An unusual reaction of propargylamines with CH2I2 and Et3Al

Article abstract of DOI:10.1007/s11172-010-0293-y

N-{2-[(1-R-Cyclopropyl)methyl]prop-2-enyl}-N,N-dimethylamines were prepared in 80-90% yields by the reaction (5 h, 23-25 C) of propargylamines R-C=C-CH₂NMe₂ (where R = alkyl, Ph) with a system of reactants CH2I2-Et₃Al take

Full text of DOI:10.1007/s11172-010-0293-y

Russian Chemical Bulletin, International Edition, Vol. 59, No. 8, pp. 1668—1670, August, 2010
1668
An unusual reaction of propargylamines with CH2I2 and Et3Al
I. R. Ramazanov,a A. V. Yaroslavova,a L. M. Khalilov,a U. M. Dzhemilev,a and O. M. Nefedovb
aInstitute of Petroleum Chemistry and Catalysis, Russian Academy of Sciences,
141 prosp. Oktyabrya, 450075 Ufa, Bashkortostan, Russian Federation.
Fax: +7 (347) 284 2750. Eꢀmail: iramazan@inbox.ru
bN. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (495) 135 5328
Nꢀ{2ꢀ[(1ꢀRꢀCyclopropyl)methyl]propꢀ2ꢀenyl}ꢀN,Nꢀdimethylamines were prepared in
80—90% yields by the reaction (5 h, 23—25 °C) of propargylamines R—C≡C—CH2NMe2
(where R = alkyl, Ph) with a system of reactants CH2I2—Et3Al taken in the molar ratio
[propargylamine] : [Et3Al] : [CH2I2] = 1 : 6 : 6. In the case of phenylꢀsubstituted propargylꢀ
amine, Nꢀ({1ꢀ[(1ꢀphenylcyclopropyl)methyl]cyclopropyl}methyl)ꢀN,Nꢀdimethylamine is
selectively formed in 76% yield upon the elongation of the reaction time to 4 days.
Key words: cyclopropanes, propargylamines, diiodomethane, triethylaluminum.
Compounds of the cyclopropane series are important
Scheme 1
intermediates in organic synthesis, because many of them
are biologically active.1 We have previously2—4 found that
alkylꢀ and phenylꢀsubstituted acetylenes react with CH2I2
in the presence of Et3Al to form cyclopropane compounds.
The role of various functional substituents in biological
activity induction is very high and, hence, the reactions of
functionally substituted acetylene compounds with diiodoꢀ
methane in the presence of trialkylalanes was studied to
develop a general method of transformation of acetylenes
into cyclopropanes. Substituted propargyl alcohols and
amines were chosen as objects of transformation due to
their accessibility and wide use in organic synthesis. It was
found that substituted propargyl alcohols react with the
systems of reactants CH2I2—R3Al to form bisꢀcycloproꢀ
panes in good yields.5 In this work, we present the results
of the reaction of this system of reactants with propargylꢀ
amines.
R = nꢀC6H13 (a), Bun (b), Ph (c)
Reagents, conditions, and yields: CH2I2 (6 equiv.), Et3Al (6 equiv.);
CH2Cl2, 23—25 °C, 5 h; 83% (a), 79% (b), 89% (c).
C(3)H2 group gives crossꢀpeaks with C(1), C(2), and
=CH2. All interactions observed in the COSY and HMBC
spectral also confirm the structure of compound 1а.
The products of transformation of other propargylꢀ
amines were synthesized and identified analogously,
being substituted cyclopropanes 1b,c.
N,NꢀDimethylꢀNꢀ(nonꢀ2ꢀynꢀ1ꢀyl)amine reacts with
CH2I2 and Et3Al under mild conditions (23—25 °C, 5 h)
to form Nꢀ{2ꢀ[(1ꢀhexylcyclopropyl)methyl]propꢀ2ꢀenꢀ
1ꢀyl}ꢀN,Nꢀdimethylamine (1a) in 83% yield (Scheme 1).
It is difficult to cyclopropanate propargylamines by
the systems of reactants CH2I2—Et3Al because of the
possible side formation of quaternary ammonium salts
from CH2I2 or EtI (the latter is formed upon the generaꢀ
tion of aluminum carbenoid by the exchange reaction).
We established that N,NꢀdimethylꢀNꢀ(nonꢀ2ꢀynꢀ1ꢀyl)ꢀ
amine in the presence of equimolar amounts of Et3Al and
CH2I2 form no quaternary ammonium salt because of the
formation of the strong donorꢀacceptor bond N→Al. For
this reason we proposed the following order of loading of
the reactants: propargylamine, Et3Al, and CH2I2. However,
the organoaluminum complex should be decomposed with
an aqueous solution of NaOH in order to isolate the reacꢀ
1
The signals in the H and 13C NMR spectra of comꢀ
pound 1a were assigned on the basis of the 2D NMR
1
HSQC, COSY, and HMBC experiments. The H NMR
spectrum exhibits the characteristic multiplet signal with
δH = 0.25—0.4 belonging to the strongly coupled fourꢀ
spin system AA´BB´ of protons of the 1,1ꢀdisubstituted
cyclopropane moiety. In the HMBC spectrum, this
multiplet has crossꢀpeaks with the C(3), C(4), and C(5)
carbon atoms, and the singlet signals of protons of the
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1623—1625, August, 2010.
1066ꢀ5285/10/5908ꢀ1668 © 2010 Springer Science+Business Media, Inc.

(3ꢀAminoꢀ2ꢀmethylidenepropyl)cyclopropanes
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 8, August, 2010
1669
tion product. In this case, the reaction mixture can conꢀ
tain CH2I2 and EtI. It is known that EtMgBr reacts well
with iodineꢀcontaining organic compounds yielding crossꢀ
coupling products. Therefore, to prevent the formation of
quaternary ammonia salts, before hydrolysis the reaction
mixture was treated with an ethereal solution of EtMgBr.
The use of these manipulations allowed us to enhance the
yield of the reaction products.
compounds 1a—c followed by their next cyclopropanation
with CH2I2 and Et3Al according to the Yamamoto proꢀ
cedure.6
Unlike propargyl alcohols, propargylamines react with
CH2I2—Et3Al without elimination of the functional group
(Scheme 3). The structure of 2ꢀ(cyclopropylmethyl)ꢀ
allylamines 1 formed indicates that the scheme of transꢀ
formations differs from that proposed for propargyl
alcohols and alkylꢀsubstituted acetylenes.4,5 Thus, the
nature of the functional group of propargyl derivatives
substantially affects the direction of their interaction with
the system of reactants CH2I2—Et3Al. We are planning
to carry out further experiments with other nitrogenꢀconꢀ
taining unsaturated compounds, which, as we hope, would
elucidate the mechanism of this unusual transformation.
The influence of the nature of the organoaluminum
compound on the yield and composition of the reaction
products was studied. The highest yield of compound 1a
is observed when Et3Al is used. The replacement of Et3Al
by Bui Al decreases the yield of compound 1a to 45%
3
because of the incomplete conversion of the starting acetyꢀ
lene and formation of byꢀproducts. Compound 1a is not
formed in the case of Me3Al.
The highest yield of compound 1а was achieved when
the reaction was carried out in dichloromethane and
dichloroethane. The reaction does not occur in ether solꢀ
vents (THF, diethyl ether).
Scheme 3
The products of double bond cyclopropanation in
compounds 1a—c are slowly accumulated with the elonꢀ
gation of the reaction time to 4 days at room temperature.
In the case of N,NꢀdimethylꢀNꢀ(3ꢀphenylpropꢀ2ꢀinyl)ꢀ
amine, bisꢀcyclopropane 2c is formed selectively in 76%
yield (Scheme 2). The addition of 2 equivalents of Et3Al
and CH2I2 to the reaction mixture on the next day after
the starting the reaction does not accelerate cycloꢀ
propanation. Alkylꢀsubstituted propargylamines are transꢀ
formed into bisꢀcyclopropane compounds 2b,c in 40—50%
yields. In these cases, the reaction is nonꢀselective with
the side formation of unidentified isomeric compounds
(according to the GC—MS data) in amounts of 30—40%.
It is difficult to isolate individual compounds, because
their Rf are close. A more convenient approach to bisꢀ
cyclopropane derivatives 2a—c includes the isolation of
Conditions and yields: i. CH2Cl2, ~20 °C, 3 h, 77%; ii. CH2Cl2,
~20 °C, 5 h, 83%.
Experimental
Commercially available reagents were used. Dichloroꢀ
methane was distilled over P2O5. Reaction products were
analyzed on a Carlo Erba chromatograph (Ultraꢀ1 glass capillary
column (Hewlett Packard) 25 m×0.2 mm, flameꢀionization
detector, temperature of the thermostat 50—170 °C, helium as
carrier gas). Mass spectra were measured using a Finnigan 4021
instrument with an electron impact ionization energy of 70 eV
and the temperature of the ionization chamber 200 °C. The
elemental composition of the samples was determined on a Carlo
Erba elemental analyzer (model 1106). 1H and 13C NMR spectra
were recorded on a Bruker Avance 400 spectrometer (1H, 400
MHz; 13C, 100 MHz) using SiMe4 and CDCl3, respectively, as
internal standards. The yields of compounds 2b,c were deterꢀ
mined by GC using an internal standard. TLC was carried out
on Silufol UVꢀ254 plates in an EtOAc—petroleum ether (1 : 4)
system. Compound 1c was cyclopropanated to form product 2c
according to the Yamamoto procedure.6
Scheme 2
av1
av2
Synthesis of substituted cyclopropanes 1 (general procedure).
A 25ꢀmL glass reactor immersed in an ice bath and mounted on
a magnetic stirrer was consecutively loaded in an inert gas
atmosphere with CH2Cl2 (5 mL), propargylamine (2 mmol),
Et3Al (12 mmol), and CH2I2 (0.97 mL, 12 mmol). This sequence
Reagents, conditions, and yields: i. CH2I2 (6 equiv.), Et3Al (6 equiv.),
CH2Cl2, 23—25 °C, 3 h, 89%; ii. CH2I2 (6 equiv.), Et3Al
(6 equiv.), CH2Cl2, 23—25 °C, 4 days, 76%; iii. CH2I2 (2 equiv.),
Et3Al (2 equiv.), CH2Cl2, 23—25 °C, 6 h, 91%.

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Russ.Chem.Bull., Int.Ed., Vol. 59, No. 8, August, 2010
Ramazanov et al.
of loading prevents the formation of ammonium salts. The
mixture was stirred at ∼20 °C for 5 h to obtain 1а—c and for
4 days to obtain 2a—c). Then a 3 M solution (10 mL) of EtMgBr
in Et2O was added to the reaction mixture (to decompose CH2I2
and EtI). The mixture was stirred for 1 h, hydrolyzed with a 25%
aqueous solution of NaOH, and filtered through the paper filter.
The aqueous layer was extracted with diethyl ether, and the
extract was combined with the organic layer, dried with anhydrous
CaCl2, and concentrated in vacuo. Individual products were
isolated on a column with silica gel. The eluent was EtOAc—
petroleum ether (gradient 1 : 10→1 : 3).
65.72 (C(1)). MS, m/z (Irel (%)): 237 [M]+ (1), 236 (1), 235 (1),
222 [M – Me]+ (5), 208 [M – C2H5]+ (5), 194 [M – C3H7]+
(12), 180 [M – C4H9]+ (10).
Nꢀ({1ꢀ[(1ꢀButylcyclopropyl)methyl]cyclopropyl}methyl)ꢀ
N,Nꢀdimethylamine (2b). The yield was 41%, Rf 0.5. Found (%):
C, 79.73; H, 12.32; N, 6.50. C14H27N. Calculated (%): C, 80.31;
1
H, 13.00; N, 6.69. H NMR, δ: 0.15—0.45 (m, 8 H, C(av1)H2,
C(av2)H2); 0.88 (t, 3 H, C(8)H3, J = 7.2 Hz); 1.20—1.40 (m,
6 H, C(5)H2, C(6)H2, C(7)H2); 2.09 (s, 2 H, C(3)H2); 2.17 (s,
6 H, Me2N); 2.20 (s, 2 H, C(1)H2). 13C NMR, δ: 10.49, 11.76
(4 C, C(av1), C(av2)); 14.16 (C(8)); 23.12(C(7)); 28.89 (C(6));
35.90 (C(5)); 39.72 (C(3)); 45.73 (2 C, Me2N); 65.74 (C(1)).
MS, m/z (Irel (%)): 209 [M]+ (1), 208, 207 (1) (1), 194
[M – Me]+ (5), 180 [M – C2H5]+ (5), 166 [M – C3H7]+ (10).
Nꢀ({1ꢀ[(1ꢀPhenylcyclopropyl)methyl]cyclopropyl}methyl)ꢀ
N,Nꢀdimethylamine (2c). The yield was 0.35 g (76%), Rf 0.57.
Found (%): C, 83.29; H, 10.11; N, 6.11. C16H23N. Calculꢀ
Nꢀ{2ꢀ[(1ꢀHexylcyclopropyl)methyl]propꢀ2ꢀenꢀ1ꢀyl}ꢀ
N,Nꢀdimethylamine (1а). The yield was 0.37 g (83%), Rf 0.63.
Found (%): C, 80.42; H, 12.88; N, 6.07. C15H29N. Calculꢀ
1
ated (%): C, 80.65; H, 13.08; N, 6.27. H NMR, δ: 0.25—0.40
(m, 4 H, C(av)H2); 0.88 (t, 3 H, C(10)H3, J = 7.0 Hz);
1.15—1.40 (m, 10 H, C(5)H2, C(6)H2, C(7)H2, C(8)H2,
C(9)H2); 2.02 (s, 2 H, C(3)H2); 2.18 (s, 6 H, Me2N); 2.83 (s,
2 H, C(1)H2); 4.95 (s, 2 H, =CH2). 13C NMR, δ: 11.79 (2 C,
C(m)); 14.07 (C(10)); 17.69 (C(4)); 22.65 (C(9)); 26.45 (C(6));
29.60 (C(7)); 31.91(C(8)); 35.75 (C(3)); 40.11 (C(5)); 45.34
(2 C, Me2N); 65.47 (C(1)); 113.48 (=CH2); 145.66 (C(2)).
MS, m/z (Irel (%)): 223 [M]+ (1), 222 [M – H]+ (10), 208
[M – Me]+ (8), 194 [M – C2H5]+ (15).
Nꢀ{2ꢀ[(1ꢀButylcyclopropyl)methyl]propꢀ2ꢀenꢀ1ꢀyl}ꢀ
N,Nꢀdimethylamine (1b). The yield was 0.21 g (79%), Rf 0.71.
Found (%): C, 79.15; H, 12.90; N, 7.17. C13H25N. Calculated
(%): C, 79.55; H, 13.02; N, 6.93%. 1H NMR, δ: 0.30—0.40 (m,
4 H, C(av)H2); 0.88 (t, 3 H, C(8)H3, J = 7.2 Hz); 1.15—1.40
(m, 6 H, C(5)H2, C(6)H2, C(7)H2); 2.03 (s, 2 H, C(3)H2); 2.17
(s, 6 H, Me2N); 2.84 (s, 2 H, C(1)H2); 4.96 (s, 2 H, =CH2).
13C NMR, δ: 11.78 (2 C, C(av)); 14.16 (C(8)); 17.67 (C(4));
22.97 (C(7)); 28.74 (C(6)); 35.41 (C(5)); 40.12 (C(3)); 45.35
(2 C, Me2N); 65.46 (C(1)); 113.58 (=CH2); 145.57 (C(2)).
MS, m/z (Irel (%)): 195 [M]+ (1), 194 [M – H]+ (8), 180
[M – Me]+ (8), 166 [M – C2H5]+ (20), 152 [M – C3H7]+ (9),
138 [M – C4H9]+ (7), 135 (19).
Nꢀ{2ꢀ[(1ꢀPhenylcyclopropyl)methyl]propꢀ2ꢀenꢀ1ꢀyl}ꢀ
N,Nꢀdimethylamine (1c). The yield was 0.38 g (89%), Rf 0.45.
Found (%): C, 83.79; H, 9.57; N, 6.31. C15H21N. Calculated
(%): C, 83.67; H, 9.83; N, 6.50. 1H NMR, δ: 0.80—0.95 (m,
4 H, C(av)H2); 2.13 (s, 6 H, Me2N); 2.50 (s, 2 H, C(3)H2); 2.75
(s, 2 H, C(1)H2); 4.70—4.90 (m, 2 H, =CH2); 7.30—7.40 (m,
5 H, Ph). 13C NMR, δ: 13.93 (2 C, C(av)); 23.48 (C(4)); 43.31
(C(3)); 45.32 (2 C, Me2N); 65.91 (C(1)); 114.44 (=CH2); 125.50
(C(8)); 127.87, 128.06 (4 C, C(6), C(6´), C(7), C(7´)); 145.62
(C(2)). MS, m/z (Irel (%)): 215 [M]+ (1).
1
ated (%): C, 83.51; H, 9.92; N, 6.17. H NMR, δ: –0.15—0.00
(m, 4 H, C(av1)H2); 0.80—0.90 (m, 4 H, C(av2)H2); 1.67 (s,
2 H, C(3)H2); 2.10 (s, 2 H, C(1)H2); 2.20 (s, 6 H, Me2N);
6.90—7.50 (m, 5 H, Ph). 13C NMR, δ: 10.42, 11.98 (4 C, C(av2),
C(av2)); 17.02 (C(2)); 24.34 (C(4)); 44.48 (C(3)); 45.59 (2 C,
Me2N); 65.88 (C(1)); 125.79 (C(8)); 128.64, 129.82 (4 C, C(6),
C(6´), C(7), C(7´)); 146.30 (C(5)). MS, m/z (Irel (%)): 229
[M]+ (1).
This work was financially supported by the Council on
Grants at the President of the Russian Federation (Program
for State Support of the Leading Scientific Schools of
the Russian Federation, Grant NShꢀ4105.2010.3) and the
Division of Chemistry and Materials Science of the
Russian Academy of Sciences (Program No. 1).
References
1. J. Salaun, in Small Ring Compounds in Organic Synthesis,
Vol. 6, Ed. A. de Meijere, SpringerꢀVerlag, Berlin, 2000.
2. U. M. Dzhemilev, I. R. Ramazanov, A. G. Ibragimov, L. I.
Dyachenko, M. P. Lukyanova, O. M. Nefedov, J. Organomet.
Chem., 2001, 636, 91.
3. I. R. Ramazanov, M. P. Luk´yanova, A. Z. Sharipova, A. G.
Ibragimov, U. M. Dzhemilev, O. M. Nefedov, Izv. Akad.
Nauk, Ser. Khim., 2001, 1338 [Russ. Chem. Bull., Int. Ed.,
2001, 50, 1406].
4. I. R. Ramazanov, L. K. Dil´mukhametova, U. M. Dzhemilev,
O. M. Nefedov, Izv. Akad. Nauk, Ser. Khim., 2009, 1311
[Russ. Chem. Bull., Int. Ed., 2009, 58, 1311].
5. I. R. Ramazanov, A. V. Yumagulova, U. M. Dzhemilev,
O. M. Nefedov, Tetrahedron Lett., 2009, 50, 4233.
6. K. Maruoka, Y. Fukutani, H. Yamamoto, J. Org. Chem., 1985,
50, 4412.
Nꢀ({1ꢀ[(1ꢀHexylcyclopropyl)methyl]cyclopropyl}methyl)ꢀ
N,Nꢀdimethylamine (2a). The yield was 48%, Rf 0.54. Found (%):
C, 80.21; H, 12.79; N, 6.01. C16H31N. Calculated (%): C, 80.94;
1
H, 13.16; N, 5.90. H NMR, δ: 0.15—0.45 (m, 8 H, C(cp1)H2,
C(av2)H2); 0.89 (t, 3 H, C(10)H3, J = 6.8 Hz); 1.20—1.35 (m,
10 H, C(5)H2, C(6)H2, C(7)H2, C(8)H2, C(9)H2); 2.11 (s, 2 H,
C(3)H2); 2.18 (s, 6 H, Me2N); 2.22 (s, 2 H, C(1)H2). 13C NMR,
δ: 10.49, 11.77 (4 C, C(av1), C(av2)); 14.13 (C(10)); 16.88
(C(4)); 18.21 (C(2)); 22.61 (C(9)); 26.51 (C(6)); 29.48 (C(7));
31.83 (C(8)); 39.69 (C(3)); 40.04 (C(5)); 45.74 (2 C, Me2N);
Received March 10, 2010;
in revised form May 12, 2010