Tandem synthesis of trichloromethylated [3.3.3]propellanes from trichloroacetamidines and a ninhydrin-malononitrile adduct

Article abstract of DOI:10.1016/j.tetlet.2014.03.124

The trichloroacetamidine intermediates, generated by addition of benzylamine derivatives to trichloroacetonitrile, react with the Knoevenagel condensation product of ninhydrin and malononitrile to afford trichloromethylated [3.3.3]propellanes, in good yields. When benzylamine was used, a plane-symmetrical spiro-compound was obtained.

Full text of DOI:10.1016/j.tetlet.2014.03.124

Accepted Manuscript
Tandem synthesis of trichloromethylated [3.3.3]propellanes from trichloroace-
tamidines and a ninhydrin-malononitrile adduct
Issa Yavari, Alaleh Malekafzali, Stavroula Skoulika
PII:
S0040-4039(14)00556-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.03.124
TETL 44446
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
17 February 2014
17 March 2014
27 March 2014
Please cite this article as: Yavari, I., Malekafzali, A., Skoulika, S., Tandem synthesis of trichloromethylated
[3.3.3]propellanes from trichloroacetamidines and a ninhydrin-malononitrile adduct, Tetrahedron Letters (2014),
doi: http://dx.doi.org/10.1016/j.tetlet.2014.03.124
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Graphical Abstract
Tandem synthesis of trichloromethylated [3.3.3]propellanes from trichloroacetamidines
and a ninhydrin-malononitrile adduct
Issa Yavari, Alaleh Malekafzali, Stavroula Skoulika
Cl3CCN
Ar
NH2
solvent-free
0 oC
NH
NH2
O
O
O
Ar
N
CCl3
CN
H
CN
CN
O
O
N
CH2Cl2, r.t.
N
CCl3
Ar
1

Tandem synthesis of trichloromethylated [3.3.3]propellanes from
trichloroacetamidines and a ninhydrin-malononitrile adduct
Issa Yavari*,a, Alaleh Malekafzalia, Stavroula Skoulikab
a Department of Chemistry, Tarbiat Modares University, PO Box 14115-175, Tehran, Iran.
b
Laboratory of Physical Chemistry, Department of Chemistry, The University of Ioannina,
45110 Ioannina, Greece
ABSTRACT
The trichloroacetamidine intermediates, generated by addition of benzylamine derivatives
to trichloroacetonitrile, react with the Knoevenagel condensation product of ninhydrin and
malononitrile to afford trichloromethylated [3.3.3]propellanes, in good yields. When
benzylamine was used, a plane-symmetrical spiro-compound was obtained.
Keywords:
[3.3.3]propellanes
trichloroacetonitrile
ninhydrin
malononitrile
______________________________
* Corresponding author. Tel.: +98 21 82883465; fax: +98 21 82883455. E-mail address:
yavarisa@modares.ac.ir (I. Yavari).
2

Propellanes are defined as compounds having three non-zero bridges and one zero bridge
between a pair of bridgehead carbons. The interesting chemical and physical properties of
propellanes stem from their fascinating topology.1 The propellane skeleton is present in some
natural products, and bioactive aza-propellane skeletons have been reported. Various methods
for the synthesis of propellanes have been described.2
The presence of a trihalomethyl group in a molecule can result in significant changes in
its physical, chemical, and biological properties. Many bioactive trihalomethylated compounds
have found important applications in medicine and agriculture.3
As part of our studies on the development of new routes for the synthesis of
trihalomethylated compounds,4 we herein report a tandem method for the synthesis of
trichloromethylated [3.3.3]propellanes from trichloroacetamidine derivatives and the
Knoevenagel condensation product of ninhydrin and malononitrile.
Reaction of benzylamine derivatives 1 with trichloroacetonitrile (2), under solvent-free
conditions, produced trichloroacetamidine derivatives 3 (Table 1). Addition of amidines 3 to a
mixture of ninhydrin (4) and malononitrile (5) in CH2Cl2 at room temperature led to the
formation of [3.3.3]propellanes 6.5
3

Table 1
Synthesis of trichloromethylated [3.3.3]propellanes 6
Cl3CCN
Ar
NH2
1
2
solvent-free
0 oC
NH
NH2
O
O
O
Ar
N
CCl3
CN
H
CN
CN
3
O
O
N
CH2Cl2, r.t.
N
CCl3
Ar
5
4
6
Entry
Ar
Yield of 6 (%)
1, 3, 6
1
2
3
4
5
4-Me-C6H4
4-MeO-C6H4
4-Br-C6H4
4-Cl-C6H4
2-Cl-C6H4
85
91
81
88
78
a
b
c
d
e
1
The structures of products 6 were deduced from their IR, H NMR, and 13C NMR
1
spectral data and by single-crystal X-ray analysis of 6a. The H NMR spectrum of 6a showed
two sharp singlets (δ 2.34 and δ 7.10) for the methyl and amino protons, and an AB-quartet for
the methylene (δ 5.12) protons. In the 13C NMR spectrum, signals corresponding to the
trichloromethyl, cyanide, and carbonyl groups of 6a were observed at δ 89.4, 116.1 and 193.9,
respectively.6
4

Unequivocal evidence for the structure of 6a was obtained from single-crystal X-ray
analysis.7 The ORTEP8 diagram of 6a is shown in Figure 1. The structure was deduced from the
crystallographic data and those of 6b-e were assumed to be analogous on account of their NMR
spectroscopic similarities.
Figure 1. X-ray crystal structure (ORTEP) of 6a.
When benzylamine was used, plane-symmetrical 6'-amino-1'-benzyl-1,3-dioxo-2'-
(trichloromethyl)-1,3-dihydro-1'H-spiro[indene-2,4'-pyrimidine]-5'-carbonitrile (7), instead of
the [3.3.3]propellane system, was obtained in 75% yield (Scheme 1).6 The 13C NMR spectrum of
7 was consistent with the presence of a local plane of symmetry in the ninhydrin residue of the
1
molecule. In addition, the observation of a singlet for the benzylic protons in the H NMR
spectrum of 7 is in accord with this conclusion.
5

Scheme 1. Synthesis of spiro-compound 7.
Although the detailed mechanism of this reaction remains to be clarified, a plausible
mechanism for the formation of products 6 and 7 is shown in Scheme 2. It is conceivable that the
reaction involves the initial formation of Knoevenagel adduct 8 between ninhydrin and
malononitrile, which reacts with acetamidine 3 to produce 9. This intermediate undergoes
proton-transfer to afford 10. Intermediate 10 can follow two paths: a) attack of the nitrogen atom
on the carbonyl group, followed by formation of the propellane system 12, which is converted
into product 6 by imine-enamine tautomerization in 13; and b) attack of the nitrogen atom on one
of the cyanide groups to generate spiro-system 14, which affords product 7 via a proton shift and
imine-enamine tautomerization (Scheme 2).
6

Scheme 2. Proposed mechanisms for the formation of products 6 and 7.
It is not clear at present why benzylamine gives the spiro-compound 7 and 4-
methylbenzylamine gives the [3.3.3]propellane 6a. Since there is very little difference between
benzylamine and 4-methylbenzylamine, we are unable to explain this difference in terms of
steric and electronic effects. However, the carbon atom of the carbonyl group in intermediate 10
is a “harder” electrophile compared to the cyano group. Thus, benzylamine, being a “softer”
nucleophile, prefers to attack the cyano carbon atom of 10 (see Scheme 2).
In conclusion, the tandem reaction of trichloroacetonitrile, substituted benzylamines,
ninhydrin and malononitrile leads to functionalized trichloromethylated [3.3.3]propellanes.
7

When benzylamine was used, a plane-symmetrical spiro-compound was obtained. The procedure
described here has the advantage that the reaction is performed under neutral conditions.
References and notes
1. a) Ginsburg, D. Propellanes: Structure and Reactions; Verlag Chemie: Weinheim, 1975. b)
Navarro, R.; Reisman, S. E. Org. Lett. 2012, 14, 4354. c) Dyker, G.; Körning, J.;
Bubenitschek, P.; Jones, P. G. J. Chem. Res. 1997, 132. d) Wiberg, K. B. Chem. Rev. 1989,
89, 975.
2. a) Miao, M.; Cao, J.; Zhang, J.; Huang, X.; Wu, L. J. Org. Chem. 2013, 78, 2687. b) Zhang,
L. J.; Yan, C. G. Tetrahedron 2013, 69, 4915. c) Jansone-Popova, S.; May, J. A. J. Am. Chem.
Soc. 2012, 134, 17877. d) Alizadeh, A.; Rezvanian, A.; Zhu, L. G. J. Org. Chem. 2012, 77,
4385. e) Rezvanian, A.; Alizadeh, A. Zhu, L. G. Synlett 2012, 2526. f) Asahi, K.; Nishino, H.
Tetrahedron 2008, 64, 1620. g) Almog, J.; Stepanov, N.; Dubnikova, F. Tetrahedron Lett.
2008, 49, 1870. h) Nowicka-Scheibe, J.; Sośnicki, J. G.; Sawka-Dobrowolska, W.
Tetrahedron Lett. 2007, 48, 5439. i) Asahi, K.; Nishino, H. Tetrahedron Lett. 2006, 47, 7259.
j) Lee, H. Y.; Moon, D. K.; Bahn, J. S. Tetrahedron Lett. 2005, 46, 1455.
3. a) Flores, A. F. C.; Brondani, S.; Zanatta, N.; Rosa, A.; Martins, M. A. P. Tetrahedron Lett.
2002, 43, 8701. 22. b) Martins, M. A. P.; Beck, P.; Cunico, W.; Pereira, C. M. P.; Sinhorin, A.
P.; Blanco, R. F.; Peres, R.; Bonacorso, H. G.; Zanatta, N. Tetrahedron Lett. 2002, 43, 7005.
c) Chambers, R. D.; Sargent, C. R. Adv. Heterocycl. Chem. 1991, 28, 1. d) Welch, J. T.
Tetrahedron 1987, 43, 3123.
4. a) Yavari, I.; Nasiri-Gheidari, S. Helv. Chim. Acta 2011, 94, 811. b) Yavari, I.; Sabbaghan,
M.; Hossaini, Z.; Ghazanfarpour-Darjani, M. Helv. Chim. Acta 2008, 91, 1144. c) Yavari, I.;
8

Sabbaghan, M.; Hossaini, Z. Monatsh. Chem. 2008, 139, 625. d) Yavari, I.; Djahaniani, H.;
Nasiri, F. Collect. Czech. Chem. Commun. 2004, 69, 1499.
5. General procedure for the preparation of compounds 6 and 7: benzylamine derivative 1 (2
mmol) was added to Cl3CN (2) (2 mmol) at 0 ºC and the mixture stirred for 5 min. The
resulting precipitate was added to a stirred solution of ninhydrin (4) (2 mmol) of and
malononitrile (5) (2 mmol) in CH2Cl2 (15 mL) at room temperature. After completion of the
reaction [about 4 h, TLC (EtOAc/hexane, 1:5) monitoring], the formed solid was filtered and
the residue rinsed with CH2Cl2 to afford the pure product.
6. 2-Amino-9-(4-methylbenzyl)-4-oxo-10-(trichloromethyl)-4H-3a,8b-
(azenomethenoimino)indeno[1,2-b]furan-3-carbonitrile (6a): Pale yellow powder, mp
(dec.): 160 ºC. Yield 0.40 g, 85%. IR (KBr): 2196, 1729, 1657, 786, 661. 1H NMR (300
MHz, acetone-d6): δ 2.34 (3H, s, Me), 5.12 (2H, ABq, J = 17.3 Hz, ∆νAB = 105.3 Hz, CH2),
7.10 (2H, s, NH2), 7.17 (2H, d, J = 7.9 Hz, CH), 7.31 (2H, d, J = 7.9 Hz, CH), 7.34 (1H, d, J
= 2.0 Hz, CH), 7.74 (2H, m, CH), 7.94 (1H, m, CH). 13C NMR (75 MHz, acetone-d6): δ 21.1
(Me), 49.4 (CH2), 56.2 (C), 88.9 (C), 89.4 (CCl3), 111.5 (C), 116.1 (CN), 126.1 (CH), 126.9
(CH), 128.3 (CH), 130.0 (CH), 132.5 (CH), 133.8 (C), 136.8 (CH), 137.5 (C), 138.0 (C),
144.0 (C), 160.3 (C), 168.2 (C), 193.9 (C=O). MS (EI, 70 eV): m/z (%) = 301 (27), 285 (32),
260 (35), 219 (23), 185 (11), 155 (24), 117 (10), 105 (100), 91 (44), 83 (10), 77 (55). Anal.
Calcd for C22H15Cl3N4O2 (473.74): C, 55.78; H, 3.19; N, 11.83. Found: C, 56.11; H, 3.22; N,
11.91.
6'-Amino-1'-benzyl-1,3-dioxo-2'-(trichloromethyl)-1,3-dihydro-1'H-spiro[indene-2,4'-
pyrimidine]-5'-carbonitrile (7): Yellow powder, mp: 164 ºC. Yield 0.35 g, 75%. IR (KBr):
2227, 1643, 1573, 1249, 991, 772, 601. 1H NMR (300 MHz, acetone-d6): δ 4.99 (2H, s,
9

CH2), 7.43 (5H, m, CH), 7.79 (4H, s, CH). 13C NMR (75 MHz, acetone-d6): δ 50.7 (CH2),
85.5 (C), 86.4 (CCl3), 108.4 (C), 110.5 (CN), 122.7 (CH), 128.5 (CH), 129.0 (CH), 129.8
(CH), 133.3 (CH), 135.3 (C), 137.5 (C), 164.2 (C), 172.0 (C), 196.0 (C=O). MS (EI, 70 eV):
m/z (%) = 210 (100), 182 (12), 155 (45), 127 (72), 105 (48), 91 (8), 83 (7), 77 (42). Anal.
Calcd for C21H13Cl3N4O2 (459.71): C, 54.87; H, 2.85; N, 12.19. Found: C, 55.08; H, 2.90; N,
12.26.
7. X-Ray Crystal-Structure Determination of 6a: Structure determination and refinement data:
formula, C22H15Cl3N4O2. C3H6O: Mr 531.81; triclinic, space group P-1, a = 9.062(1) Å, b =
10.210(1) Å, c = 14.622(2) Å, α = 81.29(1)°, β = 75.98(1)°, γ = 75.18(1)°; Z = 2, V =
1263.1(3) Å3, Dcalc = 1.398 mg/m3, MoKα radiation (0.71073 Å), T = 293(2) K; 5288
reflections collected on a Bruker P4 diffractometer, 4375 unique (Rint = 0.0212), 3302
unique reflections with I>2σ(I). All non-hydrogen atoms have been located by difference
Fourier maps and refined anisotropically. All hydrogen atoms, except those of the amine
nitrogen, have been placed on calculated positions and refined isotropically by using the
riding model. The amine protons have been located by difference Fourier maps and refined
isotropically. Final indices [I>2σ(I)]: R1 = 0.0501, wR2 = 0.1229, GOF = 1.153. The
crystallographic data of 6a have been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication number CCDC-977644. Copies of the data can be
obtained, free of charge, via the internet (http://www.ccdc.cam.ac.uk/data_request/cif), e-
mail (data_request@ccdc.cam.ac.uk), or fax (+44-1223-336033).
8. Burnett, A. M. N.; Johnson, C. K. Oak Ridge National Laboratory Report ORNL-6895, Oak
Ridge National Laboratory: Tennessee, 1996.
10