Synthesis of 6-(arylmethylidene)octahydropyrrolo[1,2-a]pyrimidines and 5-(arylmethylidene)hexahydropyrrolo[1,2-a]imidazoles by the interaction of alk-4-ynals with a,?-diaminoalkanes in DMSO in the presence of KOH

Article abstract of DOI:10.1016/j.mencom.2013.05.006

Cyclization of alk-4-ynals with a,?-diaminoalkanes in DMSO under the action of KOH affords bicyclic N,N-enaminals - 6-(aryl- methylidene)octahydro[1,2-a] pyrimidines and 5-(arylmethylidene)hexahydro[1,2-a]imidazoles.

Full text of DOI:10.1016/j.mencom.2013.05.006

Mendeleev
Communications
Mendeleev Commun., 2013, 23, 140–141
Synthesis of 6-(arylmethylidene)octahydropyrrolo[1,2-a]pyrimidines and
5-(arylmethylidene)hexahydropyrrolo[1,2-a]imidazoles by the interaction
of alk-4-ynals with a,w-diaminoalkanes in DMSO in the presence of KOH
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.2013.05.006
Cyclization of alk-4-ynals with a,w-diaminoalkanes in DMSO under the action of KOH affords bicyclic N,N-enaminals – 6-(aryl-
methylidene)octahydro[1,2-a]pyrimidines and 5-(arylmethylidene)hexahydro[1,2-a]imidazoles.
R1
O
The cyclization of available alk-4-ynals, alk-5-ynals and cor-
responding alkynones with amines leading to various nitrogen-
containing heterocyclic compounds has been intensively studied in
recent years. Thus, new approaches to the preparation of fused
isoquinolines,1–3 1,2-dihydroisoquinolines,4–9 various pyrroles,10
chiral 2-alkoxy-5-methoxycarbonylmethylidenepyrrolidines11
and the corresponding piperidines11 have been described. Nitro-
gen-containing heterocycles with an endocyclic double bond
were obtained in the majority of these reactions. Products with
an exocyclic double bond were formed on the interaction of
amines with alk-4-ynals and alk-5-ynals that contained activated
triple bonds.11 Note that such cyclizations in the presence of
strong bases were not reported.
Previously, we have reported preparation of 5-methylidene-
hexahydropyrrolo[1,2-a]imidazoles and 6-methylideneocta-
hydropyrrolo[1,2-a]pyrimidines by the interaction of 1-alkynyl-
1-chlorocyclopropanes with the lithium derivatives of 1,2-di-
aminoethane and 1,3-diaminopropane.12,13 Compounds from
these series exhibit various biological activities,14 and they are
of considerable synthetic interest15 due to the presence of highly
reactive enamine and aminal fragments with a common nitrogen
atom. We found13 that formation of these compounds occurs
through the participation of the intermediate alk-4-ynylidene-
amines, whicharethecondensationproductsofthecorresponding
alk-4-ynalswithdiaminoalkanes.Inthiscontext,wehypothesized
that the addition of acetylenic aldehydes and an appropriate
strong base to these latter would perform a simple one-pot syn-
thesis of bicyclic N,N-enaminals with an exocyclic double bond.
This supposition was completely confirmed. We found that
N,N-enaminals 5a–h† were formed in 42–78% yields upon the
sequential addition of aldehydes 1a–e and powdered KOH to
the solutions of diaminoalkanes 2a–c in DMSO (molar ratio
amine:aldehyde:KOH of 5:1:5) (Scheme 1). The best yields
were achieved in the cases of 2,2-substituted non-enolizable
aldehydes 1a,c,e.
R2
R2
R3
1a–e
R1
KOH/DMSO
20 °C
N
NH
n
+
R3
NH2
R2
R2
3a–h
N
n
H
2a–c
1a R1 = Ph, R2 = Me
1b R1 = Ph, R2 = H
1c R1 = 4-FC6H4, R2 = Me
1d R1 = 4-F3CC6H4, R2 = H
1e R1 = 2-thienyl, R2 = Me
H
R1
N
R2
n
R2
4a–h
N
2a R3 = H, n = 1
2b R3 = H, n = 2
2c R3 = Me, n = 2
R3
n = 1
KOH/
DMSO
KOH/
DMSO
n = 2
Ph
R1
Ph
4
6
3
2
N
N
N
7
+
8
NH
NH
N
Me
Me
R2
R2
Me
Me
Z-5a
R2
R3
5b–h
E-5a
3, 4, 5 R1
R3
n
Yield of 5 (%)
a
b
c
d
e
f
g
h
Ph
Ph
Ph
Ph
Me
Me
Me
H
H
Me
H
H
H
1
2
2
2
2
2
2
2
75
77
78
42
51
60
45
58
Me
H
Me
Me
Me
Me
Ph
4-FC6H4
4-F3CC6H4
2-thienyl
Me
†
GLC analysis was performed on a Hewlett-Packard 5890 Series II
Scheme 1
instrument with an HP-1 capillary column (30 m × 0.153 mm) and a
Hewlett-Packard 3396A automated integrator. The 1H and 13C NMR spectra
were recorded on a Bruker AC-200p spectrometer using the solutions of
test compounds in CDCl3 and TMS as an internal standard. The mass
spectra were measured on a Finningan DSQ II GC-MS instrument.
Starting aldehydes 1a,c,e were prepared by the interaction of isobutyr-
aldehyde with the corresponding 3-aryl-1-chloroprop-2-ynes under phase-
transfer catalysis conditions.16 Pd(PPh3)2Cl2-catalyzed cross-coupling of
aryl iodides with pent-4-yn-1-ol followed by pyridinium chlorochromate
oxidation was used to prepare a-unsubstituted aldehydes 1b,d.
It is interesting to note high stereoselectivity of this reaction
in the case of 1,3-diaminopropane 2b and N-methyl-1,3-diamino-
propane 2c, which leads to corresponding octahydropyrrolo-
[1,2-a]pyrimidines 5b–h as individual E-isomers. Their identi-
fication was performed based on the 2D NOESY proton spectra
having correlations between the methine protons at the double
bond and the protons of the methylidene fragment at 7-position.
On the contrary, in the case of 1,2-diaminoethane 2a the reaction
© 2013 Mendeleev Communications. All rights reserved.
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Mendeleev Commun., 2013, 23, 140–141
R1
proceeds less selectively, and corresponding product 5a is formed
as a mixture of E- and Z-isomers in a ratio of 5:1.
3a–h
4a–h
N
KOH/DMSO
R2
n
R2
R1
N
The structure of the diamine used had a considerable effect
on the rate of this reaction. Thus, in the case of 1,2-diaminoethane
and 1,3-diaminopropane, the reaction with all aldehydes 1 was
complete in 2 h, whereas analogous processes with N-methyl-
1,3-diaminopropane occurred more slowly and required 10–15 h.
Studying of these reactions in DMSO-d6 with periodical
checking of the reaction mixture by NMR spectroscopy showed
that an equilibrium mixture of linear imine 3a and cyclic aminal
4a in a ratio that strongly depends on temperature (1:5.5 at 23°C
and 1:2.3 at 50°C) was quantitatively formed on the addition
of aldehyde 1a to a fivefold molar amount of 1,2-diaminoethane
at room temperature in a short time (10–20 min).
R3
H(D)
R1
H(D)+
N
N
N
n
n
N
R2
R2
R2
R2
R3
R3
5a–h
Scheme 2
Upon the interaction of aldehyde 1a with N-methyl-1,3-di-
aminopropane 2c only linear product 3c was detected in the
reaction mixture, whereas the exclusive formation of cyclic aminal
4e was observed in an analogous reaction with a-unsubstituted
aldehyde 1b. It is most likely that this difference was due to the
steric effect of two methyl groups, which prevents the cyclization
of imine 3c into corresponding aminal 4c and strongly shifts
the equilibrium toward imine 3c. In all cases, the reaction mix-
tures were analyzed by comparing their NMR spectra with the
spectra of corresponding adducts 3 and 4, which were inde-
pendently prepared by the reactions of aldehydes 1a,b with
diamines 2a,c in CH2Cl2 in the presence of Na2SO4.
Stirring the products of the reaction of aldehydes 1a,d and
diamines 2a,c with freshly powdered KOH resulted in the disap-
pearance of signals of compounds 3 and 4 and the appearance
of the signals of corresponding aminals 5. In this case, in all
experiments performed in DMSO-d6, the integral intensity of the
signal, corresponding to the methine proton at a double bond in
the NMR spectra of products 5 was much lower than the calculated
value, which suggests a considerable degree of deuteration at
this position. Since we showed in special experiment that the
stirring of compound 5c with KOH in DMSO-d6 at room tem-
perature did not lead to deuterium exchange, it can be concluded
that the final step of the studied reaction – the intramolecular
addition of the amino group to the triple bond – has a considerably
ionic character and occurs in accordance with Scheme 2.
The proposed new methodology for synthesis of bicyclic
N,N-enaminals 5 has several advantages in comparison with pre-
viously described12,13 approach. First of all, the scope of the
present reaction is much wider, allowing obtaining products
(5d,e,g) without substituents in a-position to the carbon atom
of NCHN-fragment, as well as N-substituted enaminals 5c,e–h
as single entity. Moreover, this reaction does not demand using
organometallic reagents and absolute conditions, providing better
yields of target products.
This work was supported by the President of the Russian
Federation (Programme for Support of Leading Scientific Schools,
grant no. NSh-604.2012.3) and the Russian Academy of Sciences
(programme OKh-01).
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi:10.1016/j.mencom.2013.05.006.
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For characteristics of compounds 5d–h, see Online Supplementary
Materials.
Received: 4th February 2013; Com. 13/4061
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