hz), 7.25–7.38 m (5Н).
Н 7.02. C H BrO. Calculated, %: C 49.33; H 6.89.
9
15
1
3
cis-2-Bromo-3,3-dimethylcyclopropan-1-yl-methyl
С NMR spectrum (CDCl ), δ, ppm: 27.92, 29.67,
3
1
acetate (XVIIa). Colorless oily substance. H NMR spec-
32.43, 127.53, 128.27, 129.01, 136.63, 174.61. Found,
trum (CDCl ), δ, ppm: 1.12 m (1Н, J 7.6 Hz), 1.16 s (3Н),
%: С 49.86; Н 3.78. C H BrO . Calculated, %: C 49.82;
3
10
9
2
1
.17 s (3Н), 2.07 s (3Н), 3.0 d (1Н, J 7.6 Hz), 4.12–4.21 m
H 3.76.
13
(2Н). С NMR spectrum (CDCl ), δ, ppm: 19.95, 22.19,
3
cis-2-Bromo-2-deutero-3,3-dimethylcyclopropane-
carboxylic acid (XXa). Colorlessые crystals. H NMR
2
2.62, 24.88, 29.63, 34.35, 63.36, 170.99.
1
trans-2-Bromo-3,3-dimethylcyclopropan-1-ylmeth-
yl acetate (XVIIb). Colorless oily substance. H NMR
spectrum (CDCl ), δ, ppm: 1.28 s (3Н), 1.39 s (3Н),
3
1
1.79 s (1Н). Found, %: С 37.01; Н 4.38. C H BrDO .
6
8
2
spectrum (CDCl ), δ, ppm: 1.16 s (3Н), 1.28 s (3Н),
Calculated, %: C 37.11; H 5.15.
3
1
.30 m (1Н, J 4.3, 4.5, 8.1 Hz), 2.07 s (3Н), 2.75 d (1Н,
trans-2-Bromo-2-deutero-3,3-dimethylcyclo-
propanecarboxylic acid (XXb). Colorlessые crys-
J 4.3 Hz), 3.98 d.d (1Н, J 11.9, 8.1 Hz), 4.12–4.21 m (1Н,
J 11.9, 4.5 Hz). С NMR spectrum (CDCl ), δ, ppm:
1
3
1
3
tals. H NMR spectrum (CDCl ), δ, ppm: 1.33 s
3
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 11 2013

1592
BOLESOV et al.
(
3Н), 1.39 s (3Н), 1.82 s (1Н). Found %: С 37.38;
form, the combined organic extracts were neutralized with
the saturated solution of potassium carbonate, the water
fraction was washed with chloroform and acidified with
conc. HCl to рН 1. The obtained acid XVIII was extracted
from the water phase with chloroform, and the extract
was dried with magnesium sulfate. The drying agent was
separated, after the solvent was distilled off we isolated
the mixture of cis- and trans-isomers of carboxylic acids
XVIIIa, XVIIIb.
Н 4.38. C H BrDO . Calculated, %: C 37.11; H 5.15.
6
8
2
cis-1-Bromo-2-methyl-2-phenylcyclopropane
XXIа) [17, 18, 21]. Colorless oily substance.
(
1
H NMR spectrum (CDCl ), δ, ppm: 1.34–1.40 m
3
(2Н, J 4.6, 7.3 Hz), 1.45 s (3Н), 3.08 d.d (1Н, J 4.6,
7
.3 Hz), 7.18–7.37 m (5Н).
trans-1-Bromo-2-methyl-2-phenylcyclopropane
1
(XXIb) [17, 18, 21]. Colorlessое oily substance. H NMR
Reaction of 2,2-dibromo-3,3-dimethylcyclo-
propanecarboxylic acid (VII) with methyllithium
spectrum (CDCl ), δ, ppm: 1.06 d.d (1Н, J 4.8, 6.3 Hz),
1
J 4.8, 8.0 Hz), 7.18–7.37 m (5Н).
3
.61 s (3Н), 1.64 d.d (1Н, J 6.3, 8.0 Hz), 3.21 d.d (1Н,
[7, 18, 20, 28, 35, 36]. Into a dry flask filled with argon
was charged 0.5 g (1.84 mmol) of acid VII, and 5 mL of
anhydrous ether was added with a syringe. If needed, the
solution was cooled with a bath of ethanol–liquid nitrogen
to the desired temperature (–50, –25, 0°С) or the synthesis
was carried out at room temperature. To the solution
obtained vigorously stirred with a magnetic stirrer was
added at the required temperature within 10 min 1.5 mol-
equiv (2.76 mmol) of ether solution of methyllithium.
The mixture was stirred for 15 min under the same
conditions, then the reaction mixture was warmed to
room temperature within 2 h. To the reaction mixture
was added carefully, first dropwise, 10 mL of water. The
water fraction was separated, the organic fraction was
washed with water. The combined water phases were
washed with ether, acidified with 20% hydrochloric acid
solution to рН 1, the organic acids were extracted with
dichloromethane, the extract was dried with magnesium
sulfate. The solvent was distilled off, the corresponding
acids XVIIIb and XXII were isolated. Compound
XVIIIb was isolated by preparative chromatography on
silica gel (eluent petroleum–ethyl ether, 3 : 1); acid XXII
decomposed under the chromatography conditions.
Reactions of 2,2-dibromo-3,3-dimethylcyclopro-
panecarboxylic acid (VII) with isopropylmagnesium
bromide in the presence of magnesium bromide
(Table 2). Into a dried three-neck flask heated for 30 min
in a vacuum of an oil pump (1 mm Hg) with the help of
heat gun (to no less than 200°С) was charged 3 mmol of
acid VII. Two necks of the flask were closed with septa,
and into the third neck a thermometer was placed with a
scale from –90 to 20°С. The flask was filled with argon,
and 9 mL of THF was added with a syringe.
To an Erlenmeyer flask dried with a hot air (T > 200°С)
and filled with argon was charged 2–4 mol-equiv of
magnesium bromide, the flask was again flushed with
argon, and 20–40 mL of THF was added with a syringe.
At heating and stirring the salt dissolved completely. To
the obtained yellow solution was added with a syringe
2–4 mol-equiv of isopropylmagnesium bromide solution
in THF. In the course of the addition the solution turned
colorless; the mixture was stirred for 15 min.
At stirring with a magnetic stirrer to the solution of
acid VII cooled to –65°С with a bath of ethanol–liquid
nitrogen was added dropwise the solution in THF of the
mixture of isopropylmagnesium bromide with magne-
sium bromide. The rate of addition was chosen so that the
temperature of the reaction mixture did not exceed –60°С.
The stirring at this temperature continued for 45 min, then
the mixture was cooled to –70°С and 1 mL of methanol
was added maintaining the temperature between–70 and
1
4
-Methylpenta-2,3-dienoic acid (XXII). H NMR
spectrum, δ, ppm: 1.82 d (6Н, J 2.7 Hz), 5.46 m (1Н,
J 2.7 Hz).
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