Synthesis of 5-methylidenehexahydropyrrolo[l,2-a]imidazoles and 6-methylideneoctahydropyrrolo[l,2-a]pyrimidines by the reaction of 1-alkynyl-1-chlorocyclopropanes with lithium derivatives of 1,2- and 1,3-diaminoalkanes

Article abstract of DOI:10.1007/s11172-010-0261-6

A reaction of 1-alkynyl-1-chlorocyclopropanes with excess of lithium derivative of 1,2-diaminoethane leads to 5-methylidenehexahydropyrrolo[l,2-a] imidazoles in 35-72% yields, whereas analogous reaction with lithium derivative of 1,3-diaminopropane gives 6-methyl-ideneoctahydropyrrolo[l,2-a]pyrimidine in up to 50% yield. A mechanism of these unusual multi-step processes includes dehydrochlorination of 1-alkynyl-1-chlorocyclopropanes to form conjugated alkynylcyclopropenes capable of addition of monoalkylamide ions at the double bond, leading to the corresponding secondary cyclopropylamines; the latter under the reaction conditions isomerize to the linear imines, which further undergo a cascade cyclization with sequential involvement of the C=N and C≡C bonds.

Full text of DOI:10.1007/s11172-010-0261-6

Russian Chemical Bulletin, International Edition, Vol. 59, No. 7, pp. 1451—1458, July, 2010
1451
Synthesis of 5ꢀmethylidenehexahydropyrrolo[1,2ꢀa]imidazoles
and 6ꢀmethylideneoctahydropyrrolo[1,2ꢀa]pyrimidines by the reaction
of 1ꢀalkynylꢀ1ꢀchlorocyclopropanes with lithium derivatives
of 1,2ꢀ and 1,3ꢀdiaminoalkanes*
K. N. Shavrin, V. D. Gvozdev, and O. M. Nefedov
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5328. Eꢀmail: vgvozdev2006@yandex.ru
A reaction of 1ꢀalkynylꢀ1ꢀchlorocyclopropanes with excess of lithium derivative of 1,2ꢀdiꢀ
aminoethane leads to 5ꢀmethylidenehexahydropyrrolo[1,2ꢀa]imidazoles in 35—72% yields,
whereas analogous reaction with lithium derivative of 1,3ꢀdiaminopropane gives 6ꢀmethylꢀ
ideneoctahydropyrrolo[1,2ꢀa]pyrimidine in up to 50% yield. A mechanism of these unusual
multiꢀstep processes includes dehydrochlorination of 1ꢀalkynylꢀ1ꢀchlorocyclopropanes to form
conjugated alkynylcyclopropenes capable of addition of monoalkylamide ions at the double
bond, leading to the corresponding secondary cyclopropylamines; the latter under the reaction
conditions isomerize to the linear imines, which further undergo a cascade cyclization with
sequential involvement of the C=N and C≡C bonds.
Key words: alkynylchlorocyclopropanes, 1,2ꢀdiaminoethane, 1,3ꢀdiaminopropane, hexaꢀ
hydropyrrolo[1,2ꢀa]imidazoles, octahydropyrrolo[1,2ꢀa]pyrimidines, hexahydropyrimidines,
elimination, nucleophilic addition, cyclopropane ring opening, cascade cyclization.
Recently, we have shown2 that the action of sterically
hindered lithium dialkylamides on 1ꢀ(alkꢀ1ꢀynyl)ꢀ1ꢀ
chlorocyclopropanes 1 in situ generates conjugated alkyꢀ
nylcyclopropenes. The latter readily add nucleophiles of
various nature at the double bond of the cyclopropene
ring, such as dialkylamide ions,2,3 diazoles,3 alcohols,4
phenols,4 thiophenols, and alkanethiols,5 forming the corꢀ
responding functionalized alkynylcyclopropanes in up to
80% yields. Analogous reactions with lithium monoalkylꢀ
amides,6 depending on the nature of substituent at the
triple bond, lead either to 1,2ꢀdienes, having in the moleꢀ
cule one carbon atom less than in the starting compound,
or conjugated iminoalkylcyclopropenes. When monolithꢀ
ium derivatives of 1,2ꢀ and 1,3ꢀdiaminoalkanes are used
in these reactions, carbon skeleton of the starting comꢀ
pounds undergoes complete transformation to form the
earlier unknown 5ꢀmethylidenehexahydropyrrolo[1,2ꢀa]ꢀ
imidazoles and 6ꢀmethylideneoctahydropyrrolo[1,2ꢀa]ꢀ
pyrimidines.1 Compounds of these series exhibit awide range
of biological activity,7—10 as well as are convenient precurꢀ
sors for obtaining chiral pyrrolidines.11 The present work
is devoted to the detailed study of these new unusual reactions.
The reaction of 1ꢀchloroꢀ2,2ꢀdimethylꢀ1ꢀphenylethyꢀ
nylcyclopropane (1a) and 1ꢀchloroꢀ1ꢀphenylethynylꢀ
spiro[2.5]octane (1b) with a fourꢀfold excess of lithium
2ꢀaminoethylamide** in THF at 20 °C with subsequent
aqueous quenching the reaction mixture leads to 5ꢀbenzylꢀ
idenehexahydropyrrolo[1,2ꢀa]imidazoles 3a,b in 65 and
72% yields, respectively (Scheme 1). In both cases, the
formation of mixtures of Zꢀ and Eꢀisomers was observed
with predominance of the latter (1 : 4 for 3a and 1 : 4.2 for
3b). Their identification was accomplished based on the
NOESYꢀ2D proton spectra having correlations between
the methine protons at the double bond and the protons of
the methylidene fragment at position 6. In the case of the
starting cyclopropane 1c, having a bulky tertꢀbutyl substitꢀ
uent at the triple bond, an exclusive formation of the
Eꢀisomer of the corresponding bicyclic derivative 3c in
lower (~35%) yield took place. The latter was isolated
from the reaction mixture in the individual state by chroꢀ
matography on Al2O3.
The use of lithium derivative of 1,3ꢀdiaminopropane
in these reactions changes their stereoꢀ and regioselectiviꢀ
ty. For instance, the reaction of cyclopropanes 1a and 1b
with a fourꢀfold excess of this compound leads to 6ꢀbenzylꢀ
ideneoctahydropyrrolo[1,2ꢀa]pyrimidines 4a and 4b as exꢀ
** In all the cases, the required lithium derivatives of α,ωꢀdiꢀ
aminoalkanes were obtained by addition of a solution of BuLi in
hexane to a small excess of the corresponding diamine in THF.
* For preliminary communication, see Ref. 1.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1418—1425, July, 2010.
1066ꢀ5285/10/5907ꢀ1451 © 2010 Springer Science+Business Media, Inc.

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Shavrin et al.
Scheme 1
Scheme 2
1, 2
R1
Ph
Ph
But
R2
Me
(CH2)5
Me
R3
Me
3
a
b
R2
Me
(CH2)5
R3
Me
4a: R2 = R3 = Me; 4b: R2 + R3 = (CH2)5
a
b
c
Reagents and conditions: i. NH2(CH2)3NH2—BuLi, THF, 20 °C;
ii. H2O.
Me
Reagents and conditions: i. NH2(CH2)2NH2—BuLi, THF, 20 °C;
ii. H2O.
The structure of the minor product 5a was also confirmed
by alternative synthesis.
clusive Eꢀisomers in 50 and 27% yields, respectively
(Scheme 2). In contrast to compounds 3, which are liqꢀ
uids, these both products are crystalline substances, that
allowed us to isolate them in the individual state by recrysꢀ
tallization from hexane.
As it could have been supposed, the lithium derivative
of Nꢀmethylꢀ1,3ꢀdiaminopropane reacts with chlorocycloꢀ
propane 1a nonselectively. Competition of the primary
and secondary amino groups results in the formation of
a mixture of the corresponding Eꢀisomer of Nꢀmethylꢀ
substituted pyrimidine 7 and transꢀisomer of aminocycloꢀ
propane 8 in the ratio 1.5 : 1 in 68% total yield (Scheme 3).
Compound 7 was successfully isolated by crystallization
from hexane in >90% purity and 37% yield, whereas the
structure of product 8 was confirmed by comparison of the
1H and 13C NMR spectra of the reaction mixture with the
spectral data for other analogous aminocyclopropanes obꢀ
tained earlier.3
Proceeding from the available data published earliꢀ
er3,12—14 and the data obtained in this work, the formation
of products 3, 4, and 7 can be described as follows (Scheme 4).
In the first step, the starting chlorocyclopropanes 1 upon
the action of lithium monoalkylamides present in the reacꢀ
tion medium undergo elimination of HCl to generate conꢀ
jugated alkynylcyclopropenes 2, which under conditions
used add monoalkylamide ions to form cyclopropylamines
9 (see Ref. 3). The latter undergo the ring opening to form
linear imines 10,12 which due to the presence of the amino
group give intramolecular cascade cyclization with sequenꢀ
At the same time, the reaction of chlorocyclopropane
1c with the same reagent, independent on the reaction
time, gives no expected bicyclic compounds, rather forꢀ
mation of two similar in the structure products in the ratio
1 : 1.35 in 72% total yield was observed. Comparison of
the integral intensities of the signals for the protons of the
tertꢀbutyl and methyl groups, as well as methylene fragꢀ
ments at the nitrogen atoms (δ 2.6—3.5) reveals that the
molecules of these both compounds contain a tertꢀbutylꢀ
ethynyl, propaneꢀ2,2ꢀdiyl, and propyleneꢀ1,3ꢀdiamine
fragments in the ratio 1 : 1 : 1, whereas the number of the
signals for the CH2 groups in their 13C NMR spectra indiꢀ
cates the symmetry of the structure with respect to the
central carbon atom of the trimethylene bridge. Proceedꢀ
ing from these data, the minor component of the mixture
obtained was identified as aminal 5a, whereas a predomiꢀ
nant one, as its isomer 6, differing in position of the triple
bond (see Scheme 2) and arising, obviously, due to the
migration of the latter under the strongly basic conditions.

5ꢀMethylidenehexahydropyrrolo[1,2ꢀa]imidazoles
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 7, July, 2010
1453
Scheme 3
pected that lithium monoalkylamides would behave simiꢀ
larly, giving the corresponding secondary cyclopropylꢀ
amines 9.
A possibility of the key step of the mechanism sugꢀ
gested, i.e., isomerization of cyclopropylamines 9 to imiꢀ
nes 10, was confirmed by the data,12 from which it folꢀ
lows that the lithiation of NꢀalkylꢀNꢀcyclopropylꢀ
amines results in the threeꢀmembered ring opening to
form the corresponding linear imines. Formation of
hexahydropyrimidine 5a by the reaction of chlorocycloꢀ
propane 1c with lithium derivative of 1,3ꢀdiaminopropane
is an evidence of the analogous process followed by the
intramolecular cyclization at the C=N bond (see Scheme 2).
The outcome of the reactions of arylchlorocycloproꢀ
panes 12a,b, containing no triple bond with lithium
monoalkylꢀ and aminoalkylamides confirms a generality
of similar transformations. It turned out that heating comꢀ
pounds 12a,b with a fourꢀfold excess of lithium propylꢀ
amide in THF at 60 °C for 4—5 h leads to the correspondꢀ
ing imines 15a,b in 50—55% yield. The latter, obviously,
are formed due to the threeꢀmembered ring opening in the
Nꢀlithium derivatives of aminocyclopropanes 14, which
result from the addition of lithium propylamide at the
double bond of the in situ generated conjugated arylcycloꢀ
propenes 13 (Scheme 5).
Reagents and conditions: i. MeNH(CH2)3NH2—BuLi, THF,
20 °C; ii. H2O.
tial involvement of the C=N (see Ref. 13) and C≡C bonds
(see Ref. 14) through the intermediate formation of the
nitrogenꢀcontaining cyclic structures 11.
The following data confirm the scheme suggested. Earꢀ
lier,3 it has been shown that alkynylchlorocyclopropanes
1 react with lithium dialkylamides by the addition—elimiꢀ
nation mechanism to form the corresponding dialkylꢀ
amino(alkynyl)cyclopropanes. Therefore, it could be exꢀ
When lithium derivative of 1,3ꢀdiaminopropane is used
in these reactions, further cyclization of the arising linear
imine 16 occurs, consisting in the addition of the primary
amino group to the C=N bond and leading to hexahydroꢀ
pyrimidine 17 in 63% yield (Scheme 6).
Scheme 4
Reagents and conditions: i. R4NH(CH2)n+1NH2—BuLi (n = 1, 2, R4 = H, Me; R5 = H, Li), THF, 20 °C.

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Shavrin et al.
aldimine described in the literature,15 the latter is
formed due to the threeꢀmembered ring opening in
the unstable intermediate lithium cyclopropylamide
(Scheme 7).
Scheme 5
To confirm possible involvement of aminals 11 in the
last step of the mechanism suggested (see Scheme 4), we
accomplished an independent synthesis of two represenꢀ
tatives of this class of compounds. In the first step, the
starting acetylenic chlorides 20 reacted with isobutyraldeꢀ
hyde in the twoꢀphase system toluene—50% aqueous KOH
in the presence of tetrabutylammonium iodide.16 The thus
obtained aldehydes 21 (the yields were 58 and 53% for 21a
and 21b, respectively) further reacted with a threeꢀfold
excess of 1,3ꢀdiaminopropane in CH2Cl2 at room temperꢀ
ature in the presence of anhydrous Na2SO4, that led to the
target hexahydropyrimidine derivatives 5a,b in 78—85%
yields (Scheme 8).
Addition of compound 5b to equimolar amount of lithꢀ
ium derivative of 1,3ꢀdiaminopropane in THF at room
temperature gives exclusively 6ꢀbenzylideneoctahydropyꢀ
rrolo[1,2ꢀa]pyrimidine (4a), which was isolated in the inꢀ
dividual state by recrystallization from hexane in 72% yield
(Scheme 9). Compound 5a, similarly treated, does not
undergo the intramolecular cyclization, only being isomerꢀ
ized to aminal 6 by ~50% and forming a mixture of subꢀ
stances analogous to that obtained in the reaction of chloꢀ
rocyclopropane 1c with lithium derivative of 1,3ꢀdiamiꢀ
nopropane (see Scheme 2).
Formation of isomer 6, obviously, results from the
triple bond migration upon the action of the strongly baꢀ
sic lithium derivative of 1,3ꢀdiaminopropane present
in the reaction mixture. Significant difference in the beꢀ
havior of compounds 5a and 5b under conditions used,
by all accounts, is due to the considerably lower polariꢀ
14a—17a: R = Ph; 14b—17b: R = 4ꢀMeOC6H4
Reagents and conditions: i. PrNHLi, THF, 20 °C.
A separate experiment showed that the ring openꢀ
ing also takes place during lithiation of unsubstituted
cyclopropylamine 18. When 0.5 equiv. of ButLi was addꢀ
ed to its solution in THFꢀd8 at –90 °C with subseꢀ
quent heating to –20 °C and quenching with water, the
NMR spectroscopic data indicated a complete converꢀ
sion of the starting compound and formation of
2,4,6ꢀtriethylhexahydroꢀ1,3,5ꢀtriazine 19, whose yield
determined from the spectral data was 49%. This prodꢀ
uct, obviously, results from the trimerization of propanꢀ
Scheme 6
R = H, Li
Reagents and conditions: i. NH2(CH2)3NH2—BuLi, THF, 50—60 °C; ii. H2O.

5ꢀMethylidenehexahydropyrrolo[1,2ꢀa]imidazoles
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 7, July, 2010
1455
Scheme 7
In conclusion, we have suggested an original approach
to the synthesis of 5ꢀmethylidenepyrrolo[1,2ꢀa]imidazoles
and 6ꢀmethylideneoctahydropyrrolo[1,2ꢀa]pyrimidines
based on the reaction of 1ꢀalkynylꢀ1ꢀchlorocyclopropanes
with lithium derivatives of 1,2ꢀ and 1,3ꢀdiaminoalkanes.
A mechanism of these unusual multiꢀstep reactions has
been established with identification of the intermediates.
Experimental
GLCꢀanalysis of the starting substances and products obꢀ
tained was carried out on a HewlettꢀPackard 5890 Series II inꢀ
strument with a HPꢀ1 (30 m×0.153 mm) capillary column and
a HewlettꢀPackard 3396A automatic integrator. 1H and 13C NMR
spectra were recorded on a Bruker ACꢀ200p spectrometer for
CDCl3 solutions, using SiMe4 as an internal standard. Mass specꢀ
tra were recorded on a Finningan MAT INCOSꢀ50 and Finninꢀ
gan DSQ II GLCꢀMS spectrometers.
Reagents and conditions: i. ButLi, THFꢀd8, –90 °C; ii. THF,
–20 °C; iii. H2O.
Scheme 8
The starting 1ꢀalkynylꢀ1ꢀchlorocyclopropanes 1a—c were
synthesized according to the procedure suggested by us earlier,17
acetylenic aldehydes 21a,b were obtained from the correspondꢀ
ing chlorides 20a,b and freshly distilled isobutyraldehyde.16
Reaction of 1ꢀ(alkꢀ1ꢀynyl)ꢀ1ꢀchlorocyclopropanes 1a—c with
diaminoalkane lithium derivatives (general procedure). A solution
of BuLi in hexane (1.6 M, 5 mL, 8 mmol) was added to a solution
of the corresponding α,ωꢀdiaminoalkane (10 mmol) in anhydrous
THF (15 mL) at 0 °C. The starting alkynylchlorocyclopropane
1a—c (2 mmol) was added to the mixture obtained and this was
stirred for 2 h at room temperature. Then the reaction mixture
was treated with water, extracted with diethyl ether, the organic
layer was 3 times washed with water and dried with anhydrous
Na2SO4. The solvent was evaporated, and the residue obtained
was subjected to chromatography or recrystallization to isolate
products 3a—c, 4a—b, or a mixture of compounds 5 and 6.
5ꢀBenzylideneꢀ7,7ꢀdimethylhexahydroꢀ1Hꢀpyrrolo[1,2ꢀa]ꢀ
imidazole (3a) was obtained from chlorocyclopropane 1a and
1,2ꢀdiaminoethane in 65% yield as a mixture of Eꢀ and Zꢀisoꢀ
mers (the ratio was 4 : 1) and isolated by chromatography
on neutral Al2O3 (hexane—diethyl ether, 10 : 1). Found (%):
C, 78.56; H, 8.96; N, 12.13. C15H20N2. Calculated (%): C, 78.90;
H, 8.83; N, 12.27.
R = But (5a, 20a, 21a), Ph (5b, 20b, 21b)
Reagents and conditions: i. Me2CHCHO, KOH/H2O/PhMe,
Bu4NI, 50 °C; ii. H2N(CH2)3NH2, CH2Cl2, Na2SO4.
Scheme 9
EꢀIsomer. 1H NMR, δ: 0.92 (s, 3 H, Me); 1.20 (s, 3 H, Me);
1.35 (br.s, 1 H, NH); 2.76 (dd, 1 H, CHHC=, J = 15 Hz,
J = 1.3 Hz); 2.81 (dd, 1 H, CHHC=, J = 15 Hz, J = 1.9 Hz);
3.10—3.22 (m, 4 H, NCH2CH2N); 4.29 (s, 1 H, CH); 5.36
(dd, 1 H, PhCH=, J = 1.9 Hz, J = 1.3 Hz); 7.02 (br.t, 1 H, pꢀH,
J = 7 Hz); 7.14 (br.d, 2 H, oꢀH, J = 7 Hz); 7.25 (br.t, 2 H, mꢀH,
J = 7 Hz). 13C NMR, δ: 21.5 (Me); 26.4 (Me); 39.5 (CMe2);
46.3, 47.9, 48.7 (3 CH2); 87.8 (NCHN); 96.7 (PhCH=); 122.9,
126.4, 128.0 (Ph); 139.5 (C(1), Ph); 149.8 (PhCH=C). MS, m/z:
229 [M+], 228 [M – H]+.
ZꢀIsomer. 1H NMR, δ: 0.99 (s, 3 H, Me); 1.17 (s, 3 H, Me);
1.35 (br.s, 1 H, NH); 2.46 (dd, 1 H, CHHC=, J = 15.1 Hz,
J = 1.5 Hz); 2.52 (dd, 1 H, CHHC=, J = 15.1 Hz, J = 1.4 Hz);
3.1—3.3 (m, 4 H, NCH2CH2N); 4.29 (s, 1 H, CH); 5.25 (dd, 1 H,
PhCH=, J = 1.5 Hz, J = 1.4 Hz); 7.00—7.35 (m, 5 H, Ph).
13C NMR, δ: 21.3 (Me); 26.2 (Me); 38.4 (CMe2); 46.6, 47.6,
52.2 (3 CH2); 90.3 (NCHN); 96.7 (PhCH=); 123.2, 127.3, 127.6
(Ph); 138.5 (C(1), Ph); 149.7 (PhCH=C). MS, m/z: 229 [M+],
228 [M – H]+.
Reagents and conditions: i. 1) NH2(CH2)3NH2—BuLi, THF,
20 °C; 2) H2O.
zation of the triple bond in the first compound than in
the second, that sharply decreases its reactivity toward
nucleophiles.

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Shavrin et al.
5´ꢀBenzylidenehexahydrospiro[cyclohexaneꢀ1,7´ꢀpyrroloꢀ
[1,2ꢀa]imidazole] (3b) was obtained from chlorocyclopropane
1b and 1,2ꢀdiaminoethane in 72% yield as a mixture of Eꢀ and
Zꢀisomers (the ratio was 4.2 : 1) and isolated by chromatography
on neutral Al2O3 (hexane—diethyl ether, 10 : 1). Found (%):
C, 80.67; H, 8.79; N, 9.97. C18H24N2. Calculated (%): C, 80.55;
H, 9.01; N, 10.44.
EꢀIsomer. 1H NMR, δ: 1.20—1.85 (m, 11 H, 5 CH2 + NH);
2.72 (dd, 1 H, CHHC=, J = 15.6 Hz, J = 1.7 Hz); 2.81 (dd, 1 H,
CHHC=, J = 15.6 Hz, J = 1.1 Hz); 3.05—3.30 (m, 4 H,
NCH2CH2N); 4.17 (s, 1 H, CH); 5.39 (dd, 1 H, PhCH=,
J = 1.7 Hz, J = 1.1 Hz); 7.01 (br.t, 1 H, pꢀH, J = 7 Hz);
7.20—7.45 (m, 4 H, oꢀ, mꢀH). 13C NMR, δ: 22.9, 23.3, 25.2,
30.3, 36.5 (5 CH2); 41.8, 47.3, 49.7 (CH2C=, NCH2CH2N);
42.3 (Cquat); 88.1 (NCHN); 97.9 (PhCH=); 123.1, 126.5, 128.1
(Ph); 139.6 (C(1), Ph); 150.9 (PhCH=C). MS, m/z: 268 [M+],
267 [M – H]+.
ZꢀIsomer. 1H NMR, δ: 1.20—1.85 (m, 11 H, 5 CH2 + NH);
2.48 (dd, 1 H, CHHC=, J = 15.8 Hz, J = 1.3 Hz); 2.73 (dd, 1 H,
CHHC=, J = 15.8 Hz, J = 1.3 Hz); 2.90—3.15 (m, 4 H,
NCH2CH2N); 4.23 (s, 1 H, CH); 5.26 (dd, 1 H, PhCH=,
J = 1.3 Hz, J = 1.3 Hz); 7.0—7.48 (m, 5 H, Ph). 13C NMR, δ:
22.7, 25.2, 26.0, 29.9, 35.6 (5 CH2); 37.6 (Cquat); 43.4, 46.6, 52.6
(CH2C=, NCH2CH2N); 90.2 (NCHN); 97.4 (PhCH=); 123.3,
127.3, 127.7 (Ph); 138.7 (C(1), Ph); 150.5 (PhCH=C). MS, m/z:
268 [M+], 267 [M – H]+.
(E)ꢀ5ꢀ(2,2ꢀDimethylpropylidene)ꢀ7,7ꢀdimethylhexahydroꢀ
1Hꢀpyrrolo[1,2ꢀa]imidazole (3c) was obtained from chlorocyꢀ
clopropane 1c and 1,2ꢀdiaminoethane in 35% yield and isolated
by chromatography on neutral Al2O3 (hexane—diethyl ether,
20 : 1). Found (%): C, 75.05; H, 11.41; N, 13.23. C13H24N2.
Calculated (%): C, 74.94; H, 11.61; N, 13.45. 1H NMR, δ: 0.91
(s, 9 H, But); 1.05 (s, 3 H, Me); 1.11 (s, 3 H, Me); 1.82 (s, 2 H,
CH2C=); 2.75—3.10 (m, 4 H, NCH2CH2N); 3.89 (s, 1 H, CH);
4.31 (ButCH=). 13C NMR, δ: 19.7 (Me); 29.6 (Me); 29.9 (3 Me);
32.2 (CMe3); 41.5, 45.9, 48.1 (3 CH2); 42.1 (CMe2); 90.2
(NCHN); 112.9 (ButCH=); 127.1 (ButCH=C). MS, m/z: 208 [M+].
(E)ꢀ6ꢀBenzylideneꢀ8,8ꢀdimethyloctahydropyrrolo[1,2ꢀa]ꢀ
pyrimidine (4a) was obtained from chlorocyclopropane 1a and
1,3ꢀdiaminopropane in 50% yield and isolated from the reaction
mixture by recrystallization from hexane. Found (%): C, 79.37;
H, 9.02; N, 11.39. C16H22N2. Calculated (%): C, 79.29; H, 9.15;
N, 11.56. 1H NMR, δ: 1.02 (s, 3 H, Me); 1.19 (s, 3 H, Me); 1.40
(br.s, 1 H, NH); 1.60—1.72 (m, 2 H, NCH2CH2CH2NH); 2.55
(dd, 1 H, CHHC=, J = 16.3 Hz, J = 2.0 Hz); 2.65—2.90 (m, 2 H,
CHHN, CHHNH); 2.73 (dd, 1 H, CHHC=, J = 16.3 Hz,
J = 1.6 Hz); 3.21—3.35 (m, 1 H, CHHNH); 3.50 (s, 1 H, CH);
3.65—3.78 (m, 1 H, CHHN); 5.21 (dd, 1 H, PhCH=, J = 2.0 Hz,
J = 1.6 Hz); 6.99 (br.t, 1 H, pꢀH, J = 7 Hz); 7.19 (br.d, 2 H, oꢀH,
J = 7 Hz); 7.25 (br.t, 2 H, mꢀH, J = 7 Hz). 13C NMR, δ: 21.8
(Me); 25.2 (CH2CH2CH2); 25.8 (Me); 36.7 (CMe2); 43.9, 44.0,
45.0 (3 CH2); 82.4 (NCHN); 93.7 (PhCH=); 122.8, 126.1, 128.1
(Ph); 139.7 (C(1), Ph); 146.6 (PhCH=C). MS, m/z: 242 [M+],
241 [M – H]+.
J = 1.4 Hz); 2.60—2.84 (m, 2 H, CHHN, CHHNH); 2.92
(dd, 1 H, CHHC=, J = 16.3 Hz, J = 1.3 Hz); 3.20—3.35 (m, 1 H,
CHHNH); 3.46 (s, 1 H, NCHN); 3.60—3.74 (m, 1 H, CHHN);
5.19 (br.s, 1 H, PhCH=); 7.00 (br.t, 1 H, pꢀH, J = 7 Hz);
7.15—7.35 (m, 4 H, oꢀ, mꢀH). 13C NMR, δ: 22.5, 23.5,
25.4, 26.3, 29.4, 35.9 (6 CH2); 39.2, 44.3, 45.4 (CH2C=,
NCH2CH2CH2N); 40.7 (Cquat); 83.3 (NCHN); 94.0 (PhCH=);
123.0, 126.3, 128.4 (Ph); 139.9 (C(1), Ph); 147.1 (PhCH=C).
MS, m/z: 282 [M+], 281 [M – H]+.
Compounds 5a and 6.The reaction of chlorocyclopropane 1c
with 1,3ꢀdiaminopropane lithium derivative according to the
general procedure gives a mixture of aminals 5a and 6 in the
ratio 1 : 1.35 in 72% total yield, which was purified from highꢀ
molecularꢀweight products by passing through a short layer of
neutral Al2O3 and characterized without separation.
2ꢀ(2,6,6ꢀTrimethylheptꢀ4ꢀynꢀ2ꢀyl)hexahydropyrimidine (5a).
1H NMR, δ: 0.91 (s, 6 H, 2 Me); 1.15 (s, 9 H, 3 Me); 1.30—1.52
(m, 4 H, NCH2CH2CH2N, 2 NH); 2.06 (s, 2 H, CH2C≡C);
2.62—2.71 and 3.08—3.21 (both m, 4 H, NCH2CH2CH2N);
3.24 (s, 1 H, NCHN). 13C NMR, δ: 23.3 (CMe2); 27.4 (CMe3);
27.8, 29.2 (C≡CCH2, NCH2CH2CH2N); 31.3 (CMe3);
37.2 (CMe2); 46.6 (NCH2CH2CH2N); 75.9, 91.1 (C≡C); 78.2
(NCHN). MS, m/z: 222 [M]+, 221 [M – H]+.
2ꢀ(2,6,6ꢀTrimethylheptꢀ3ꢀynꢀ2ꢀyl)hexahydropyrimidine (6).
1H NMR, δ: 0.95 (s, 9 H, 3 Me); 1.22 (s, 6 H, 2 Me); 1.28—1.50
(m, 4 H, NCH2CH2CH2N, 2 NH); 2.12 (s, 2 H, CH2C≡C);
2.72—2.85 and 3.20—3.30 (both m, 4 H, NCH2CH2CH2N);
3.15 (s, 1 H, NCHN). 13C NMR, δ: 26.6 (CMe2); 28.1, 33.7
(NCH2CH2CH2N, C≡CCH2); 29.0 (CMe3); 31.1, 36.3 (CMe3,
CMe2); 46.1 (NCH2CH2CH2N); 78.0 (NCHN); 80.8, 86.1
(C≡C). MS, m/z: 223.2169 [M + H]+ (calculated: 223.2174).
Compounds 7 and 8.The reaction of chlorocyclopropane 1a
with Nꢀmethylꢀ1,3ꢀdiaminopropane lithium derivative accordꢀ
ing to the general procedure after passing through a short layer
of neutral Al2O3 in a mixture hexane and dichloromethane (2 : 1)
gave a mixture of products 7 and 8 in the ratio 1.5 : 1 in 68% total
yield, from which compound 7 was isolated in the individual
state by recrystallization from hexane in 37% yield.
(E)ꢀ6ꢀBenzylideneꢀ1,8,8ꢀtrimethyloctahydropyrrolo[1,2ꢀa]ꢀ
pyrimidine (7). Found (%): C, 79.62; H, 10.12; N, 10.05.
C18H28N2. Calculated (%): C, 79.36; H, 10.36; N, 10.28.
1H NMR, δ: 1.11 (s, 3 H, Me); 1.27 (s, 3 H, Me); 1.6—2.15 (m, 3 H,
NCH2CH2CH2NMe, NCH2CH2CHHNMe); 2.29 (s, 3 H,
NMe); 2.53 (dd, 1 H, CHHC=, J = 16.3 Hz, J = 2.1 Hz);
2.50—2.62 (m, 1 H, NCH2CH2CH2NMe); 2.72 (dd, 1 H,
CHHC=, J = 16.3 Hz, J = 1.6 Hz); 2.75 (s, 1 H, CH);
2.87—2.99 (m, 1 H, NCH2CH2CHHNMe); 3.52—3.64 (m, 1 H,
NCHHCH2CH2NMe); 5.19 (dd, 1 H, PhCH=, J = 2.1 Hz,
J = 1.6 Hz); 6.98 (br.t, 1 H, pꢀH, J = 7 Hz); 7.19 (br.d, 2 H, oꢀH,
J = 7 Hz); 7.24 (br.t, 2 H, mꢀH, J = 7 Hz). 13C NMR, δ: 22.4
(Me); 24.0 (CH2CH2CH2); 27.9 (Me); 38.2 (CMe2); 42.2
(NMe); 42.8, 45.9, 56.2 (3 CH2); 89.8, 93.0 (NCHN, PhCH=);
122.7, 126.2, 128.1 (Ph); 139.9 (C(1), Ph); 146.5 (PhCH=C).
MS, m/z: 256 [M+], 255 [M – H]+.
(E)ꢀ6´ꢀBenzylidenehexahydroꢀ1´Hꢀspiro[cyclohexaneꢀ1,8´ꢀ
pyrrolo[1,2ꢀa]pyrimidine] (4b) was obtained from chlorocycloꢀ
propane 1a and 1,3ꢀdiaminopropane in 27% yield and isolated
from the reaction mixture by recrystallization from hexane.
Found (%): C, 80.56; H, 9.09; N, 10.06. C19H26N2. Calculatꢀ
ed (%): C, 80.80; H, 9.28; N, 9.92. 1H NMR, δ: 1.18—1.85
(m, 13 H, 6 CH2 + NH); 2.47 (dd, 1 H, CHHC=, J = 16.3 Hz,
transꢀ1ꢀ[Nꢀ(3ꢀAminopropyl)ꢀNꢀmethylamino]ꢀ2,2ꢀdimethylꢀ
3ꢀphenylethynylcyclopropane (8). 1H NMR, δ: 1.09 (d, 1 H,
CCH, cycloꢀC3H2, J = 3.8 Hz); 1.21 (s, 3 H, Me); 1.22
(s, 3 H, Me); 1.35 (br.s, 2 H, NH2); 1.60—1.72 (m, 1 H,
NCH2CH2CH2NH2); 1.67 (d, 1 H, NCH, cycloꢀC3H2, J = 3.8 Hz);
1.75—2.15 (m, 4 H, NCH2CH2CH2N); 2.25 (s, 3 H, NMe);
7.1—7.4 (m, 5 H, Ph). 13C NMR, δ: 19.3, 21.5, 22.0 (2 Me,

5ꢀMethylidenehexahydropyrrolo[1,2ꢀa]imidazoles
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 7, July, 2010
1457
C≡CCH); 26.8 (CMe2); 31.1 (NCH2CH2CH2N); 40.6
(NCH2CH2CH2NH2); 41.8 (NMe); 55.6 (MeNCH2); 59.9
(CHN); 78.8, 90.1 (C≡C); 124.2 (C(1), Ph); 127.2, 128.1,
131.4 (Ph).
Reaction of cyclopropylamine with tertꢀbutyllithium. Tetraꢀ
hydrofuranꢀd8 (0.4 mL) and cyclopropylamine (45 mg, 0.78 mmol)
were placed into an NMR tube thoroughly purged with dry
1
argon, a H NMR spectrum was recorded, then, the solution
Reaction of chlorocyclopropanes 12a,b with lithium propylꢀ
amide (general procedure). A solution of BuLi in hexane (1.6 M,
5 mL, 8 mmol) was added to a solution of 1ꢀaminopropane
(590 mg, 10 mmol) in anhydrous THF (10 mL) at 0 °C, followed
by addition of the starting chlorocyclopropane 12 (2 mmol) to
the mixture obtained, the reaction mixture was heated to 60 °C
and stirred at this temperature for 5 h. Then the reaction mixture
was treated with water, 2 times extracted with diethyl ether, the
organic layer was washed with water and dried with anhydrous
Na2SO4. Then, the solvent was evaporated, and the residue obꢀ
tained was subjected to microdistillation in vacuo (a bath temꢀ
perature was 120—140 °C, 1 Torr) to isolate products 15a,b.
Nꢀ(2,2ꢀDimethylꢀ3ꢀphenylpropylidene)ꢀNꢀpropylamine (15a)
was obtained from chlorocyclopropane 12a in 55% yield. Found
(%): C, 82.52; H, 10.33; N, 7.05. C14H21N. Calculated (%): C,
was cooled to –90 °C, followed by injection of a solution of
tertꢀbutyllithium in pentane (1.5 M, 0.26 mL, 0.39 mmol). The
temperature of the tube was slowly raised to –20 °C, 1 drop of
1
water was added, and H and 13C NMR spectra were recorded,
which showed a complete absence of the starting cyclopropyꢀ
lamine and the formation of 2,4,6ꢀtriethylꢀ1,3,5ꢀtriazine 19 as
a major product, which was identified based on the comparison
of chemical shifts in the 13C NMR spectrum with the literature
data.18 The yield of compound 19 was 49%, which was deterꢀ
mined from the spectrum by comparison of the integral intensiꢀ
ties of the methine proton signal (δ = 3.42) and the residual
protons of the solvent (δ = 3.68) used as an internal standard.
Condensation of acetylenic aldehydes 21a,b with 1,3ꢀdiamiꢀ
nopropane. Synthesis of hexahydropyrimidines 5a,b (general proꢀ
cedure). Anhydrous Na2SO4 (5 g) was added to a solution of
1,3ꢀdiaminopropane (1480 mg, 20 mmol) in dichloromethane
(20 mL), then, a solution of the corresponding aldehyde 21
(10 mmol) in dichloromethane (5 mL) was poured in over 5 min.
The mixture obtained was kept at room temperature for 1 day,
then 3 times washed with water, dried with anhydrous Na2SO4.
The solvent was evaporated in vacuo, a residual viscous oily subꢀ
stance obtained, according to the NMR spectroscopic data, was
hexahydropyrimidine derivatives 5a,b in >90% purity.
2ꢀ(2,6,6ꢀTrimethylheptꢀ4ꢀynꢀ2ꢀyl)hexahydropyrimidine (5a)
was obtained in 85% yield from aldehyde 21a. Its spectra were
completely identical to the spectra of the minor product of the
reaction of cyclopropane 1c with lithium derivatives of 1,3ꢀdiꢀ
aminopropane.
2ꢀ(2ꢀMethylꢀ5ꢀphenylpentꢀ4ꢀynꢀ2ꢀyl)hexahydropyrimidine
(5b) was obtained in 78% yield from aldehyde 21b. 1H NMR, δ:
1.08 (s, 6 H, 2 Me); 1.25—1.60 (m, 4 H, NCH2CH2CH2N,
2 NH); 2.46 (s, 2 H, CH2C≡C); 2.71—2.90 and 3.15—3.29
(both m, 4 H, NCH2CH2CH2N); 3.38 (s, 1 H, NCHN). 13C NMR,
δ: 22.8 (CMe2); 27.5, 29.6 (C≡CCH2, NCH2CH2CH2N); 37.3
(CMe2); 46.3 (NCH2CH2CH2N); 77.9 (NCHN); 82.3, 87.7
(C≡C); 123.7 (C(1), Ph); 127.2, 127.9, 131.2 (Ph).
Cyclization of compound 5b upon the action of lithium derivaꢀ
tive of 1,3ꢀdiaminopropane. A solution of BuLi in hexane (1.6 M,
0.6 mL, 1 mmol) was added to a solution of 1,3ꢀdiaminopropane
(74 mg, 1 mmol) in anhydrous THF (5 mL) at 0 °C, followed by
addition of compound 5b (242 mg, 1 mmol), and the mixture
obtained was stirred at room temperature for 30 min. Then, the
reaction mixture was treated with water, extracted with diethyl
ether, the organic layer was 3 times washed with water and dried
with anhydrous Na2SO4. The solvent was evaporated in vacuo.
A residue obtained was recrystallized from hexane to obtain comꢀ
pound 4a (175 mg, 72%), whose spectra were identical to
the product obtained by the reaction of lithium derivative of
1,3ꢀdiaminopropane with chlorocyclopropane 1a.
1
82.70; H, 10.41; N, 6.89. H NMR, δ: 0.84 (t, 3 H, MeCH2,
J = 7.4 Hz); 1.03 (s, 6 H, 2 Me); 1.50—1.71 (m, 2 H, MeCH2);
2.70 (s, 2 H, PhCH2); 3.32 (br.t, 2 H, NCH2, J = 6.9 Hz);
7.05—7.30 (m, 5 H, Ph); 7.54 (br.s, 1 H, CH=NPr). 13C NMR,
δ: 11.6 (MeCH2); 23.9 (MeCH2); 24.7 (2 Me); 39.9 (CMe2);
46.4 (CH2Ph); 63.2 (NCH2); 126.0, 127.4, 130.5 (Ph); 138.1
(C(1), Ph); 171.2 (CH=NPr).
Nꢀ[2,2ꢀDimethylꢀ3ꢀ(4ꢀmethoxyphenyl)propylidene]ꢀNꢀproꢀ
pylamine (15b) was obtained from chlorocyclopropane 12b in
51% yield. Found (%): C, 77.35; H, 9.72; N, 5.88. C15H23NO.
1
Calculated (%): C, 77.21; H, 9.93; N, 6.00. H NMR, δ: 0.85
(t, 3 H, MeCH2, J = 7.4 Hz); 1.02 (s, 6 H, 2 Me); 1.51—1.72
(m, 2 H, MeCH2); 2.65 (s, 2 H, PhCH2); 3.32 (br.t, 2 H, NCH2,
J = 6.9 Hz); 3.77 (s, 3 H, OMe); 6.75—6.83 (m, 2 H, mꢀH);
6.95—7.05 (m, 2 H, oꢀH); 7.52 (br.s, 1 H, CH=NPr). 13C NMR,
δ: 11.6 (MeCH2); 23.8 (MeCH2); 24.5 (2 Me); 39.9 (CMe2);
46.5 (CH2Ph); 55.0 (OMe); 63.2 (NCH2); 113.1, 131.3 (Ph);
130.3 (C(1), Ph); 157.9 (COMe); 171.3 (CH=NPr).
Reaction of chlorocyclopropane 12b with lithium derivative of
1,3ꢀdiaminopropane. A solution of BuLi in hexane (1.6 M, 5 mL,
8 mmol) was added to a solution of 1,3ꢀdiaminopropane (740 mg,
10 mmol) in anhydrous THF (15 mL) at 0 °C, followed by adꢀ
dition of chlorocyclopropane 12b (420 mg, 2 mmol), the reacꢀ
tion mixture was heated to 60 °C and stirred at this temperature
for 5—6 h until the starting substance completely converted (GLC
monitoring). Then the reaction mixture was workedꢀup with
water, extracted with diethyl ether, the organic layer was 3 times
washed with water and dried with anhydrous Na2SO4. The solꢀ
vent was evaporated in vacuo, the residue obtained was dissolved
in the hexane—diethyl ether (2 : 1) mixture, passed through
a short layer of neutral Al2O3, a viscous substance obtained after
repeated concentration (312 mg, 63%) according to the NMR
spectroscopic data contained ~90% of 2ꢀ[1ꢀ(4ꢀmethoxyphenyl)ꢀ
2ꢀmethylpropꢀ2ꢀyl]hexahydropyrimidine (17). 1H NMR, δ: 0.89
(s, 6 H, 2 Me); 1.35—1.54 (m, 2 H); 2.08 (br.s, 2 H, 2 NH); 2.62
(s, 2 H, CH2CMe2); 2.72—2.86 (m, 2 H, NCH2CH2CH2N);
3.14 (s, 1 H, NCHN); 3.17—3.26 (m, 2 H, NCH2CH2CH2N);
3.81 (s, 3 H, OMe); 6.82—6.89 (m, 2 H, mꢀH); 7.09—7.16 (m, 2 H,
pꢀH). 13C NMR, δ: 23.2 (CMe2); 27.6 (NCH2CH2CH2N);
37.8 (CMe2); 46.4 (CH2); 46.7 (NCH2CH2CH2N); 54.8 (OMe);
80.5 (NCHN); 111.6, 130.8 (Ph); 133.2 (C(1), Ph); 158.3
(COMe).
Under analogous conditions, aminal 5a after aqueous treatꢀ
ment of the reaction mixture and evaporation of the solvent
gives a mixture of the starting compound and its isomer 6 in the
molar ratio 1 : 1 in 76% total yield, which were characterized
without separation.
This work was financially supported by the Council on
Grants at the President of the Russian Federation (Proꢀ

1458
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 7, July, 2010
Shavrin et al.
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Received March 31, 2010