Facile synthesis of fluorine-containing 1,10-phenanthrolines by the pyridine-ring formation reaction of N-propargyl-5,7-bis(trifluoroacetyl)-8-quinolylamine with amines: isolation of the intermediates 1,4-dihydro-1,10-phenanthrolin-4-ols

Article abstract of DOI:10.1016/j.tetlet.2008.09.172

Novel fluorine-containing 1,10-phenanthrolines having dialkyl-, alkyl, and arylaminomethyl substituents at the 3-position were easily synthesized in moderate yields by the pyridine-ring formation reaction of N-propargyl-5,7-bis(trifluoroacetyl)-8-quinolyl

Full text of DOI:10.1016/j.tetlet.2008.09.172

Tetrahedron Letters 49 (2008) 7161–7164
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Facile synthesis of fluorine-containing 1,10-phenanthrolines by the
pyridine-ring formation reaction of N-propargyl-5,7-bis(trifluoroacetyl)-
8-quinolylamine with amines: isolation of the intermediates 1,4-dihydro-
1,10-phenanthrolin-4-ols
c
c
Dai Shibata a, Etsuji Okada b, , Jérôme Molette , Maurice Médebielle
*
a Graduate School of Science and Technology, Kobe University, Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan
b Department of Chemical Science and Engineering, Graduate School of Engineering, Kobe University, Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan
c Université de Lyon, Université Claude Bernard Lyon 1 (UCBL), Institut de Chimie et Biochimie Moléculaires et Supramoléculaires (ICBMS),
Laboratoire de Synthése de Biomolécules (LSB), UMR 5246 CNRS-UCBL-INSA Lyon-CPE Lyon, 43 Bd Novembre, Villeurbanne 69622, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel fluorine-containing 1,10-phenanthrolines having dialkyl-, alkyl, and arylaminomethyl substitu-
ents at the 3-position were easily synthesized in moderate yields by the pyridine-ring formation reaction
of N-propargyl-5,7-bis(trifluoroacetyl)-8-quinolylamine with various amines. Unexpectedly, the reactive
intermediates 1,4-dihydro-1,10-phenanthrolin-4-ols were isolated for the first time in the reactions with
dialkylamines.
Received 2 September 2008
Revised 26 September 2008
Accepted 29 September 2008
Available online 7 October 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
1,10-Phenanthrolines
Fluorine
Pyridine-ring
formation
Propargylamines
8-Quinolylamines
In recent years, considerable attention has been paid to the
development of new methodologies for the synthesis of many
kinds of fluorine-containing heterocycles, since these compounds
are now widely recognized as important organic materials showing
interesting biological activities for their potential use in medicinal
and agricultural scientific fields.1
and alcohols under mild conditions to afford the corresponding N–
N, N–S, and N–O exchanged products 3 and 4 in excellent yields
(Scheme 1). Moreover we succeeded in applying this type of aro-
matic nucleophilic substitution to the simple syntheses of various
CF3-containing heterocycles that are having a naphthalene10 and a
quinoline11 skeletons.
1,10-Phenanthroline and the related derivatives2 have attracted
much attention for their various biological activities, such as anti-
bacterial,3a,c antifungal,3a and antitumor3b,d activities. They are also
important heterocyclic systems because of being applicable to che-
lating ligands forming stable complexes with transition metals.4 In
particular, some of these complexes have been used as useful novel
catalysts in phase-transfer5 and asymmetric6 reactions, and they
are also potential DNA binding agents,7,3d which can be expected
to be developed as novel probes of nucleic acid structure and
function.
In continuation of these studies, it was found that N-propar-
gyl-2,4-bis(trifluoroacetyl)-1-naphthylamine 5, prepared by N–N
exchange reaction of 1 with propargylamine, undergoes novel pyr-
idine-ring formation reaction with various nucleophiles to give
the corresponding fluorine-containing benzo[h]quinolines 6 in
excellent yields (Scheme 2).12
NMe2
COCF3
Nu
X
X
COCF3
NuH
Previously, we had reported that N,N-dimethyl-2,4- bis(trifluo-
roacetyl)-1-naphthylamine 18 and N,N-dimethyl- 5,7-bis(trifluoro-
acetyl)-8-quinolylamine 29 react easily with various amines, thiols,
(NuH=RR'NH, RSH, ROH)
COCF3
COCF3
1: X=CH
2: X=N
3: X=CH
4: X=N
* Corresponding author. Tel./fax: +81 78 803 6194.
E-mail address: okaetsu@kobe-u.ac.jp (E. Okada).
Scheme 1.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.09.172

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D. Shibata et al. / Tetrahedron Letters 49 (2008) 7161–7164
In contrast, when the reaction with bulky primary amine such
as t-butylamine was performed under mild conditions (at room
temperature for 4 h), a mixture of dihydrophenanthrolinol 8d
and phenanthroline 9d was obtained, and separation of the mix-
ture was unsuccessful. Therefore, we performed the two-step reac-
tion in a one-pot manner to obtain selectively the final target
product 9d. After stirring the solution of a mixture of 7 and t-butyl-
amine in CH3CN for 4 h at room temperature, TFA (5 equiv) was
added to the reaction mixture, and then it was further stirred for
5 min at the same temperature to afford 9d in 58% yield (entry
4). In a similar one-pot manner, aromatic primary amines, for
example, p-anisidine and p-chloroaniline, reacted in the presence
of triethylamine as a base to give the desired 1,10-phenanthrolines
9e and 9f in moderate yields (entries 5 and 6).15 Unfortunately, the
reactions with less bulky aliphatic primary amines such as
methyl-, ethyl-, and i-propylamines furnished a complex mixture
of the corresponding N–N exchanged 8-quinolylamine derivatives
4 (Nu: MeNH, EtNH and i-PrNH) and decomposed products.
A possible mechanistic pathway for the formation of 1,10-phen-
anthrolines is depicted in Scheme 4. Both the addition of amines to
the terminal acetylenic carbon and the attack of carbonyl carbon
onto the internal acetylenic carbon occur concertedly to give the
cyclization product 80 having exo-methylene moiety. The subse-
quent 1,3-shift of allylic hydrogen in 80 takes place to afford the
intermediates, 1,4-dihydro-1,10-phenanthrolin-4-ols 8, which un-
dergo dehydration to give 1,10-phenanthrolines 9. More studies
are underway to elucidate clearly the mechanism.
HN
N
Nu
CF3
COCF3
NuH
(NuH=RR'NH, RSH, ROH)
COCF3
5
COCF3
6
Scheme 2.
Herein, we report a facile synthetic method for novel fluorine-
containing 1,10-phenanthrolines 9 by the pyridine-ring formation
reaction of N-propargyl-5,7-bis(trifluoroacetyl)-8-quinolylamine 7
with amines and the isolation of the reactive intermediates 1,4-
dihydro-1,10-phenanthrolin-4-ols, 8a–c. To the best of our knowl-
edge, this is the first example of the isolation of 1,4-dihydro-1,10-
phenanthrolin-4-ols as the precursor of 1,10-phenanthrolines.
The requisite starting material 7 was quantitatively prepared by
the aromatic nucleophilic N–N exchange reaction of
2 with
propargylamine.9
We first examined the reaction of 7 with secondary amines
(Scheme 3), and the results are summarized in Table 1. The cycli-
zation of 7 with dimethylamine proceeded rapidly at room tem-
perature in CH3CN to give the unexpected intermediate, 1,4-
dihydro-1,10-phenanthrolin-4-ol 8a, in an almost quantitative
yield without dehydration (entry 1; in the first step).13 Secondary
amines such as diethylamine and piperidine also reacted cleanly
to provide dihydrophenanthrolinols 8b and 8c quantitatively
(entries 2 and 3). Treatment of dihydrophenanthrolinols 8a–c with
trifluoroacetic acid (TFA) caused dehydration to furnish the corre-
sponding phenanthrolines 9a–c in 60–63% yields (entries 1–3; in
the second step).14 The dehydration of piperidino derivative 8c
was carried out under mild conditions (with 1 equiv of TFA at room
temperature in CHCl3). However, forced reaction conditions (in
refluxing TFA) were required for dimethyl- and diethylamino
derivatives 8a and 8b. The reason is not clear at this stage. Interest-
ingly, the 6-trifluoroacetyl group of prepared 1,10-phenanthrolines
9 was found to exist in hydrate form, and this phenomenon was
not observed in the case of benzo[h]quinolines 6.
The structures of all new compounds (8 and 9) were easily
determined on the basis of their 1H NMR and IR spectra, together
with elemental analyses. For example, in 1H NMR spectrum of
8a, two adjacent protons (amine and olefin protons) at 1- and 2-
positions appeared at 8.88 and 6.72 ppm as doublets with coupling
constant J = 4.0 Hz. When the H–D exchange of the amine proton
(H-1) was carried out, the multiplicity of olefin proton (H-2) signal
was changed to singlet. The data clearly show that the structure of
the isolated intermediate is not 80 but 8.
It is noteworthy that we first succeeded in the isolation of the
intermediates 8a–c, which are the precursors of stable-aromatized
final products, 1,10-phenanthrolines 9a–c, and which seem to be
HN
HN
NR1R2
CF3
OH
N
NR1R2
CF3
R1R2NH (1 equiv.)
rt in CH3CN
1st step
N
COCF3
N
N
TFA
2nd step
COCF3
COCF3
C(OH)2CF3
9a-f
7
8a-f
(isolated for 8a-c)
Scheme 3.
Table 1
Synthesis of 1,10-phenanthrolines 9 by the reaction of 7 with amines
Entry
1st step
Time (h)
2nd step
R1R2NH
Product
Yield (%)
TFA (equiv)
Temperature
Time (min)
Solvent
Product
Yield (%)
1
2
3
Me2NHa
Et2NH
Piperidine
t-BuNH2
4-MeOC6H4NH2
4-ClC6H4NH2
2
2
1
4
4
4
8a
8b
8c
—
—
—
98
100
100
—
—
—
54
54
1
5
5
Reflux
Reflux
rt
rt
rt
rt
30
30
30
5
5
5
None
None
CHCl3
CH3CN
CH3CN
CH3CN
9a
9b
9c
9d
9e
9f
62b
60b
63b
58c
51c
58c
4
5d
6d
5
a
Aqueous solution (50%) of dimethylamine was used.
Isolated yields based on 8.
Isolated yields based on 7.
b
c
d
Triethylamine (0.5 equiv) was added.

D. Shibata et al. / Tetrahedron Letters 49 (2008) 7161–7164
7163
R1R2NH
H
H
NR1R2
OH
N
NR1R2
H
N
NR1R2
CF3
H
N
N
N
N
N
N
1,3-H Shift
CF3
O
O
CF3
CF3
—H2O
COCF3
7
COCF3
8'
COCF3
8
C(OH)2CF3
9
Scheme 4.
1996, 3017–3022; (c) Okada, E.; Tsukushi, N. Synthesis 2000, 499–501; (d)
Gladiali, S.; Chelucci, G.; Mudadu, M. S.; Gastaut, M.-A.; Thummel, R. P. J. Org.
Chem. 2001, 66, 400–405; (e) Elmaaty, T. A.; Castle, L. W. Synthesis 2006, 1402–
1404; (f) Chelucci, G.; Addis, D.; Baldino, S. Tetrahedron Lett. 2007, 48, 3359–
3362; (g) Chelucci, G.; Baldino, S. Tetrahedron Lett. 2008, 49, 2738–2742; (h)
Weitgenant, J. A.; Mortison, J. D.; O’Neill, D. J.; Mowery, B.; Puranen, A.;
Helquist, P. J. Org. Chem. 2004, 69, 2809–2815.
1
N
H
10N
H
NMe2
H
NMe2
H
N
no hydrogen bond
O
O
CF3
CF3
COCF3
8a
COCF3
10
3. (a) Kumar, R. S.; Arunachalam, S. Polyhedron 2007, 26, 3255–3262; (b) Liu, J.;
Zheng, W.; Shi, S.; Tan, C.; Chen, J.; Zheng, K.; Ji, L. J. Inorg. Biochem. 2008, 102,
193–202; (c) Efthimiadou, E. K.; Katsarou, M. E.; Karaliota, A.; Psomas, G. J.
Inorg. Biochem. 2008, 102, 910–920; (d) Mei, W.-J.; Wang, N.; Liu, Y.-J.; Ma, Y.-
Z.; Wang, D.-Y.; Liang, B.-X. Trans. Met. Chem. 2008, 33, 499–503.
Figure 1.
4. (a) Altman, R. A.; Buchwald, S. L. Org. Lett. 2006, 8, 2779–2782; (b) Durand, J.;
Gladiali, S.; Erre, G.; Zangrando, E.; Milani, B. Organometallics 2007, 26, 810–
818; (c) Glazer, E. C.; Magde, D.; Tor, Y. J. Am. Chem. Soc. 2007, 129, 8544–8551;
(d) Mo, W.; Liu, H.; Xiong, H.; Li, M.; Li, G. Appl. Catal. A 2007, 333, 172–176; (e)
Yu, X.; Lin, H.; Caia, Z.; Lin, H. Tetrahedron Lett. 2007, 48, 8615–8618.
5. Tzalis, D.; Knochel, P. Tetrahedron Lett. 1999, 40, 3685–3688.
6. (a) Chelucci, G.; Thummel, R. P. Chem. Rev. 2002, 102, 3129–3170; (b) Chelucci,
G.; Loriga, G.; Murineddub, G.; Pinnab, G. A. Tetrahedron Lett. 2003, 43,
3601–3604; (c) Elke, S. Eur. J. Org. Chem. 2003, 1145–1152; (d) Sheen, W.-S.;
Gau, H.-M. Inorg. Chim. Acta 2004, 357, 2279–2284; (e) Chelucci, G.; Muroni, D.;
Manca, I. J. Mol. Catal. A 2005, 225, 11–14; (f) Roelfes, G.; Boersma, A. J.; Feringa,
B. L. Chem. Commun. 2006, 635–637.
7. (a) Liu, Y.-J.; Guan, X.-Y.; Wei, X.-Y.; He, L.-X.; Mei, W.-J.; Yao, J.-H. Trans. Met.
Chem. 2008, 33, 289–294; (b) Kumar, R. S.; Arunachalam, S.; Periasamy, V. S.;
Preethy, C. P.; Riyasdeen, A.; Akbarsha, M. A. Polyhedron 2008, 27, 1111–1120;
(c) Rao, R.; Patra, A. K.; Chetana, P. R. Polyhedron 2008, 27, 1343–1352; (d) Gao,
F.; Chao, H.; Weia, Y.-F.; Yuana, Y.-X.; Penga, B.; Chena, X.; Zhenga, K.-C.; Ji,
L.-N. Helv. Chim. Acta 2008, 91, 395–410.
8. (a) Hojo, M.; Masuda, R.; Okada, E. Tetrahedron Lett. 1987, 28, 6199–6200; (b)
Hojo, M.; Masuda, R.; Okada, E.; Miya, H. Synthesis 1989, 870–873.
9. (a) Okada, E.; Tsukushi, N. Synlett 1999, 210–212; (b) Okada, E.; Tsukushi, N.;
Shimomura, N. Synthesis 2000, 237–242.
unstable. This is a great difference in reactivity between the 8-
quinoline system 7 and the naphthalene one 5, as in the naphtha-
lene system this type of intermediate, for example, 10 was not iso-
lated and also not detected (Fig. 1).12 Probably, it is thought that in
8a–c, the additional hydrogen bond between H-1 and N-10, which
cannot exist in the naphthalene system 10, has contributed to the
stability of 8a–c, namely, has interrupted the dehydration accom-
panied by aromatization. We attempted the NMR experiment,
where 8a was solved in DMSO-d6 as a solvent to disfavor the
hydrogen bond between H-1 and N-10, allowed to stand at 33 °C,
and the reaction progress was monitored by 1H NMR. It was found
that 8a is gradually converted to 9a under the above-described
conditions as follows: conversion/standing time; 38%/3 days;
100%/7 days. It is thought that this result supports our speculation
on stabilization of the intermediates 8a–c by the intramolecular
hydrogen bond.
10. Okada, E.; Tsukushi, N.; Otsuki, Y.; Nishiyama, S.; Fukuda, T. Synlett 1999, 126–
128 and references cited therein.
In summary, we have demonstrated a simple and efficient ac-
cess to CF3-containing 1,10-phenanthrolines 9, which are not easily
obtained by other methods, via the pyridine-ring formation reac-
tion of N-propargyl-8-quinolylamine derivative 7 with amines.
Moreover, we succeeded in the isolation of the intermediates,
1,4-dihydro-1,10-phenanthrolin-4-ols 8a–c. Our literature search
did not reveal any previous reports on the isolation of 1,4-dihy-
dro-1,10-phenanthrolin-4-ols.
11. Okada, E.; Tsukushi, N.; Shimomura, N. Synthesis 2000, 1822–1824 and
references cited therein.
12. Okada, E.; Tone, H.; Tsukushi, N.; Otsuki, Y.; Takeuchi, H.; Hojo, M. Heterocycles
1997, 45, 339–346.
13. A typical procedure for the synthesis of 1,4-dihydro-1,10-phenanthrolin-4-ols 8a–
c: To a solution of 7 (187 mg, 0.5 mmol) in CH3CN (5 mL) was added aqueous
solution (50%) of dimethylamine (51 mg, 0.56 mmol), and the mixture was
stirred at room temperature for 2 h. Evaporation of the solvent in vacuo gave
practically pure 8a (205 mg, 98%); mp 123–124 °C (dec) (n-hexane/AcOEt); 1H
NMR (500 MHz, CDCl3): d 9.48 (dd, 1H, J = 1.5, 8.5 Hz, H-7), 8.88 (br d, 1H,
J = 4.0 Hz, NH), 8.81 (dd, 1H, J = 1.5, 4.0 Hz, H-9), 8.72 (s, 1H, H-5), 7.62 (dd, 1H,
J = 4.0, 8.5 Hz, H-8), 7.76–7.28 (br, 1H, OH), 6.72 (d, 1H, J = 4.0 Hz, H-2), 3.99 (d,
1H, Jgem = 13.0 Hz, CH2), 2.82 (d, 1H, Jgem = 13.0 Hz, CH2), 2.31 (s, 6H, N(CH3)2);
IR (KBr, cmꢀ1): 3402, 3094, 1697, 1676; Anal. Calcd for C18H15F6N3O2: C, 51.56;
H, 3.61; N, 10.02. Found: C, 51.63; H, 3.32; N, 9.89.
Acknowledgments
We would like to thank the Japan Society for the Promotion of
Science (JSPS), and the Centre National de la Recherche Scientifique
(CNRS) for support of this research, the Direction des Relations
Internationales (DRI) of the CNRS for travel funds (M.M.) and JSPS
for a research fellowship (M.M.).
14. A typical procedure for the synthesis of 1,10-phenanthrolines 9a–c from 1,4-
dihydro-1,10-phenanthrolin-4-ols 8a–c: A solution of 8a (210 mg, 0.5 mmol) in
CF3CO2H (2 mL) was stirred at reflux temperature for 30 min. The mixture was
washed with saturated solution of Na2CO3, extracted with AcOEt, and dried
over Na2SO4. The solvent was evaporated in vacuo, and the crude product was
purified by recrystallization from n-hexane and AcOEt to give 9a (130 mg,
62%); mp 161–162 °C (n-hexane/AcOEt); 1H NMR (500 MHz, CD3CN): d 9.38 (d,
1H, J = 8.5 Hz, H-7), 9.30 (s, 1H, H-2), 9.12 (d, 1H, J = 4.0 Hz, H-9), 8.79 (s, 1H, H-
5), 7.95 (br s, 2H, OH), 7.74 (dd, 1H, J = 4.0, 8.5 Hz, H-8), 3.88 (s, 2H, CH2), 2.28
(s, 6H, N(CH3)2); IR (KBr, cmꢀ1): 3352, 3115; Anal. Calcd for C18H15F6N3O2: C,
51.56; H, 3.61; N, 10.02. Found: C, 51.83; H, 3.85; N, 9.75.
References and notes
1. (a) Filler, R.; Kobayashi, Y. Biomedicinal Aspects of Fluorine Chemistry; Kodansha
& Elsevier Biomedical: Tokyo, 1982; pp 1–240; (b) Welch, J. T. Tetrahedron
1987, 43, 3123–3197; (c) Filler, R.; Kobayashi, Y.; Yagupolskii, L. M.
Organofluorine Compounds in Medicinal Chemistry and Biomedical Applications;
Elsevier: Amsterdam, 1993; pp 1–380; (d) Burger, K.; Wucherpfennig, U.;
Brunner, E. Adv. Heterocycl. Chem. 1994, 60, 1–64.
15. A typical procedure for the one-pot synthesis of 1,10-phenanthrolines 9d–f from N-
propargyl-5,7-bis(trifluoroacetyl)-8-quinolylamine 7: To a solution of 7 (187 mg,
0.5 mmol) in CH3CN (5 mL) were added p-anisidine (65 mg, 0.53 mmol) and
triethylamine (25 mg, 0.25 mmol), and the mixture was stirred at room
temperature for 4 h. Without work-up, to the reaction mixture was added
CF3CO2H (0.19 mL, 2.6 mmol), and then it was further stirred for 5 min at room
temperature. The mixture was washed with saturated solution of Na2CO3,
extracted with AcOEt, and dried over Na2SO4. Evaporation of the solvent gave a
2. (a) Katritzky, A. R.; Long, Q.-H.; Malhotra, N.; Ramanarayanan, T. A.; Vedage, H.
Synthesis 1992, 911–913; (b) Riesgo, E. C.; Jin, X.; Thummel, R. P. J. Org. Chem.

7164
D. Shibata et al. / Tetrahedron Letters 49 (2008) 7161–7164
crude mixture which was subjected to column chromatography on silica gel
OH), 7.66 (dd, 1H, J = 4.0, 9.0 Hz, H-8), 6.72 (d, 2H, J = 8.5 Hz, Harom), 6.60 (d, 2H,
J = 8.5 Hz, Harom), 4.90–4.68 (br, 1H, NH), 4.81 (s, 2H, CH2), 3.70 (s, 3H, OCH3);
IR (KBr, cmꢀ1): 3415, 3363, 3115; Anal. Calcd for C23H17F6N3O3: C, 55.54; H,
3.44; N, 8.45. Found: C, 55.75; H, 3.47; N, 8.23.
eluting with n-hexane/AcOEt (1:1) to give 9e (127 mg, 51%); mp 136–137 °C
(dec) (n-hexane/AcOEt); 1H NMR (500 MHz, CDCl3): d 9.44 (d, 1H, J = 9.0 Hz, H-
7), 9.41 (s, 1H, H-2), 9.15 (d, 1H, J = 4.0 Hz, H-9), 8.88 (s, 1H, H-5), 7.68 (br s, 2H,