5-Methylenehexahydropyrrolo[1,2-a]imidazoles and 6-methyleneoctahydropyrrolo[1,2-a]pyrimidines in the reactions of 1-(alk-1-ynyl)-1-chlorocyclopropanes with lithium derivatives of 1,2- and 1,3-diaminoalkanes

Article abstract of DOI:10.1016/j.mencom.2008.11.003

Unusual reactions of 1-(alk-1-ynyl)-1-chlorocyclopropanes with lithium derivatives of 1,2-diaminoethane, 1,3-diaminopropane and 1-methylamino-3-aminopropane in THF at 20 °C give previously unknown 5-methylenehexahydropyrrolo[1,2-a]imidazoles and 6-methyleneoctahydropyrrolo[1,2-a]pyrimidines with up to 60% yields.

Full text of DOI:10.1016/j.mencom.2008.11.003

Mendeleev
Communications
Mendeleev Commun., 2008, 18, 300–301
5-Methylenehexahydropyrrolo[1,2-a]imidazoles and
6-methyleneoctahydropyrrolo[1,2-a]pyrimidines in the
reactions of 1-(alk-1-ynyl)-1-chlorocyclopropanes
with lithium derivatives of 1,2- and 1,3-diaminoalkanes
Konstantin N. Shavrin, Valentin D. Gvozdev* and Oleg M. Nefedov
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian Federation.
Fax: +7 499 135 5328; e-mail: vgvozdev2006@yandex.ru
DOI: 10.1016/j.mencom.2008.11.003
Unusual reactions of 1-(alk-1-ynyl)-1-chlorocyclopropanes with lithium derivatives of 1,2-diaminoethane, 1,3-diaminopropane
and 1-methylamino-3-aminopropane in THF at 20 °C give previously unknown 5-methylenehexahydropyrrolo[1,2-a]imidazoles and
6-methyleneoctahydropyrrolo[1,2-a]pyrimidines with up to 60% yields.
Previously, we found that the treatment of 1-(alk-1-ynyl)-
1-chlorocyclopropanes1,2 with lithium N,N-dialkylamides yields
alkynyl(dialkylamino)cyclopropanes,3 whereas in similar reac-
tions with lithium monoalkylamides, depending on the nature
of substituent at the triple bond in starting alkynylchlorocyclo-
propanes 1, conjugated iminocyclopropenes or substituted propa-
1,2-dienes4 were obtained. According to the published data,3,4
these reactions proceed via intermediate formation of conjugated
alkynylcyclopropenes 2, which are characterized by the com-
bination of two highly reactive fragments, a triple bond and an
unsaturated three-membered ring. Therefore, it could be expected
that by the interaction of alkynylchlorocyclopropanes 1 with
lithium derivatives of 1,2- and 1,3-diaminoalkanes the latter due
to the presence of two amino groups would consequently add to
both unsaturated fragments of intermediate alkynylcyclopropenes
2 with formation of nitrogen-containing heterocyclic systems.
We found that the interaction of 1-chloro-2,2-dimethyl-
1-phenylethynylcyclopropane 1a and 1-chloro-2,2-dimethyl-
1-(3,3-dimethylbut-1-ynyl)chlorocyclopropane 1b with a four-fold
excess of lithium (2-aminoethyl)amide in THF at 20 °C after
aqueous workup gives previously unknown 5-methylenehexa-
hydropyrrolo[1,2-a]imidazoles 3a,b† in 60 and 35% yields,
respectively. Compound 3a is formed as a mixture of E- and
Z-isomers in a ratio of 4:1, whereas 3b with its bulky tert-butyl
substituent, is obtained exclusively as the E-isomer (Scheme 1).
Under the same conditions, the reaction of cyclopropane
1a with lithium (3-aminopropyl)amide gives 8,8-dimethyl-
6-(E)-phenylmethylideneoctahydropyrrolo[1,2-a]pyrimidine 4‡
in 50% yield. The lithium derivative of 1-methylamino-3-amino-
propane reacts with alkynylchlorocyclopropane 1a unselectively.
†
Structures of all new compounds have been proved by 1H and 13C NMR
spectroscopy. Spectra were recorded for solutions in CDCl3 on Bruker
AC-200p and Bruker AM-300 spectrometers (200 and 300 MHz for
1H, 50 and 75 MHz for 13C), using tetramethylsilane as an internal
standard. Identification of E- and Z-isomers of compounds 3–5 was
based on 2D-NOESY experiments.
General procedure for reactions of 1-(alk-1-ynyl)-1-chlorocyclopropanes
1a,b with lithium derivatives of diaminoalkanes. A 1.6 M solution of
BuLi in hexane (5 ml, 8 mmol) was added to the solution of corre-
sponding diaminoalkane (10 mmol) in 15 ml of anhydrous THF, at 0 °C.
Alkynylchlorocyclopropane 1a,b (2 mmol) was added to the resulting
mixture followed by stirring at room temperature for 2 h. After that
reaction mixture was quenched with water and extracted with diethyl
ether; the organic layer was washed three times with water and dried
over anhydrous Na2SO4. After removal of the solvent, products 3a,b, 4
or a mixture of compounds 5 and 6 were isolated by passage through a
silica gel layer in hexane–diethyl ether as an eluent.
7,7-Dimethyl-5-phenylmeth-(E)-ylenehexahydropyrrolo[1,2-a]imidazole
1
(E)-3a: H NMR (CDCl3) d: 0.92 (s, 3H, Me), 1.20 (s, 3H, Me), 1.35
(br. s, 1H, NH), 2.76 (dd, 1H, CHHC=, J 15 Hz, J 1.3 Hz), 2.81 (dd, 1H,
CHHC=, J 15 Hz, J 1.9 Hz), 3.1–3.22 (m, 4H, NCH2CH2N), 4.29 (s, 1H,
CH), 5.36 (dd, 1H, PhCH=, J 1.9 Hz, J 1.3 Hz), 7.02 (br. t, 1H, p-H,
J 7 Hz), 7.14 (br. d, 2H, o-H, J 7 Hz), 7.25 (br. t, 2H, m-H, J 7 Hz).
13C NMR (CDCl3) d: 21.5 (Me), 26.4 (Me), 39.5 (CMe2), 46.3, 47.9,
48.7 (3CH2), 87.8 (NCHN), 96.7 (PhCH=), 122.9, 126.4, 128.0 (Ph),
139.5 (C-1, Ph), 149.8 (PhCH=C).
R
i
– HCl
Cl
R
7,7-Dimethyl-5-phenylmeth-(Z)-ylenehexahydropyrrolo[1,2-a]imidazole
a R = Ph
b R = But
1
(Z)-3a: H NMR (CDCl3) d: 0.99 (s, 3H, Me), 1.17 (s, 3H, Me), 1.35
1a,b
2a,b
(br. s, 1H, NH), 2.46 (dd, 1H, CHHC=, J 15.1 Hz, J 1.5 Hz), 2.52 (dd,
1H, CHHC=, J 15.1 Hz, J 1.4 Hz), 3.1–3.3 (m, 4H, NCH2CH2N), 4.29
(s, 1H, CH), 5.25 (dd, 1H, PhCH=, J 1.5 Hz, J 1.4 Hz), 7.0–7.35 (m, 5H,
Ph). 13C NMR (CDCl3) d: 21.3 (Me), 26.2 (Me), 38.4 (CMe2), 46.6,
47.6, 52.2 (3CH2), 90.3 (NCHN), 96.7 (PhCH=), 123.2, 127.3, 127.6
(Ph), 138.5 (C-1, Ph), 149.7 (PhCH=C).
i
R = Ph
NH
R = But
NH
NH
+
N
N
N
7,7-Dimethyl-5-[2,2-dimethylprop-(E)-ylene]hexahydropyrrolo[1,2-a]-
1
imidazole 3b: H NMR (CDCl3) d: 0.91 (s, 9H, But), 1.05 (s, 6H, Me),
Ph
Ph
(Z)-3a
1.11 (s, 6H, Me), 1.82 (s, 2H, CH2C=), 2.75–3.10 (m, 4H, NCH2CH2N),
3.89 (s, 1H, CH), 4.31 (s, 1H, ButCH=). 13C NMR (CDCl3) d: 19.7 (Me),
29.6 (Me), 29.9 (3Me), 32.2 (CMe3), 41.5, 45.9, 48.1 (3CH2), 42.1 (CMe2),
90.2 (NCHN), 112.9 (ButCH=), 127.1 (ButCH=C). Found (%): C, 74.04;
H, 11.52; N, 14.31. Calc. for C12H22N2 (%): C, 74.17; H, 11.41; N, 14.42.
(E)-3a
3b
Scheme 1 Reagents and conditions: i, LiNH(CH2)2NH2, THF, 20 °C,
followed by treatment with H2O.
– 300 –
© 2008 Mendeleev Communications. All rights reserved.

Mendeleev Commun., 2008, 18, 300–301
H
R
N
i, ii
i
i
1a
2a
N
– HCl
Cl
R
ii
Ph
4
1
2
Ph
N
N
+
n
N
N
NH2
NLi(H)
n
N
NH2
R
R1
Ph
Ph
Li(H)
5
6
7
8
Scheme 2 Reagents and conditions: i, [H2N(CH2)3NHMe + BuLi], THF,
20 °C, followed by treatment with H2O; ii, [H2N(CH2)3NHMe + BuLi],
THF, 20 °C, followed by treatment with H2O.
R1
N
R1
N
i, H2O
R
Due to the concurrence of primary and secondary amino groups,
the formation of a mixture of corresponding N-methyl sub-
stituted pyrimidine 5‡ (E-isomer) and aminocyclopropane 6‡ in
a 1.5:1 ratio is observed (Scheme 2).
n
n
(H)LiN
N
9
R
3a,b, 4, 5
R = Ph, But
R1 = H, Me
n = 2, 3
Most likely, the reaction proceeds as depicted in Scheme 3.
At first, starting cyclopropanes 1, as was previously shown,3,4
under the action lithium amides, undergo elimination of HCl
with the formation of conjugated cyclopropenes 2. Further, addi-
tion of an amide ion to the double bond of the cyclopropene
ring takes place giving intermediate 7, which isomerizes with
opening of the three-membered ring into acyclic imine 8. Under
the reaction conditions the latter, due to the presence of an
amino group, undergoes a cascade cyclization with consecutive
participation of the C=N5 and CºC bonds via intermediate
formation of monocyclic structure 9 (Scheme 3).
Scheme 3 Reagents and conditions: i, LiNH(CH2)nNHR1, THF, 20 °C.
The possibility of previously unknown isomerization of
secondary cyclopropylamines into acyclic imines of type 8, which
is a key step of the proposed mechanism, was demonstrated for
the reaction of 1-chloro-2,2-dimethyl-1-phenylcyclopropane 10
with an excess of lithium propylamide. In this case, imine 11,‡
arising obviously via the intermediate formation of aminocyclo-
propane 12, was obtained in 52% yield (Scheme 4).
‡
8,8-Dimethyl-6-phenylmeth-(E)-yleneoctahydropyrrolo[1,2-a]pyrimidine
Ph
Cl
i
1
4: H NMR (CDCl3) d: 1.02 (s, 3H, Me), 1.19 (s, 3H, Me), 1.40 (br. s,
1H, NH), 1.60–1.72 (m, 1H, NCH2CH2CH2NH), 2.55 (dd, 1H, CHHC=,
J 16.3 Hz, J 2.0 Hz), 2.65–2.90 (m, 2H, NCH2CH2CH2NH), 2.73 (dd,
1H, CHHC=, J 16.3 Hz, J 1.6 Hz), 3.21–3.35 [m, 1H, NCH2(CH2)2NH],
3.50 (s, 1H, CH), 3.65–3.78 [m, 1H, NCH2(CH2)2NH], 5.21 (dd, 1H,
PhCH=, J 2.0 Hz, J 1.6 Hz), 6.99 (br. t, 1H, p-H, J 7 Hz). 7.19 (br. d,
2H, o-H, J 7 Hz), 7.25 (br. t, 2H, m-H, J 7 Hz). 13C NMR (CDCl3) d:
21.8 (Me), 25.2 (CH2CH2CH2), 25.8 (Me), 36.7 (CMe2), 43.9, 44.0, 45.0
(3CH2), 82.4 (NCHN), 93.7 (PhCH=), 122.8, 126.1, 128.1 (Ph), 139.7
(C-1, Ph), 146.6 (PhCH=C). Found (%): C, 78.56; H, 8.52; N, 12.94.
Calc. for C14H18N2 (%): C, 78,46; H, 8.47; N, 13.07.
Ph
Ph
NLi(H)Pr
12
10
H2O
Ph
N
Ph
N
Li(H)
Pr
Pr
11
Scheme 4 Reagents and conditions: i, PrNHLi, PrNH2, THF, 60 °C.
1,1,8-Trimethyl-6-phenylmeth-(E)-yleneoctahydropyrrolo[1,2-a]pyri-
midine 5: 1H NMR (CDCl3) d: 1.11 (s, 3H, Me), 1.27 (s, 3H, Me), 1.60–1.72
(m, 2H, NCH2CH2CH2NMe), 2.29 (s, 3H, NMe), 2.53 (dd, 1H, CHHC=,
J 16.3 Hz, J 2.1 Hz), 2.50–2.62 [m, 2H, N(CH2)2CH2NMe], 2.72 (dd,
1H, CH2C=, J 16.3 Hz, J 1.6 Hz), 2.75 (s, 1H, CH), 2.87–2.99 [m, 1H,
NCHH(CH2)2NMe], 3.52–3.64 [m, 1H, NCHH(CH2)2NMe], 5.19 (dd,
1H, PhCH=, J 2.1 Hz, J 1.6 Hz), 6.98 (br. t, 1H, p-H, J 7 Hz), 7.19 (br. d,
2H, o-H, J 7 Hz), 7.24 (br. t, 2H, m-H, J 7 Hz). 13C NMR (CDCl3) d:
22.4 (Me), 24.0 (CH2CH2CH2), 27.9 (Me), 38.2 (CMe2), 42.2 (NMe),
42.8, 45.9, 56.2 (3CH2), 89.8, 93.0 (NCHN, PhCH=), 122.7, 126.2,
128.1 (Ph), 139.9 (C-1, Ph), 146.5 (PhCH=C).
(E)-1-[3-Aminopropyl(methyl)amino]-2,2-dimethyl-3-phenylethynyl-
cyclopropane 6: 1H NMR (CDCl3) d: 1.09 (d, 1H, CºCCH, cyclo-C3H2,
J 3.8 Hz), 1.21 (s, 3H, Me), 1.22 (s, 3H, Me), 1.35 (br. s, 2H, NH2),
1.6–1.72 (m, 1H, NCH2CH2CH2NH2), 1.67 (d, 1H, NCH, cyclo-C3H2,
J 3.8 Hz), 1.75–2.15 (m, 4H, NCH2CH2CH2N), 2.25 (s, 3H, NMe),
7.1–7.4 (m, 5H, Ph). 13C NMR (CDCl3) d: 19.3, 21.5, 22.0 (2Me,
CºCCH), 26.8 (CMe2), 31.1 (NCH2CH2CH2N), 40.6 [N(CH2)2CH2NH2],
41.8 (NMe), 55.6 (MeNCH2), 59.9 (CHN), 78.8, 90.1 (CºC), 124.2 (C-1,
Ph), 127.2, 128.1, 131.4 (Ph).
Thus, an original approach to previously unknown 5-methylene-
pyrrolo[1,2-a]imidazoles and 6-methyleneoctahydropyrrolo-
[1,2-a]pyrimidines, based on the reaction of 1-(alk-1-ynyl)-
1-chlorocyclopropanes with lithium derivatives of 1,2- and
1,3-diaminoalkanes, has been developed.
This work was supported by the President of the Russian
Federation (programme for the support of leading scientific
schools, grant no. NSh-3237.2008.3), Russian Foundation for
Basic Research (project no. 06-03-33045-a) and the Russian
Academy of Sciences (programme no. OKh-01).
References
1 K. N. Shavrin, I. V. Krylova, I. B. Shvedova, G. P. Okonnishnikova, I. E.
Dolgy and O. M. Nefedov, J. Chem. Soc., Perkin Trans. 2, 1992, 1875.
2 K. N. Shavrin, V. D. Gvozdev and O. M. Nefedov, Izv. Akad. Nauk, Ser.
Khim., 2002, 1143 (Russ. Chem. Bull., Int Ed., 2002, 51, 1237).
3 K. N. Shavrin, V. D. Gvozdev, D. V. Budanov, S. V. Yurov and O. M.
Nefedov, Mendeleev Commun., 2006, 73.
4 K. N. Shavrin, V. D. Gvozdev, S. V. Yurov and O. M. Nefedov, Mendeleev
Commun., 2008, 18, 16.
5 R. B. Moodre, M. Z. Moustras, G. S. Read and P. B. John, J. Chem. Res.
Miniprint, 1996, 3, 855.
2,2-Dimethyl-3-phenylpropenylidenepropylamine 11: 1H NMR (CDCl3)
d: 0.84 (t, 3H, MeCH2, J 7.4 Hz), 1.03 (s, 6H, 2Me), 1.50–1.71 (m, 2H,
MeCH2), 2.70 (s, 2H, PhCH2), 3.32 (br. t, 2H, NCH2, J 6.9 Hz), 7.05–7.30
(m, 5H, Ph), 7.54 (br. s, 1H, CH=NPr). 13C NMR (CDCl3) d: 11.6 (MeCH2),
23.9 (MeCH2), 24.7 (2Me), 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). Found (%): C, 82.52;
H, 10.33; N, 7.05. Calc. for C14H21N (%): C, 82.70; H, 10.41; N, 6.89.
Received: 14th May 2008; Com. 08/3140
– 301 –