An efficient and selective route to hybrid trifluoromethyl-substituted γ-lactones or fused nitrogen derivatives via cascade reactions

Article abstract of DOI:10.1016/j.tetlet.2011.09.093

A straightforward, efficient and selective route for obtaining hybrid trifluoromethyl-substituted γ-lac-tones and fused nitrogen heterocycles is presented. The reaction could be guided either to γ-lactones with a nitrogen-containing heterocyclic skeleton

Full text of DOI:10.1016/j.tetlet.2011.09.093

Tetrahedron Letters 52 (2011) 6439–6442
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Tetrahedron Letters
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An efficient and selective route to hybrid trifluoromethyl-substituted
c-lactones or fused nitrogen derivatives via cascade reactions
Roxana Tucaliuc d, Valeriu V. Cotea d, Costel Moldoveanu a, Gheorghita Zbancioc a, Calin Deleanu b,
Peter G. Jones c, Ionel I. Mangalagiu a,
⇑
a ‘‘Al. I. Cuza’’ University of Iasi, Organic Chemistry Department, Bd. Carol 11, 700506 Iasi, Romania
b ‘‘P. Poni’’ Institute of Macromolecular Chemistry, Aleea Grigore Ghica Voda 41-A, RO-700487 Iasi, Romania
c Institut fur Anorganische and Analytische Chemie, Technische Universität Braunschweig, Postfach 3329, 38023 Braunschweig, Germany
d University of Agriculture and Veterinary Medicine ‘‘Ion Ionescu de la Brad’’ Iasi, Aleea Mihail Sadoveanu, Iasi, Romania
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 June 2011
Revised 5 September 2011
Accepted 19 September 2011
Available online 22 September 2011
A straightforward, efficient and selective route for obtaining hybrid trifluoromethyl-substituted
c
-lac-
-lactones
with a nitrogen-containing heterocyclic skeleton (for monocyclic systems) or to fused nitrogen heterocy-
cles (for fused bicyclic systems). A new class of -lactone with a nitrogen heterocyclic skeleton was
obtained. Feasible reaction mechanisms involving cascade reactions are presented.
Ó 2011 Elsevier Ltd. All rights reserved.
tones and fused nitrogen heterocycles is presented. The reaction could be guided either to
c
c
Keywords:
Trifluoromethyl groups
c
-Lactone
Fused nitrogen heterocycles
Cascade reaction
Diazine
Pyridazine derivatives have been reported to display a wide
range of biological effects; these include activities against viruses
(including anti-HIV),1 cancer,2 cardiovascular disorders,3 bacteria,
fungi and tuberculosis, as well as anti-inflammatory4 and other
activities.5 Similarly, fluorine-containing compounds currently fea-
ture significantly in the provision of anti-HIV,6 antiviral and anti-
cancer,7 antibacterial and antifungal8 medicines.
One of the strategies adopted for the synthesis of pyridazine
derivatives involves nitrogen ylides as reactive species.4a,c,5,9–11
The reaction pathway involves a Huisgen [3+2] dipolar cycloaddi-
tion of ylides to dipolarophiles (activated alkenes and alkynes).
One of our goals is to synthesize a hybrid pyridazine–fluorine
moiety, in order to combine their respective biological potentials.
As a part of our work in this field,4,5,11 we report here our results
concerning the cycloaddition reactions of diazinium ylides with
2-(trifluoromethyl) acrylic acid.
The structures of c-lactones 4 and 5 were proved by elemental
and spectral analyses (IR, 1H NMR, 13C NMR, and two-dimensional
experiments 2D-COSY, 2D-HETCOR (HMQC), long range 2D-HET-
COR (HMBC) and finally single crystal X-ray structure determina-
tions (Figs. 1 and 2).12
The mechanism for the formation of c-lactones 4 and 5 can be
explained via a cascade reaction (Scheme 2). Initially, a typical
3+2 dipolar cycloaddition takes place, leading to the intermediate
compounds ia. Because of the powerful electronegativity of the
CF3 group, the hydrogen atom from the carboxylic group becomes
very acidic and protonate the double bonded nitrogen atom, lead-
ing to the tautomeric form ib. A nucleophilic attack of the negative
oxygen (from the carboxylate group) to the adjacent endocyclic
carbocation is leading to the c-lactones iia, which undergoes a sub-
sequent tautomeric rearrangement to iib.
In order to ascertain if this is a general behaviour for the six-
membered nitrogen heterocycles, and whether compounds similar
to the c-lactones 4 and 5 are formed in the related cases, we repeated
Pyridazinium ylides 2 (generated in situ from the corresponding
cycloimmonium salts 1, were treated with 2-(trifluoro-
methyl)acrylic acid (Scheme 1). Unexpectedly, instead of the fused
pyridazine 3, we obtained a new class of organic compounds: fused
the reactions with other nitrogen heterocycles. Thus, in the pyrimi-
dine series, when pyrimidinium ylides 7 were treated with 2-(tri-
c-lactones with nitrogen heterocyclic skeletons, type 4 and 5. Two
fluoromethyl) acrylic acid, c-lactone 8 was obtained, with a
stereoisomers were obtained, the reaction being stereoselective (4
is the major product).
structure analogous to lactone 4 (Scheme 3). A single stereoisomer
is obtained, the reaction being stereospecific. The mechanistic con-
siderations as for the pyridazine system probably remain valid.
In the case of the fused benzo-pyridazine, phthalazine, the re-
sults were different. The reaction starts as a classical [3+2] dipolar
⇑
Corresponding author. Tel.: +40 232 201343; fax: +40 232 201313.
E-mail address: ionelm@uaic.ro (I.I. Mangalagiu).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.09.093

6440
R. Tucaliuc et al. / Tetrahedron Letters 52 (2011) 6439–6442
R
O
R
O
C
C
COOH
CF3
CH
COC6H4R-4
CH
COC6H4R-4
N
N
5
5
N
1
N
N
H
N
N
4
H2C
C
N
4
O
Ha
Hb
CF3
Br
CH2
COC6H4R-4
1 a-c
H
6
6
7
N
TEA
N
Ha
Hb
3
H
2
3
H
O
H''
H''
2a
7
+
7b
2a
7a
H
H'
7a
O
1
H'
H
CF3
2 a-c
R= Cl, F, CH3
2
O
5a-c. R= Cl, F, CH3
R = Cl, F, CH3
4 a-c. R= Cl, F, CH3
COC6H4R-4
N
N
HOOC CF3
3
Scheme 1. Reaction pathway to c-lactones with nitrogen heterocyclic skeleton.
The structures of compound 12 were proved by elemental and
spectral (IR, 1H NMR, 13C NMR, and two-dimensional experiments
2D-COSY, 2D-HETCOR (HMQC), long range 2D-HETCOR (HMBC)
and X-ray analyses (Fig. 3).
Concerning the reaction mechanism we presume that such a
different behaviour is related to the influence of the nitrogen
heterocycle. After an initial cycloaddition of ylide
9
to
2-(trifluoromethyl)acrylic acid, the formation of the -lactone is
c
prevented by the benzene ring fused with pyridazine (its aromatic
nature prevents canonical structures such as ib). The intermediate
10 undergoes subsequent decarboxylation to the tetrahydropyrrol-
ophthalazine 11, which via spontaneous oxidative dehydrogenation
(by air) generates the aromatized pyrrolophthalazine compound 12.
In conclusion, a straightforward, efficient and selective route for
obtaining hybrid fluorine nitrogen heterocycle is presented. A new
Figure 1. The ORTEP diagram of compound 4a including atom numbering scheme.
class of
c-lactone with a nitrogen heterocyclic skeleton was
obtained. The reaction mechanism for
c-lactone formation was ex-
plained via a cascade reaction: a 3+2 dipolar cycloaddition, followed
by a concomitant protonation of the nitrogen atom and nucleophilic
attack of the carboxylate oxygen at the adjacent endocyclic carbo-
cation. The reaction pathway is straightforward, efficient and stere-
oselective (for pyridazine) or stereospecific (for pyrimidine).
Depending on the nature of the heterocycle, the reaction leads to
either c-lactones with a nitrogen heterocyclic skeleton (for monocy-
cles) or to fused nitrogen heterocycle (for fused bicyclic systems).
The corresponding cycloimmonium salt (1) (2 mmol) was sus-
pended in 50 mL of chloroform.
A solution of 2-(trifluoro-
methyl)acrylic acid (2 mmol) and triethylamine (2.2 mmol) in the
same solvent (5 mL) was then added. The solution was refluxed
for 3 h, then the solution was filtered and the solvent evaporated.
The crude product was purified by flash chromatography (silica,
CH2Cl2–MeOH) and then crystallized from an appropriate solvent.
Compound (4a): White crystals, mp 183–184 °C. IR (KBr, cmꢀ1):
3042, 2976, 1778, 1686, 1596, 1509, 1467, 1152. 1H NMR (CDCl3,
400 MHz): d 2.18–2.13 (dd, J = 4.8, J = 16.4 Hz, 1H, H700), 2.61–
2.56 (dd, J = 6.0, J = 14.4 Hz, 1H, H3b), 2.78–2.72 (ddd, J = 4.8,
J = 8.0, J = 16.4 Hz, 1H, H70), 3.00–2.93 (dd, J = 11.2, J = 14.4 Hz,
1H, H3a), 4.62–4.60 (d, J = 7.6 Hz, 1H, H7b), 4.82–4.78 (dd, J = 6.0,
Figure 2. The ORTEP diagram of compound 5a including atom numbering scheme.
cycloaddition of phthalazinium ylide 9 to the dipolarophile, and fi-
nally the aromatized pyrrolophthalazine compounds 12 were ob-
tained (Scheme 4).
COC6H4R-4
COC6H4R-4
H
COC6H4R-4
COOH
CF3
COC6H4R-4
H
N
COC6H4R-4
CH
N
H
H2C
C
H
H
N
N
H
N
Ha
H
Ha
N
H
N
Ha
H
N
N
Ha
H
N
Hb
Hb
H
Hb
H
Hb
CF3
CF3
CF3
H''
CF3
2a-c.
R= Cl, F, CH3
O
O
H'
H
O
O
O
H
O
O
ia
iia
iib
ib
O
Scheme 2. Reaction mechanism to c-lactones with nitrogen heterocycle skeleton.

R. Tucaliuc et al. / Tetrahedron Letters 52 (2011) 6439–6442
6441
4'
Cl
C6H4Cl-4
N
C6H4Cl-4
C6H4Cl-4
11
10
COOH
CF3
1'
7
7a
5
O
C
N
8
N
N
H2C
C
N
N
H
Cl
H
TEA
4
N
CF3
N
H
Br
1 O
Ha
Hb
H2C
CH
CH
COC6H4Cl-4
3
2a
2
COC6H4Cl-4
COC6H4Cl-4
O
8
6
7
Scheme 3. Reaction pathway of pyrimidinium ylides with 2-(trifluoromethyl)acrylic acid.
13
12
O
COC6H4Cl-4
COC6H4Cl-4
COOH
C
7
Cl
1
H
H
N
N
H
H2C
CH
C
H
N
H
H
N
N
2
3
N
N
N
H
8
CF3
H
-4[H+]
4
2a
- CO2
H
CF3
6b
6a
CF3
CF3
HOOC
10
6
COC6H4Cl-4
5
9
11
12
Scheme 4. Reaction pathway of phthalazinium ylides with 2-(trifluoromethyl)acrylic acid.
H6), 8.77 (s, 1H, H2).13C NMR (CDCl3, 100 MHz): d 116.81 (C8),
119.78 (C7), 121.61 (C6), 124.57 (CF3), 125.37 (C3), 126.16 (C6a),
128.27 (C6b), 128.79 (C13), 129.62 (C4), 131.05 (C12), 133.63
(C5), 137.18 (C11), 138.98 (C14), 146.49 (C2), 183.06 (C10).
Acknowledgment
This work was co-financed from the European Social Fund Sec-
toral Operational Human Resources Development 2007-2013, pro-
ject number POSDRU/I.89/1.5/S62371 Postdoctoral School in
Agriculture and Veterinary Medicine area.
Supplementary data
Figure 3. The ORTEP diagram of compound 12 including atom numbering scheme.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.09.093.
J = 11.2 Hz, 1H, H4), 5.14–5.12 (dd, J = 7.6, J = 8.0 Hz, 1H, H7a),
6.92–6.91 (dd, J = 4.8 Hz, 1H, H6), 7.43–7.41 (d, J = 8.8 Hz, 2H,
H11), 8.10–8.08 (d, J = 8.8 Hz, 2H, H10). 13C NMR (CDCl3,
100 MHz): d 24.73 (C7), 33.89 (C3), 58.83 (C2a), 65.86 (C7b),
71.27 (C7a), 72.43 (C4), 123.33 (CF3), 128.87 (C11), 130.59 (C10),
134.07 (C9), 139.79 (C12), 142.30 (C6), 170.31 (C2), 192.02 (C8).
Compound (5a): White crystals, mp 140–142 °C. IR (KBr, cmꢀ1):
3044, 2982, 1778, 1688, 1590, 1510, 1475, 1182. 1H NMR (CDCl3,
400 MHz): d 2.27–2.22 (dd, J = 4.8, J = 17.2 Hz, 1H, H700), 2.84–
2.80 (dd, J = 2.8, J = 14.4 Hz, 1H, H3b), 2.76–2.70 (dd, J = 4.0,
J = 7.2, J = 17.2 Hz, 1H, H70), 2.92–2.86 (dd, J = 9.2, J = 14.4 Hz, 1H,
H3a), 4.42–4.41 (d, J = 6.0 Hz, 1H, H7b), 5.04–5.03 (d, J = 2.8 Hz,
1H, H4), 5.43–5.40 (dd, J = 4.0, J = 5.2 Hz, 1H, H7a), 6.83–6.82 (dd,
J = 4.8 Hz, 1H, H6), 7.48–7.46 (dd, J = 8.8 Hz, 2H, H11), 7.99–7.97
(dd, J = 8.8 Hz, 2H, H10).13C NMR (CDCl3, 100 MHz): d 24.00 (C7),
32.26 (C3), 62.23–61.40 (C2a), 63.28 (C7b), 69.80 (C7a), 72.10
(C4), 125.23–122.43 (CF3), 129.20 (C11), 130.56 (C10), 132.84
(C12), 135.77 (C6), 140.44 (C9), 171.06 (C2), 194.31 (C8).
Compound (8): White-beige crystals, mp 218–220 °C. 1H NMR
(CDCl3, 400 MHz): d 2.00–1.96 (dd, 1H, H7), 3.04–3.01 (dd, 1H,
H3b), 3.07–3.04 (dd, 1H, H3a), 4.82–4.80 (d, 1H, H7b), 5.63–5.62
(d, 1H, H7a), 6.00–5.98 (d, 1H, H4), 7.45–7.43 (dd, J = 8.0 Hz, 2H,
H11), 7.72–7.67 (m, 5H, H1, 2H2, 3H3), 7.74–7.73 (d, 1H, H5),
8.09–8.07 (dd, J = 8.0 Hz, 2H, H10).
Compound (12): White crystals, mp 172–174 °C. 1H NMR
(CDCl3, 400 MHz): d 7.42 (s, 1H, H8), 7.51–7.49 (d, J = 8.4 Hz, 2H,
H13), 7.78–7.75 (dd, J = 7.6 Hz, 1H, H4), 7.89–7.87 (d, J = 8.4 Hz,
2H, H12), 7.95–7.91 (dd, 2H, H3, H5), 8.45–8.43 (d, J = 7.2 Hz, 1H,
References and notes
1. (a) Fan, S. Y.; Zeng, Z. B.; Mi, C. L.; Zhou, X. B.; Yan, H.; Gong, Z. H.; Li, S. Bioorg.
Med. Chem. 2009, 17, 621–624; (b) De Clercq, E. Nat. Rev. Drug Disc. 2007, 6,
1001–1018.
2. (a) Zbancioc, A. M.; Zbancioc, G.; Tanase, C.; Miron, A.; Ursu, C.; Mangalagiu, I. I.
Lett. Drug Des. Discov. 2010, 7, 644–649; (b) Pogacic, V.; Bullock, A. N.; Fedorov,
O.; Filippakopoulos, P.; Gasser, C.; Biondi, A.; Meyer, S.; Knapp, S.; Schwaller, J.
Cancer Res. 2007, 67, 6916–6924.
3. (a) Kumar, D.; Carron, R.; De La Calle, C.; Jindal, D. P.; Bansal, R. Acta Pharm.
2008, 58, 393–405; (b) Demirayak, S.; Karaburn, A. C.; Beis, R. Eur. J. Med. Chem.
2004, 39, 1089–1095.
4. (a) Mantu, D.; Luca, M. C.; Moldoveanu, C.; Zbancioc, G.; Mangalagiu, I. I. Eur. J.
Med. Chem. 2010, 45, 5164–5168; (b) Butnariu, R.; Mangalagiu, I. I. Bioorg. Med.
Chem. 2009, 17, 2823; (c) Nagawade, R. R.; Khanna, V. V.; Bhagwat, S. S.; Shinde,
D. B. Eur. J. Med. Chem. 2005, 40, 1325–1330.
5. Mangalagiu, I. I. Curr. Org. Chem. 2011, 15, 730–752.
6. Mackman, R. L.; Lin, K. Y.; Boojamara, C. G.; Hui, H.; Douglas, J.; Grant, D.;
Petrakovsky, O.; Prasad, V.; Ray, A. S.; Cihlar, T. Bioorg. Med. Chem. Lett. 2008, 18,
1116–1119.
7. (a) Li, C.; Prichard, M. N.; Korba, B. E.; Zemlicka, J. Bioorg. Med. Chem. 2008, 16,
2148–2155; (b) Tran, J. A.; Jiang, W.; Tucci, F. C.; Fleck, B. A.; Wen, J.; Sai, Y.;
Madan, A.; Chen, T. K.; Markison, S.; Foster, A. C.; Hoare, S. R.; Marks, D.;
Harman, J.; Chen, C. W.; Arellano, M.; Marinkovic, D.; Bozigian, H.; Saunders, J.;
Chen, C. J. Med. Chem. 2007, 50, 6356–6366.
8. (a) Ren, Q.; Cui, Z.; He, H.; Gu, Y. J. Fluorine Chem. 2007, 128, 1369–1375; (b)
Dong, C.; Huang, F.; Deng, H.; Schaffrath, C.; Spencer, J. B.; O’Hagan, D.;
Naismith, J. H. Nature 2004, 427, 561–565.
9. (a) Padwa, A. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; John Wiley
& Sons: New York, 1984; Vol. 2, pp 277–406; (b) Houk, K. N.; Yamaguchi, K. In
Theory of 1,3-Dipolar Cycloadditions in 1,3-Dipolar Cycloaddition Chemistry;
Padwa, A., Ed.; John Wiley and Sons: New York, 1984; Vol. 2, pp 407–450.
10. Klamann, D.; Hagen, H. In Organische Stickstoff-Verbindungen mit einer C, N-
Doppelbindung; Claus, P. C., Ed.; Houben-Weyl: Thieme, Stuttgart, New York,
1991; Vol. E14b, pp 1–160. Chapter Teil 1: Stickstoff-Ylide.

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R. Tucaliuc et al. / Tetrahedron Letters 52 (2011) 6439–6442
11. (a) Zbancioc, G.; Huhn, T.; Groth, U.; Deleanu, C.; Mangalagiu, I. I. Tetrahedron
2010, 66, 4298–4306; (b) Zbancioc, G.; Mangalagiu, I. I. Tetrahedron 2010, 66,
278–282; (c) Moldoveanu, C.; Jones, P.; Mangalagiu, I. I. Tetrahedron Lett. 2009,
50, 7205–7208.
12. The following crystal structures have been deposited at the Cambridge
Crystallographic Data Centre and allocated the deposition numbers: 4b:
CCDC 679536, 5b: CCDC 691746, 14: CCDC 827693.