The reagent Et2AlX/CH2N2 in cyclopropanation of sterically hindered olefins, as well as oxygen- and nitrogen-containing unsaturated compounds

Article abstract of DOI:10.1007/s11172-019-2638-5

A transition-metal-free method of cyclopropanation of sterically hindered olefins, substituted allylic alcohols, allylamines, and vinyl silyl ethers was developed using diazomethane in the presence of organic aluminum halides.

Full text of DOI:10.1007/s11172-019-2638-5

Russian Chemical Bulletin, International Edition, Vol. 68, No. 10, pp. 1869—1873, October, 2019
1869
The reagent Et AlX/CH N in cyclopropanation of sterically hindered olefins,
2
2 2
as well as oxygen- and nitrogen-containing unsaturated compounds
I. R. Ramazanov, A. V. Yaroslavova, N. R. Yaubasarov, E. N. Gil´manova, and U. M. Dzhemilev
Institute of Petrochemistry and Catalysis, Russian Academy of Sciences,
1
41 prosp. Oktyabrya, 450075 Ufa, Russian Federation.
E-mail: ilfir.ramazanov@gmail.com
A transition-metal-free method of cyclopropanation of sterically hindered olefins, substi-
tuted allylic alcohols, allylamines, and vinyl silyl ethers was developed using diazomethane in
the presence of organic aluminum halides.
Key words: organoaluminum compounds, diazomethane, aluminum carbenoids, cyclo-
propanation.
Reactions of metal carbenoids with olefinic compounds
approach to the synthesis of cyclopropane compounds
from sterically hindered olefins, as well as oxygen- and
nitrogen-containing unsaturated compounds, the interest
in which has recently grown significantly due to the high
is one of the most well-known and widely used approaches
1
for the design of cyclopropane systems. The most com-
monly used are zinc carbenoids, which are the basis
of such well-known cyclopropanation reagents as the
Simmons—Smith, Furukawa, Wittig, Shi, and Charette
1
0,11
synthetic potential of donor-acceptor cyclopropanes.
Initially, we investigated the cyclopropanation reac-
2
12
reagents. Recently, we have demonstrated the high effi-
tion of sterically hindered olefins: 2-cyclopropylidene-
ciency of aluminum carbenoids in cyclopropanation of
adamantane, 2-cyclobutylideneadamantane, bicyclo-
butylidene, and 2,2´-bi(adamantanylidene). It was found
that the reaction of 2-cyclopropylideneadamantane with
sterically hindered3 and nitrogen-containing olefins
,4
5,6
as compared to the reagents based on CH N and zinc
2
2
carbenoids traditionally used for cyclopropanation. This
feature determines the prospects of using aluminum car-
benoids for the synthesis of cyclopropane and polycyclo-
propane compounds. However, the relatively high price of
5 equiv. of CH N (solution in CH Cl ) and 5 equiv. of
2 2 2 2
Et AlCl for 5 h at room temperature proceeds with com-
2
plete conversion of the starting olefin, but unselectively
gives a difficult-to-separate mixture of products. When
CH I used in the generation of aluminum carbenoid using
Et AlCl was replaced with Et AlI, which was generated
2 2
2
2
trialkylalanes significantly limits the practical importance
of the developed methods for preparation of poorly avail-
able cyclopropane compounds. In addition, it is known
that aluminum carbenoids can also be prepared by the
reaction of organic aluminum halides with a diazomethane
solution. From the practical point of view, the "diazo-
methane" method is more preferable. However, depending
on the method for generating aluminum carbenoids, the
composition of the reaction mixture and the reactivity of
aluminum carbenoids can significantly differ. While the
reactivity of aluminum carbenoid obtained from diiodo-
methane was studied using a wide range of unsaturated
substrates, very little is known of such studies of an or-
ganoaluminum reagent based on diazomethane. We can
by the reaction of equimolar amounts of Et Al and I in
3 2
CH Cl , 2-cyclopropylideneadamantane was selectively
2
2
converted to the cyclopropanation product 1a in 87% yield
without the formation of rearrangement by-products
(Scheme 1, Table 1).
Cyclopropanation of 2-cyclobutylideneadamantane,
bicyclobutylidene, and 2,2´-bi(adamantanylidene) in the
presence of Et AlI also proceeds selectively.
2
Thus, the reactivity of aluminum carbenoids with re-
spect to sterically hindered olefins depends little on the
method of their generation. However, the high Lewis
acidity of diethylaluminium chloride does not allow its
use for cyclopropanation of readily rearrangeable poly-
cyclic compounds; in this case it is advisable to use diethyl-
aluminum iodide, which has a lower Lewis acidity.
7
mention only the innovative work of Hoberg on cyclo-
propanation of 1-pentene and our work on cyclopropana-
tion of fulvenes,8 in which poorly available polycyclo-
propane compounds were synthesized in high yields and
Aluminum carbenoids generated from CH2I2 and
trialkylalanes have proven themselves in the synthesis of
cyclopropyl alcohols and amines from allylic alcohols,
vinyl silyl ethers, allylamines, and enamines. A remarkable
feature of these processes is that the reaction with nitrogen-
containing unsaturated compounds is not accompanied
,9
selectivity using the reagent Et AlX/CH N . In this regard,
2
2
2
we hoped that the diazomethane method for generating
aluminum carbenoid could prove to be a practically useful
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 10, pp. 1869—1873, October, 2019.
066-5285/19/6810-1869 © 2019 Springer Science+Business Media, Inc.
1

1870
Russ. Chem. Bull., Int. Ed., Vol. 68, No. 10, October, 2019
Ramazanov et al.
Scheme 1
which is very different from the positive results we obtained
4
earlier when the reagent based on CH I was used. The
2
2
reason for this may be a higher concentration of aluminum
halides in solution in the case of the reaction with diazo-
methane, which leads to the binding of a significant amount
of allylamine to a less reactive complex. In the case of
CH I , aluminum halide is formed after the cyclopropana-
2
2
tion step and can be bound by the resulting cyclopropyl-
amine. Thus, when comparing the diiodomethane and
diazomethane methods for the generation of aluminum
carbenoids in the reaction with allylamines, the former
should be preferred.
Scheme 2
2
: R1 = R2 = Et (a), R1 + R2 = (CH2)5 (b)
by side N-alkylation. The latter reaction is a serious prob-
lem in the preparation of cyclopropylamines using the
Simmons—Smith reagent. In this regard, cyclopropanation
with aluminum carbenoids generated from diiodomethane
and trialkylalanes is a good alternative to the Kulinkovich—
de Meijere reaction. However, the high acidity of alumi-
num halides can be a serious problem in the diazomethane
method for generating aluminum carbenoids. Vinyl silyl
ethers and enamines are unstable in the presence of strong
Lewis acids, while allylamines can form with them poorly
reactive adducts.
The high Lewis acidity of Et AlCl favors the de-
2
composition of vinyl silyl ethers under the reaction condi-
tions, and their cyclopropanation with diazomethane
satisfactorily proceeds only when 3 mol. equiv. of Et AlI
2
is used (Scheme 3). The yields of cyclopropyl alcohols
3a—c and 4 were from 63 to 83%. Cyclopropanation of
(E)-oct-2-en-1-ol and geraniol proceeded in good yield
when 5 mol. equiv. of Et AlI and CH N were used, giv-
2
2
2
ing compound 5 and a mixture of diastereomers 6 and 6´
in a ratio of ~1 : 1.
Continuing the study of the reactivity of aluminum
In conclusion, the high Lewis acidity of aluminum
chloride poses a serious problem in the cyclopropanation
of substituted oxygen- and nitrogen-containing unsatu-
carbenoids generated using CH N , we tried to develop a
2
2
method for cyclopropanation of allylamines with a reagent
based on diazomethane and diethylaluminium chloride.
Unfortunately, high yields of cyclopropylamines were
rated compounds with the Et AlCl/CH N reagent sys-
2
2
2
tem. Replacing Et AlCl with Et AlI solves this problem,
2
2
achieved only with a large excess of CH N and Et AlCl,
however, the necessity to use a large excess of the iodide
somewhat eliminates the advantages of the diazomethane
method for the generation of aluminum carbenoids.
2
2
2
when a solution of CH N was added in portions over
2
2
6
h (Scheme 2), or with a large excess of CH N and Me AlI,
2 2 2
Table. 1. Cyclopropanation of allylamines with the reagent Et AlX/CH N (see Scheme 2)
2
2
2
Entry
Аllylamine
R AlX
CH N
R AlX
Product
Yield
2
2
2
2
R1
R2
(equiv.)
(equiv.)
of 2 (%)
1
2
3
4
5
6
7
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et AlCl
15
20
20
20
20
20
10
5
7
5
7
2
7
3
2a
2a
2a
2a
2a
2a
2b
55
88
2
Me AlI
2
*
Et AlI
40
2
*
*
Et AlCl
83
25
40
39
2
Et AlCl
2
i
Bu AlI
2
(CH2)5
Et AlI
2
*
Extra 2 equiv. of I were added.
2
*
*
The solution of CH N was added in portions over 6 h.
2
2

Cyclopropanation with Et AlHal/CH N
Russ. Chem. Bull., Int. Ed., Vol. 68, No. 10, October, 2019
1871
2
2
2
Scheme 3
Experimental
thick rubber gloves and goggles is a must. Contact of diazometh-
ane solutions with ground-glass joints, scratched and chipped
glassware must be avoided. The glass reactor must be sealed with
rubber septa; the edges of all glass tubes must be thoroughly
melted. A Teflon-coated magnetic rod must be used for stirring.
Exposure of diazomethane solutions to direct sunlight or a strong
artificial light source can cause an explosion.
The following commercially available organoaluminum
compounds were used in the work: 97% Me Al from Aldrich,
3
i
9
8% Et Al, 97% Bu Al, 88% Et AlCl (Redkinsky Pilot Plant,
3
3
2
Inc.). Argon of pure grade (USSR State Standard Specifications
1
0157-73) was used as an inert atmosphere. The starting com-
Preparation of a solution of diazomethane in dichloromethane.
Diazomethane was obtained according to a modified procedure
1
3
pounds: alkylidenecyclopropanes and alkylidenecyclobutanes,
biadamantanylidene,14 and vinyl silyl ethers were synthesized
using known procedures. 2-Alkenylamines were prepared by the
reaction of 2-alkenyl bromides with secondary amines. The reac-
tion products were analyzed by gas-liquid chromatography on
Carlo Erba (a 25 m×0.2 mm Hewlett Packard Ultra-1 glass
capillary column, flame-ionization detector, operating tem-
perature 50—170 С, carrier gas helium), Chrom-5 and Tsvet-102
chromatographs (flame-ionization detector, 1-, 2-, and 3-m
columns 3 mm in diameter; stationary phase silicone SE-30 (5%)
on Chromaton N-AW-HMDC (0.125—0.160 mm), carrier gas
helium (50 mL min– ), column temperature 50—220 С). Mass
spectra were recorded on a Finnigan 4021 instrument with an
ionizing electron energy of 70 eV and an ionization chamber
15
described in the work. A 45—50% aqueous KOH (100 mL) and
16
CH Cl (25 mL) were placed into a ground joint-free conical
2
2
flask equipped with a Teflon-coated magnetic rod and a thermo-
meter with cooling to –5 С and purging of argon at a rate of
–
1
80 mL min . N-Methyl-N-nitrosourea (2.5 g) was added in
small portions with continuous stirring maintaining the tem-
perature under 0 С. The solution was stirred at –5 С for 2 h.
Then, the upper aqueous layer was decanted, the organic layer
was dried over granular KOH in the refrigerator. The concentra-
tion of diazomethane in the solution was determined by reverse
titration with benzoic acid using a 0.1 M solution of KOH. The
1
yield of CH N was 45—50%.
2
2
Synthesis of polycyclic compounds by the reaction of the re-
agent Et AlI/CH N with sterically hindered olefins (general
1
13
temperature of 200 С. Н and С NMR spectra were recorded
2
2
2
1
3
on Bruker Avance 400 (100.62 MHz for С and 400.13 MHz
procedure). The reactor was a 50-mL single-neck round-bottom
glass flask without ground joints. Iodine (1.27 g, 5 mmol) was
placed in the reactor equipped with a Teflon-coated magnetic
rod, immersed into an ice-water bath, and mounted on a magnet-
ic stirrer. The flask was sealed with a rubber septum (14/23 joints),
which was pierced with two needles for argon inlet/outlet
through silicone hoses. A bubbler filled with silicone oil was
connected to the end of the outlet hose. The flask was purged
1
for Н) and Bruker Avance 500 spectrometers (125.78 MHz for
1
3
1
С and 500.17 MHz for Н), using Me Si and CDCl ( 77.36)
4
3
C
1
13
as internal standards for Н and С NMR spectra, respectively.
Chemical shifts are given in the  scale. Elemental composition
of compounds was determined using a CARLO ERBA-1106
instrument. Thin layer chromatography was performed on Silufol
UV-254 plates.
Caution! All the operations with diazomethane must be
carried out in a fume hood behind a safety screen. The use of
with dry argon. Then CH Cl (10 mL) and Et Al (0.75 mL,
2 2 3
5 mmol) were sequentially syringed through the septum and

1872
Russ. Chem. Bull., Int. Ed., Vol. 68, No. 10, October, 2019
Ramazanov et al.
the mixture was stirred for 15 min at 0 С. Next, an olefin
1 mmol) was syringed, followed by the addition of a 0.4 M solution
of diazomethane in CH Cl (12.5 mL, 5 mmol of CH N ) in
from four to five portions over 2 min at 0 С, periodically open-
ing the reactor under an enhanced flow of argon. The temperature
was raised to ambient (23 С) and the mixture was stirred for
another 6 h, followed by the work-up with 15% aqueous HCl
ed on a magnetic stirrer. The flask was sealed with a rubber
(
septum and purged with dry argon. Then CH Cl (10 mL) and
2 2
Et Al (0.45 mL, 3 mmol) (or 0.75 mL (5 mmol) of Et Al for the
2
2
2
2
3
3
reaction with geraniol) were sequentially syringed through the
septum and the mixture was stirred for 15 min at 0 С. Next,
substituted allylic alcohol (1 mmol) was syringed, followed by
the addition of a 0.4 M solution of diazomethane in CH Cl2
2
(
(
10 mL). The aqueous layer was extracted with diethyl ether
3×5 mL), the extract was combined with the organic layer, dried
(7.5 mL (3 mmol) of CH N or 12.5 mL (5 mmol) of CH N for
2 2 2 2
the reaction with geraniol) in from four to five portions over
2 min at 0 С, opening the reactor periodically with an enhanced
argon flow. The temperature was raised to ambient (23 С), the
mixture was stirred for 6 h and worked-up with 15% aqueous
HCl (10 mL). The aqueous layer was extracted with diethyl ether
(3×5 mL), the extract was combined with the organic layer, dried
over anhydrous CaCl , and concentrated in vacuo. Individual
2
compounds were isolated by column chromatography (com-
pounds 1a—c) or by distillation under reduced pressure (com-
pound 1d).
Dispiro[cyclopropane-1,1´-cyclopropane-2´,2´´-adamantane]
(
1a). The yield was 87%. R 0.71 (ethyl acetate—hexane, 1 : 20).
over anhydrous CaCl , and concentrated in vacuo. Individual
f
2
1
13
H and 3C NMR spectra are identical to those described in
compounds (compounds 3—5) and a mixture of diastereomers
the work.
(compounds 6 and 6´) were isolated by column chromatography.
Dispiro[cyclobutane-1,1´-cyclopropane-2´,2´´-adamantane]
1b). The yield was 71%. R 0.65 (ethyl acetate—hexane, 1 : 20).
1-Phenylcyclopropan-1-ol (3а). The yield was 75%. R 0.39
f
1
13
(
(ethyl acetate—hexane, 1 : 10). H and C NMR spectra are
f
1
13
5
H and 3C NMR spectra are identical to those described in
identical to those described in the work.
the work.
Dispiro[adamantane-2,1´-cyclopropane-2´,2´´-adamantane]
1-(p-Tolyl)cyclopropan-1-ol (3b). The yield was 68%. R 0.54
f
1
13
(ethyl acetate—hexane, 1 : 10). H and C NMR spectra are
5
(
1c). The yield was 80%. R 0.43 (ethyl acetate—hexane, 1 : 20).
identical to those described in the work.
f
1
13
M.p. 124—126 С. H and C NMR spectra are identical to
those described in the work.
1-(4-Bromophenyl)cyclopropan-1-ol (3с). The yield was 63%.
4
1
13
R 0.47 (ethyl acetate—hexane, 1 : 10). H and C NMR spectra
f
5
4
5,17
Dispiro[3.0.3 .1 ]nonane (1d). The yield was 69%. B.p.
are identical to those described in the works.
1
13
7
5—78 С (20 Torr). H and C NMR spectra are identical to
Bicyclo[4.1.0]heptan-1-ol (4). The yield was 83%. R 0.68
f
3
1
13
those described in the work.
(ethyl acetate—hexane, 1 : 10). H and C NMR spectra are
1
8
Synthesis of functionally substituted cyclopropanes by the
reaction of the reagent Et AlCl/CH N with substituted nitrogen-
identical to those described in the work.
(1RS,2RS)-(2-Pentylcyclopropyl)methanol (5). The yield was
2
2
2
1
13
containing unsaturated compounds (general procedure). A Teflon-
coated magnetic rod was placed in a 50-mL reactor immersed
into an ice-water bath and mounted on a magnetic stirrer, the
reactor was sealed with a rubber septum and purged with dry
82%. R 0.58 (ethyl acetate—hexane, 1 : 5). H and C NMR
f
spectra of compound 5 are identical to those described in
1
9
the work.
{(1RS,2RS)-2-[2-((RS)-2,2-Dimethylcyclopropyl)ethyl]-2-
methylcyclopropyl}methanol (6) and {(1RS,2RS)-2-[2-((SR)-2,2-
argon. Then CH Cl (5 mL), Et AlCl (0.5 mL, 3.5 mmol), and
2
2
2
allylamine (0.5 mmol) were sequentially syringed through the
dimethylcyclopropyl)ethyl]-2-methylcyclopropyl}methanol (6´).
1
septum at 0 С. A 0.4 M solution of diazomethane in CH Cl
The yield was 77%. R 0.68 (ethyl acetate—hexane, 1 : 5). H and
2
2
f
1
3
(
25 mL, 10 mmol of CH N ) was added in six portions over 6 h
C NMR spectra of compounds 6 and 6´ are identical to those
2
2
2
0
at room temperature (23 С), periodically opening the reactor
under an enhanced flow of argon. Then a 3 M solution of EtMgBr
in diethyl ether (10 mL) was added to the reaction mixture cooled
to 0 С (ice-water bath) (the organomagnesium compound is
necessary to remove the by-produced iodoethane from the reac-
tion mixture, which, when the reaction mixture is concentrated,
can react with the amine, giving quaternary salt), stirred for 1 h,
hydrolyzed with 25% aqueous NaOH (5 mL), and filtered through
a paper filter. The aqueous layer was extracted with diethyl ether,
the extract was combined with the organic layer, dried over
described in the work.
The authors are grateful to the Agidel Center for the
collective use of unique equipment at the Institute of
Petrochemistry and Catalysis of the Russian Academy of
Sciences for recording NMR spectra, mass spectra, and
determining the elemental composition of the synthesized
compounds.
This work was financially supported by the Presidium
of the Russian Academy of Sciences (Program No. 38
anhydrous CaCl , and concentrated in vacuo. Individual com-
2
"
Study of the fundamental problems of synthesis and
pounds 2a,b were isolated by distillation under reduced pressure.
N-(Cyclopropylmethyl)-N-ethylethaneamine (2а). The yield
structure-property relationship for the design of new
compounds and materials"), as well as the State assign-
ment of the Institute of Petrochemistry and Catalysis of
the UFIC RAS (Topics АААА-А19-119022290007-9,
АААА-А19-119022290008-6 for 2019—2021).
1
13
was 83%. B.p. 136—140 С. H and C NMR spectra are iden-
tical to those described in the work.6
1
-(Cyclopropylmethyl)pyperidine (2b). The yield was 72%.
1
13
B.p. 71—75 С (10 Torr). H and C NMR spectra are identical
to those described in the work.6
Synthesis of functionally substituted cyclopropanes by the
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Received April 25, 2019;
in revised form June 3, 2019;
accepted June 28, 2019