A facile synthetic method for fluorine-containing 1,7-phenanthrolines: Pyridine-ring formation reaction of n-propargyl-6,8-bis(trifluoroacetyl)- quinolin-5-amine with various nucleophiles

Article abstract of DOI:10.1055/s-0029-1216893

Novel fluorine-containing 1,7-phenanthrolines with a variety of substituents at the 3-position were easily synthesized in moderate to high yields by the pyridine-ring formation reaction of N-propargyl-6,8- bis(trifluoroacetyl)quinolin-5-amine with various

Full text of DOI:10.1055/s-0029-1216893

PAPER
3039
A Facile Synthetic Method for Fluorine-Containing 1,7-Phenanthrolines:
Pyridine-Ring Formation Reaction of N-Propargyl-6,8-bis(trifluoroacetyl)-
quinolin-5-amine with Various Nucleophiles
S
ynthetic Method
a
for Fluorin
i
S
1, 7-Phenanthr
h
olines ibata,a Etsuji Okada,*b Mamoru Hinoshita,b Maurice Médebiellec
a
Graduate School of Science and Technology, Kobe University, Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan
Department of Chemical Science and Engineering, Graduate School of Engineering, Kobe University,
Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan
b
Fax +81(78)8036194; E-mail: okaetsu@kobe-u.ac.jp
c
Université de Lyon, Institut de Chimie et Biochimie Moléculaires et Supramoléculaires (ICBMS),
Université Claude Bernard Lyon 1 (UCBL), Laboratoire de Synthèse de Biomolécules (LSB),
UMR 5246 CNRS-UCBL-INSA Lyon-CPE Lyon, 43 Bd du 11 Novembre 1918, 69622 Villeurbanne, France
Received 25 March 2009; revised 30 April 2009
bis(trifluoroacetyl)quinolin-8-amine (2)10 react easily
with various amines, thiols, and alcohols under mild con-
ditions to afford the corresponding N–N-, N–S-, and N–
O-exchanged products 3 and 4, respectively, in excellent
yields (Scheme 1). Moreover, we succeeded in extending
this type of aromatic nucleophilic substitution to the sim-
ple syntheses of various trifluoromethyl-containing het-
erocycles with naphthalene11 and quinoline12 skeletons.
During the course of our studies, we have recently re-
vealed that propargylamino derivatives 5 and 6, which
were readily prepared through a dimethylamino–propar-
gylamino exchange reaction, undergo the pyridine-ring
formation reaction with N-, S-, and O-nucleophiles
to give the corresponding novel fluorine-containing
benzo[h]quinolines 713 and 1,10-phenanthrolines 814
(Scheme 2).
Abstract: Novel fluorine-containing 1,7-phenanthrolines with a
variety of substituents at the 3-position were easily synthesized in
moderate to high yields by the pyridine-ring formation reaction of
N-propargyl-6,8-bis(trifluoroacetyl)quinolin-5-amine with various
amines, thiols, alcohols, and phenols.
Key words: 1,7-phenanthrolines, fluorine, pyridine-ring forma-
tion, propargylamines, 5-quinolines
1,7-Phenanthrolines constitute an interesting class of het-
erocyclic compounds because of their biological proper-
ties. For example, they have demonstrated potential
applications as topoisomerase I inhibitors with cytotoxic
properties towards L1210 murine leukemia cells,1 antima-
larials,2 and telomerase inhibitors.3 Besides, their applica-
tion in host–guest chemistry has also been demonstrated.4
1,7-Phenanthroline skeletons are usually elaborated by a
similar method of quinoline synthesis, for instance Skraup
and Friedländer syntheses. There are three main types of
synthetic approaches. One of the routes uses phenylene-
1,3-diamine as the starting material and thus allows the
construction of two pyridine rings at the same time.5 The
other routes start from quinolin-5-amine1,2a,6 and quinolin-
7-amine.7
NMe2
Nu
X
COCF3
X
COCF3
NuH
Nu = NR1R2, SR, OR
COCF3
COCF3
1 X = CH
2 X = N
3 X = CH
4 X = N
Scheme 1
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
and for their potential use in medicinal and agricultural
scientific fields.8 Fluorinated 1,7-phenanthroline deriva-
tives are scarce, and therefore it is of synthetic value to de-
velop convenient and mild approaches for the synthesis of
fluorine-containing 1,7-phenanthrolines, which would be
expected to exhibit new activities or functionalities.
HN
X
N
Nu
CF3
COCF3
X
NuH
Nu = NR1R2, SR, OR
COCF3
COCF3
5 X = CH
6 X = N
7 X = CH
8 X = N
Scheme 2
So far, we have found that N,N-dimethyl-2,4-bis(trifluo-
roacetyl)naphthalen-1-amine (1)9 and N,N-dimethyl-5,7-
In connection with this work, we now wish to present a
facile synthetic method for novel fluorine-containing 1,7-
phenanthrolines 10–13, which are not easily accessible by
other methods and are greatly expected to show interest-
ing biological activities, by the pyridine-ring formation
reaction of N-propargyl-6,8-bis(trifluoroacetyl)quinolin-
SYNTHESIS 2009, No. 18, pp 3039–3046
x
x.
x
x
.
2
0
0
9
Advanced online publication: 10.07.2009
DOI: 10.1055/s-0029-1216893; Art ID: F06509SS
© Georg Thieme Verlag Stuttgart · New York

3040
D. Shibata et al.
PAPER
5-amine (9) with various nucleophiles (Scheme 3). The was performed, N-benzyl-6,8-bis(trifluoroacetyl)quino-
results of this study make it possible to clarify the differ- lin-5-amine was obtained by propargylamino–benzylami-
ences in reactivities of the naphthalene,13 8-quinoline,14 no exchange at the 5-position of 9. Interestingly, it was
and 5-quinoline systems, which are caused by the differ- found that the addition of triethylamine (5 equiv) prevents
ent effects of the benzene and pyridine rings in the three the amine–amine exchange reaction, and the desired pyri-
kinds of substrates (5,13 6,14 and 9).
dine-ring formation reaction proceeds selectively to af-
ford the corresponding 10g in 82% yield (entry 7). In the
presence of triethylamine, less nucleophilic aromatic
amines (p-anisidine, p-toluidine, aniline, and p-chloro-
aniline) reacted similarly and cleanly to provide 3-[(aryl-
amino)methyl]-1,7-phenanthrolines 10h–k in 63–82%
yield (entries 8–11). The 6-trifluoroacetyl group of 1,7-
phenanthrolines 10 was found to exist in the hydrate form,
a phenomenon also observed in the case of 1,10-phenan-
throlines 8,14 but not in the case of benzo[h]quinolines 7.13
1
HN
N
Nu
CF3
5
COCF3
NuH
51–94%
N
1
N
7
COCF3
C(OH)2CF3
10a–k Nu = NR1R2
11a–h Nu = SR3
12a–k Nu = OR4
13 Nu = OH
9
In addition, the present cyclization reaction was applied to
thiols (Scheme 3, Table 2). Reactions of 9 with aliphatic
thiols such as ethanethiol, butane-1-thiol, 2-methylpro-
pane-2-thiol, and phenylmethanethiol took place at 50 °C
in acetonitrile within four to eight hours in the presence of
triethylamine as a base to afford the desired 3-[(alkylsul-
fanyl)methyl]-1,7-phenanthrolines 11a–d in about 70%
yield (entries 1–4). Aromatic thiols such as p-substituted
benzenethiols also easily underwent the pyridine-ring for-
mation reaction under almost the same mild conditions as
in the case of aliphatic thiols to give the corresponding 3-
[(arylsulfanyl)methyl]-1,7-phenanthrolines 11e–h in 65–
82% yield (entries 5–8).
Scheme 3
The requisite starting material 9 was easily prepared in
moderate yields by a dimethylamino–propargylamino ex-
change reaction of N,N-dimethyl-6,8-bis(trifluoro-
acetyl)quinolin-5-amine, which was prepared by
bis(trifluoroacetylation) of N,N-dimethylquinolin-5-
amine,15,16 with propargylamine.
The reaction of 9 with various amines was initially exam-
ined (Scheme 3), and the results are summarized in
Table 1. The cyclization of 9 with dimethylamine pro-
ceeded rapidly at 50 °C in acetonitrile to give the corre-
sponding fluorine-containing 1,7-phenanthrolines 10a in
94% yield (entry 1). Secondary and primary aliphatic
amines such as diethylamine, pyrrolidine, piperidine, iso-
propylamine, and tert-butylamine also reacted cleanly to
provide the desired phenanthrolines 10b–f in 68–89%
yield (entries 2–6). When the reaction with benzylamine
We also attempted to accomplish the ring formation reac-
tions of 9 with alcohols and phenols to obtain fluorine-
containing 1,7-phenanthrolines with alkoxymethyl or
(aryloxy)methyl substituents at the 3-position (Scheme 3,
Table 3). The cyclization reactions with methyl, ethyl, n-
butyl, allyl, and propargyl alcohols occurred as expected
to give the corresponding 1,7-phenanthrolines 12a–c, 12e,
Table 1 Pyridine-Ring Formation Reactions of 9 with Amines (R1R2NH) in Acetonitrilea
Entry
1c
2
R1
R2
Me
Et
Base (equiv)
none
Temp ( °C)
Time (h)
Product
10a
10b
10c
Yieldb (%)
Me
50
2
2
94
76
68
89
74
73
82
82
66
63
63
Et
none
50
3
(CH2)4
(CH2)5
i-Pr
none
50
1
4
none
50
1
10d
10e
5
H
H
H
H
H
H
H
none
50
16
4
6
t-Bu
none
50
10f
7
Bn
Et3N (5)
Et3N (1.5)
Et3N (1.5)
Et3N (1.5)
Et3N (1.5)
reflux
50
2
10g
10h
10i
8
4-MeOC6H4
4-MeC6H4
Ph
2
9
50
2
10
11
50
4
10j
4-ClC6H4
50
4
10k
a Molar ratio 9/R1R2NH = 1:3.
b Isolated yields.
c A 50% aq soln of Me2NH was used.
Synthesis 2009, No. 18, 3039–3046 © Thieme Stuttgart · New York

PAPER
Synthetic Method for Fluorine-Containing 1,7-Phenanthrolines
3041
Table 2 Pyridine-Ring Formation Reaction of 9 with Thiols (R3SH)
in the Presence of Triethylamine at 50 °C in Acetonitrile
conversion, and (p-nitrophenoxy)methyl derivative 12k
was obtained in 51% yield together with hydroxymethyl
derivative 13 in 19% yield (entry 11). Interestingly, in-
creasing the amount (5 equiv) of p-nitrophenol inhibited
the formation of 13, and 12k was obtained exclusively in
67% yield (entry 12).
Entry R3
Thiol, Et3N Time
Product Yielda
(%)
(equiv)
1.2
1.2
1.2
3
(h)
1
2
3
4
5
6
7
8
Et
4
11a
11b
11c
11d
11e
11f
72
74
72
72
76
65
82
75
Two possible mechanistic pathways (paths A and B) for
the formation of 1,7-phenanthrolines 10 are depicted in
Scheme 4. In path A, the addition of amines as nucleo-
philes to the terminal acetylenic carbon and the attack of
the carbonyl carbon at the internal acetylenic carbon occur
concertedly to give a cyclization product with an exo-
methylene moiety. Subsequent 1,3-shift of the allylic hy-
drogen takes place to afford the intermediate 1,4-dihydro-
1,7-phenanthrolin-4-ol 14, which undergoes dehydration
to give 1,7-phenanthroline 10. In path B, the tautomeriza-
tion of the keto to the enol form causes the isomerization
of the propargyl to an allenyl group, and subsequent in-
tramolecular cyclization gives a 3-methylene-1,7-phenan-
throline derivative. This product then reacts with amines
to give 14, leading to 10. More studies are underway to
elucidate the mechanism more clearly.
n-Bu
4
t-Bu
4
Bn
8
4-MeOC6H4
4-MeC6H4
Ph
1.2
1.2
1.2
1.2
2
2
2
11g
11h
4-ClC6H4
8
a Isolated yields.
and 12f in 51–65% yield (entries 1–3, 5, and 6). It was in-
teresting to find that the reaction of 9 with potassium tert-
butoxide in tetrahydrofuran led to the novel 1,7-phenan-
throlin-3-ylmethanol 13 (Nu = OH in Scheme 3) in 39%
yield instead of 12d (Table 3, entry 4). A tentative expla-
nation for the formation of 13 is that the hydrolysis of 12d
occurred immediately in situ due to the presence of a good
leaving group. The reactions with phenols such as p-meth-
oxyphenol, p-cresol, phenol, and p-chlorophenol went to
completion within two hours in the presence of triethyl-
amine as a base in acetonitrile to afford the corresponding
3-[(aryloxy)methyl]-1,7-phenanthrolines 12g–j in 53–
71% yield (entries 7–10). In the case of p-nitrophenol, a
prolonged reaction time (24 h) was required for complete
As depicted in Figure 1, it is noteworthy that we succeed-
ed in isolating the 1,4-dihydro-1,10-phenanthrolines 15,
which are the precursors of the stable aromatized final
products 1,10-phenanthrolines
8
(Nu = NR1R2 in
Scheme 2), and which seem to be stable.14 However, in
both the quinolin-5-amine and naphthalenamine systems,
this type of intermediate (14 and 16, Figure 1) was not iso-
lated and also not detected. Probably, it is reasonable to
postulate that in 15 the additional hydrogen bond between
H1 and N10, which cannot exist in the quinolin-5-amine
and naphthalenamine systems (14 and 16), has contribut-
Table 3 Pyridine-Ring Formation Reaction of 9 with Alcohols and Phenols (R4OH) at 50 °C
Entry
1
R4
R4OH (equiv)
Additive (equiv) Time (h)
Solvent
MeOH
Product
12a
Yielda (%)
Me
excess
Na (1)
8
2
56
2
Et
excess
Na (1)
EtOH
12b
65
3
n-Bu
excess
Na (1)
1
n-BuOH
THF
12c
56
4
t-Bub
1
none
2
12d/13
12e
0/39
62
5
CH2CH=CH2
CH2C≡CH
4-MeOC6H4
4-MeC6H4
Ph
excess
Na (3)
1
H2C=CHCH2OH
HC≡CCH2OH
MeCN
6
excess
Na (3)
1
12f
51
7
3
3
3
3
3
5
Et3N (1.5)
Et3N (1.5)
Et3N (1.5)
Et3N (1.5)
Et3N (1.5)
Et3N (1.5)
2
12g
62
8
2
MeCN
12h
71
9
2
MeCN
12i
53
10
11
12
4-ClC6H4
4-O2NC6H4
4-O2NC6H4
2
MeCN
12j
69
24
24
MeCN
12k/13
12k
51/19c
67
MeCN
a Isolated yields.
b t-BuOK was used.
c Not isolated. Determined by 1H NMR.
Synthesis 2009, No. 18, 3039–3046 © Thieme Stuttgart · New York

3042
D. Shibata et al.
PAPER
H
path A
NR1R2
N
HN
NR1R2
H
N
NR1R2
OH
CF3
R1R2NH
– H2O
1,3-H shift
O
CF3
CF3
9
N
N
N
COCF3
COCF3
C(OH)2CF3
14
10
path B
R1R2NH
H
H
O
H
H
C
H
C
H
H
H
NH
O
H
NH
N
C
H
NH
O
OH
CF3
CF3
CF3
CF3
N
N
N
N
COCF3
COCF3
COCF3
COCF3
Scheme 4
1
N-Propargyl-6,8-bis(trifluoroacetyl)quinolin-5-amine (9)
TFAA (1.79 mL, 12.75 mmol) was added dropwise to a stirred soln
of N,N-dimethylquinolin-5-amine (731 mg, 4.25 mmol) and py
(1008 mg, 12.75 mmol) in CHCl3 (4.3 mL) with cooling, and stir-
ring was continued at r.t. for 24 h. The solvent was removed under
reduced pressure, and EtOAc (100 mL) was added to the residue.
The soln was washed with H2O (100 mL) and sat. aq Na2CO3 (100
mL), and then dried (Na2SO4). The solvent was evaporated in vacuo
and the crude product was dehydrated to give N,N-dimethyl-6,8-
bis(trifluoroacetyl)quinolin-5-amine; yield: 1456 mg (94%). Prop-
argylamine (330 mg, 6.0 mmol) was then added to a soln of N,N-
dimethyl-6,8-bis(trifluoroacetyl)quinolin-5-amine (728 mg, 2.0
mmol) in MeCN (16 mL), and the mixture was stirred under reflux
for 2 h. After removal of the solvent, the crude mixture was subject-
ed to column chromatography (silica gel, n-hexane–EtOAc, 4:1, for
9, and n-hexane–EtOAc, 2:1, for 10a).
H
NR1R2
H
N
10 N
O
CF3
COCF3
15
H
NR1R2
H
N
no hydrogen bond
O
CF3
X
COCF3
14 X = N
16 X = CH
Yield (9): 420 mg (56%); yield (10a): 284 mg (34%).
Figure 1
N,N-Dimethyl-6,8-bis(trifluoroacetyl)quinolin-5-amine
Mp 97–98 °C (n-hexane–EtOAc).
IR (KBr): 1696 cm–1.
1H NMR (500 MHz, CDCl3): d = 9.01 (d, J = 4.0 Hz, 1 H, H-2),
8.58 (d, J = 8.5 Hz, 1 H, H-4), 8.19 (s, 1 H, H-7), 7.53 (dd, J = 4.0,
8.5 Hz, 1 H, H-3), 3.14 (s, 6 H, CH3).
13C NMR (126 MHz, CDCl3): d = 184.7 (q, JCF = 36.5 Hz), 181.0
(q, JCF = 35.2 Hz), 158.0, 152.9, 149.6, 134.8, 131.6, 125.8, 125.0,
121.5, 119.3, 116.3 (q, JCF = 291.8 Hz), 116.3 (q, JCF = 290.5 Hz),
45.9.
ed to the stability of 15, namely, has interrupted the dehy-
dration promoted by aromatization.
In summary, we succeeded in developing an efficient syn-
thetic method for trifluoromethyl-containing 1,7-phenan-
throlines 10–13, which are novel and not easily available
by other methods, by pyridine-ring formation reactions of
N-propargylquinolin-5-amine derivative 9 with various
nucleophiles. The methodology presented is quite remark-
able, since no kind of activation of the propargylamine
system was needed to promote addition of the nucleo-
philes and subsequent ring formation. The mechanism of
this reaction is not yet fully established, although two rea-
sonable mechanistic pathways have been presented.
Anal. Calcd for C15H10F6N2O2 (364.1): C, 49.46; H, 2.77; N, 7.69.
Found: C, 49.22; H, 3.02; N, 7.68.
N-Propargyl-6,8-bis(trifluoroacetyl)quinolin-5-amine (9)
Mp 126–127 °C (n-hexane–EtOAc).
IR (KBr): 3302, 3277, 2128, 1653 cm–1.
1H NMR (500 MHz, CDCl3): d = 10.81 (br s, 1 H, NH), 9.03 (d,
J = 4.0 Hz, 1 H, H-2), 8.76 (d, J = 8.5 Hz, 1 H, H-4), 8.40 (s, 1 H,
H-7), 7.49 (dd, J = 4.0, 8.5 Hz, 1 H, H-3), 4.56 (dd, J = 2.0, 6.0 Hz,
2 H, CH2), 2.58 (br s, 1 H, C≡CH).
13C NMR (126 MHz, CDCl3): d = 183.2 (q, JCF = 37.7 Hz), 180.4
(q, JCF = 40.2 Hz), 158.8, 154.0, 150.7, 135.4, 134.4, 121.7, 120.6,
118.5, 117.0 (q, JCF = 290.5 Hz), 116.4 (q, JCF = 291.8 Hz), 106.9,
78.0, 75.2, 38.8.
Melting points were determined on an electrothermal digital melt-
ing point apparatus and are uncorrected. NMR spectra were ob-
tained on a Bruker Avance 500 spectrometer (1H at 500 MHz, 13
C
at 126 MHz) and a Jeol PMX-60SI spectrometer (1H at 60 MHz);
TMS was used as an internal standard. IR spectra were recorded on
a PerkinElmer Spectrum ONE spectrophotometer. Microanalyses
were obtained with a Yanaco CHN-Coder MT-5 analyzer.
Synthesis 2009, No. 18, 3039–3046 © Thieme Stuttgart · New York

PAPER
Synthetic Method for Fluorine-Containing 1,7-Phenanthrolines
3043
Anal. Calcd for C16H8F6N2O2 (374.1): C, 51.35; H, 2.15; N, 7.49.
Found: C, 51.26; H, 2.46; N, 7.28.
Anal. Calcd for C21H17F6N3O (441.1) (non-monohydrate form): C,
57.15; H, 3.88; N, 9.52. Found: C, 57.54; H, 3.64; N, 9.37.
Pyridine-Ring Formation Reaction of 9 with Amines; General
Procedure
2,2,2-Trifluoro-1-{3-[(isopropylamino)methyl]-4-(trifluoro-
methyl)-1,7-phenanthrolin-6-yl}ethane-1,1-diol (10e)
Mp 122–123 °C (n-hexane–EtOAc).
IR (KBr): 3287, 3025 cm–1.
1H NMR (500 MHz, CDCl3): d (non-monohydrate form) = 9.37 (d,
J = 8.0 Hz, 1 H, H-10), 9.14 (s, 1 H, H-2), 8.97–8.44 (br, 1 H, NH),
8.92 (d, J = 4.5 Hz, 1 H, H-8), 8.68 (s, 1 H, H-5), 7.66 (dd, J = 4.5,
8.0 Hz, 1 H, H-9), 4.19 (br s, 2 H, CH2), 3.01 (hp, J = 6.5 Hz, 1 H,
CH), 1.23 (d, J = 6.5 Hz, 6 H, CH3).
The appropriate amine R1R2NH (3.00 mmol) was added to a soln of
9 (374 mg, 1.00 mmol) in MeCN (10 mL), and the mixture was
stirred at 50 °C or under reflux for 1–16 h. Evaporation of the sol-
vent in vacuo gave a crude mixture, which was subjected to column
chromatography (silica gel, n-hexane–EtOAc, 5:1 to 2:1) to give the
corresponding 10a–k. In the case of BnNH2 and p-substituted
anilines, Et3N (1.50 or 5.00 mmol) was added as a base.
1-{3-[(Dimethylamino)methyl]-4-(trifluoromethyl)-1,7-phenan-
throlin-6-yl}-2,2,2-trifluoroethane-1,1-diol (10a)
Mp 124–125 °C (n-hexane–EtOAc).
Anal. Calcd for C19H17F6N3O2 (433.1): C, 52.66; H, 3.95; N, 9.70.
Found: C, 52.61; H, 3.91; N, 9.84.
IR (KBr): 3038 cm–1.
1-{3-[(tert-Butylamino)methyl]-4-(trifluoromethyl)-1,7-
phenanthrolin-6-yl}-2,2,2-trifluoroethane-1,1-diol (10f)
Mp 140–141 °C (n-hexane–EtOAc).
IR (KBr): 3287, 3027 cm–1.
1H NMR (500 MHz, CD3CN–CDCl3): d (non-monohydrate
form) = 9.61 (dd, J = 1.5, 8.5 Hz, 1 H, H-10), 9.32 (s, 1 H, H-2),
9.04 (dd, J = 1.5, 4.5 Hz, 1 H, H-8), 8.90–8.31 (br, 1 H, NH), 8.75
(s, 1 H, H-5), 7.86 (dd, J = 4.5, 8.5 Hz, 1 H, H-9), 4.18 (br s, 2 H,
CH2), 1.21 (s, 9 H, CH3).
1H NMR (500 MHz, CDCl3): d = 9.56 (d, J = 8.0 Hz, 1 H, H-10),
9.30 (s, 1 H, H-2), 8.84 (s, 1 H, H-5), 8.80 (d, J = 4.5 Hz, 1 H, H-8),
8.73–8.29 (br, 2 H, OH), 7.60 (dd, J = 4.5, 8.0 Hz, 1 H, H-9), 3.90
(br s, 2 H, CH2), 2.35 (s, 6 H, CH3).
13C NMR (126 MHz, CDCl3): d = 154.1, 148.6, 146.0, 145.7, 134.9,
133.3 (q, JCF = 31.4 Hz), 132.4, 131.5, 128.0, 126.7, 124.3 (q,
JCF = 279.2 Hz), 123.3 (q, JCF = 290.5 Hz), 122.2, 120.9, 95.5 (q,
JCF = 32.7 Hz), 59.0, 45.6.
Anal. Calcd for C20H17F6N3O (429.1) (non-monohydrate form): C,
53.69; H, 4.28; N, 9.39. Found: C, 53.72; H, 4.38; N, 9.26.
Anal. Calcd for C18H13F6N3O (401.1) (non-monohydrate form): C,
53.87; H, 3.27; N, 10.47. Found: C, 53.65; H, 3.45; N, 10.51.
1-{3-[(Benzylamino)methyl]-4-(trifluoromethyl)-1,7-phenan-
throlin-6-yl}-2,2,2-trifluoroethane-1,1-diol (10g)
Mp 207–208 °C (dec.) (n-hexane–EtOAc).
IR (KBr): 3348, 3099 cm–1.
1-{3-[(Diethylamino)methyl]-4-(trifluoromethyl)-1,7-phenan-
throlin-6-yl}-2,2,2-trifluoroethane-1,1-diol (10b)
Mp 125–126 °C (n-hexane–EtOAc).
IR (KBr): 3151 cm–1.
1H NMR (60 MHz, CD3CN–CDCl3): d = 8.90 (dd, J = 2.0, 8.0 Hz,
1 H, H-10), 8.78 (s, 1 H, H-2), 8.53 (dd, J = 2.0, 4.0 Hz, 1 H, H-8),
8.40 (q, JHF = 2.0 Hz, 1 H, H-5), 7.43–6.97 (m, 6 H, H-9, Ph), 6.47–
5.82 (br, 3 H, NH, OH), 4.02 (q, JHF = 2.0 Hz, 2 H, CH2), 3.78 (br
s, 2 H, NCH2Ph).
1H NMR (60 MHz, DMSO-d6–CD3CN): d = 9.52 (dd, J = 2.0, 8.0
Hz, 1 H, H-10), 9.40–9.23 (m, 3 H, H-2, OH), 8.93 (dd, J = 2.0, 4.0
Hz, 1 H, H-8), 8.75 (q, JHF = 2.0 Hz, 1 H, H-5), 7.73 (dd, J = 4.0,
8.0 Hz, 1 H, H-9), 3.97 (q, JHF = 2.0 Hz, 2 H, CH2), 2.55 (q, J = 7.0
Hz, 4 H, NCH2CH3), 1.03 (t, J = 7.0 Hz, 6 H, CH3).
Anal. Calcd for C23H17F6N3O2 (463.1): C, 57.39; H, 3.56; N, 8.73.
Found: C, 57.33; H, 3.79; N, 8.56.
Anal. Calcd for C20H19F6N3O2 (447.1): C, 53.69; H, 4.28; N, 9.39.
Found: C, 53.76; H, 4.67; N, 9.03.
2,2,2-Trifluoro-1-(3-{[(4-methoxyphenyl)amino]methyl}-4-(tri-
fluoromethyl)-1,7-phenanthrolin-6-yl)ethane-1,1-diol (10h)
Mp 95–96 °C (n-hexane–EtOAc).
IR (KBr): 3312, 3060 cm–1.
2,2,2-Trifluoro-1-[3-(pyrrolidin-1-ylmethyl)-4-(trifluorometh-
yl)-1,7-phenanthrolin-6-yl]ethane-1,1-diol (10c)
Mp 138–139 °C (n-hexane–EtOAc).
IR (KBr): 3354 cm–1.
1H NMR (500 MHz, CDCl3): d = 9.73 (dd, J = 2.0, 8.5 Hz, 1 H, H-
10), 9.40 (s, 1 H, H-2), 8.96 (dd, J = 2.0, 4.5 Hz, 1 H, H-8), 8.91 (s,
1 H, H-5), 7.84–7.58 (br, 2 H, OH), 7.76 (dd, J = 4.5, 8.5 Hz, 1 H,
H-9), 4.12 (br s, 2 H, CH2), 2.63 (br s, 4 H, NCH2CH2), 1.87–1.81
(m, 4 H, NCH2CH2).
1H NMR (60 MHz, CD3CN–CDCl3):
d (non-monohydrate
form) = 9.13 (dd, J = 2.0, 8.0 Hz, 1 H, H-10), 8.95 (s, 1 H, H-2),
8.67–8.57 (m, 2 H, H-5, H-8), 7.40 (dd, J = 4.0, 8.0 Hz, 1 H, H-9),
6.52 (br s, 4 H, Harom), 6.02–5.08 (br, 1 H, NH), 4.63 (q, JHF = 2.0
Hz, 2 H, CH2), 3.53 (s, 3 H, CH3).
Anal. Calcd for C23H17F6N3O3 (497.1): C, 55.54; H, 3.44; N, 8.45.
Found: C, 55.45; H, 3.59; N, 8.73.
Anal. Calcd for C20H17F6N3O2 (445.1): C, 53.94; H, 3.85; N, 9.44.
Found: C, 53.97; H, 3.99; N, 9.26.
2,2,2-Trifluoro-1-{3-[(p-tolylamino)methyl]-4-(trifluorometh-
yl)-1,7-phenanthrolin-6-yl}ethane-1,1-diol (10i)
Mp 58–59 °C (n-hexane–EtOAc).
IR (KBr): 3398, 3044 cm–1.
2,2,2-Trifluoro-1-[3-(piperidin-1-ylmethyl)-4-(trifluorometh-
yl)-1,7-phenanthrolin-6-yl]ethane-1,1-diol (10d)
Mp 135–136 °C (n-hexane–EtOAc).
IR (KBr): 3164 cm–1.
1H NMR (60 MHz, DMSO-d6–CD3CN): d = 9.58–8.63 (br, 2 H,
OH), 9.42 (dd, J = 2.0, 8.0 Hz, 1 H, H-10), 9.06 (s, 1 H, H-2), 8.84
(dd, J = 2.0, 4.0 Hz, 1 H, H-8), 8.70 (q, JHF = 2.0 Hz, 1 H, H-5), 7.63
(dd, J = 4.0, 8.0 Hz, 1 H, H-9), 6.82 (d, J = 7.0 Hz, 2 H, Harom), 6.41
(d, J = 7.0 Hz, 2 H, Harom), 5.42–5.00 (br, 1 H, NH), 4.74 (q,
JHF = 2.0 Hz, 2 H, CH2), 2.09 (s, 3 H, CH3).
1H NMR (60 MHz, DMSO-d6–CD3CN): d = 9.35 (dd, J = 2.0, 8.0
Hz, 1 H, H-10), 9.20 (br s, 2 H, OH), 9.00 (s, 1 H, H-2), 8.82 (dd,
J = 2.0, 4.0 Hz, 1 H, H-8), 8.62 (q, JHF = 2.0 Hz, 1 H, H-5), 7.62 (dd,
J = 4.0, 8.0 Hz, 1 H, H-9), 3.75 (q, JHF = 2.0 Hz, 2 H, CH2), 2.48–
2.17 (br, 4 H, NCH2CH2), 1.43 (br s, 6 H, NCH2CH2CH2CH2).
Synthesis 2009, No. 18, 3039–3046 © Thieme Stuttgart · New York

3044
D. Shibata et al.
PAPER
Anal. Calcd for C23H17F6N3O2 (481.1): C, 57.39; H, 3.56; N, 8.73.
Found: C, 57.28; H, 3.93; N, 8.47.
Anal. Calcd for C20H18F6N2O2S (464.1): C, 51.72; H, 3.91; N, 6.03.
Found: C, 51.36; H, 4.01; N, 6.08.
2,2,2-Trifluoro-1-{3-[(phenylamino)methyl]-4-(trifluorometh-
yl)-1,7-phenanthrolin-6-yl}ethane-1,1-diol (10j)
Mp 124–125 °C (n-hexane–EtOAc).
1-{3-[(tert-Butylsulfanyl)methyl]-4-(trifluoromethyl)-1,7-
phenanthrolin-6-yl}-2,2,2-trifluoroethane-1,1-diol (11c)
Mp 136–137 °C (n-hexane–EtOAc).
IR (KBr): 3407, 3030 cm–1.
IR (KBr): 3315 cm–1.
1H NMR (60 MHz, DMSO-d6–CD3CN): d = 9.17 (dd, J = 2.0, 8.0
Hz, 1 H, H-10), 9.00 (s, 2 H, OH), 8.87 (s, 1 H, H-2), 8.65 (dd,
J = 2.0, 4.0 Hz, 1 H, H-8), 8.55 (q, JHF = 2.0 Hz, 1 H, H-5), 7.43 (dd,
J = 4.0, 8.0 Hz, 1 H, H-9), 7.03–6.27 (m, 5 H, Ph), 5.52–4.98 (br, 1
H, NH), 4.67 (q, JHF = 2.0 Hz, 2 H, CH2).
1H NMR (500 MHz, CD3CN): d = 9.71 (d, J = 8.0 Hz, 1 H, H-10),
9.19 (s, 1 H, H-2), 9.05 (d, J = 4.5 Hz, 1 H, H-8), 8.78 (s, 1 H, H-5),
8.43 (br s, 2 H, OH), 7.89 (dd, J = 4.5, 8.0 Hz, 1 H, H-9), 4.24 (br s,
2 H, CH2), 1.42 (s, 9 H, CH3).
Anal. Calcd for C20H18F6N2O2S (464.1): C, 51.72; H, 3.91; N, 6.03.
Found: C, 51.77; H, 4.00; N, 6.03.
Anal. Calcd for C22H15F6N3O2 (467.1): C, 56.54; H, 3.23; N, 8.99.
Found: C, 56.83; H, 3.57; N, 8.99.
1-{3-[(Benzylsulfanyl)methyl]-4-(trifluoromethyl)-1,7-phenan-
throlin-6-yl}-2,2,2-trifluoroethane-1,1-diol (11d)
Mp 120–121 °C (n-hexane–EtOAc).
IR (KBr): 3354 cm–1.
1H NMR (500 MHz, CD3CN): d = 9.68 (dd, J = 2.0, 8.5 Hz, 1 H, H-
10), 9.05 (dd, J = 2.0, 4.5 Hz, 1 H, H-8), 8.99 (s, 1 H, H-2), 8.75 (s,
1 H, H-5), 8.45 (br s, 2 H, OH), 7.88 (dd, J = 4.5, 8.5 Hz, 1 H, H-9),
7.30 (d, J = 7.0 Hz, 2 H, Harom), 7.23 (t, J = 7.0 Hz, 2 H, Harom), 7.14
(t, J = 7.0 Hz, 1 H, Harom), 4.16 (br s, 2 H, CH2), 3.84 (s, 2 H,
SCH2Ph).
1-(3-{[(4-Chlorophenyl)amino]methyl}-4-(trifluoromethyl)-
1,7-phenanthrolin-6-yl)-2,2,2-trifluoroethane-1,1-diol (10k)
Mp 105–106 °C (n-hexane–EtOAc).
IR (KBr): 3324, 3088 cm–1.
1H NMR (60 MHz, DMSO-d6–CD3CN): d = 9.75 (dd, J = 2.0, 9.0
Hz, 1 H, H-10), 9.62 (s, 2 H, OH), 9.39 (s, 1 H, H-2), 9.18 (dd,
J = 2.0, 4.0 Hz, 1 H, H-8), 9.03 (q, JHF = 2.0 Hz, 1 H, H-5), 7.96 (dd,
J = 4.0, 9.0 Hz, 1 H, H-9), 7.20 (d, J = 8.0 Hz, 2 H, Harom), 6.77 (d,
J = 8.0 Hz, 2 H, Harom), 6.09 (br t, J = 6.0 Hz, 1 H, NH), 5.03–4.73
(m, 2 H, CH2).
Anal. Calcd for C23H16F6N2O2S (498.1): C, 55.42; H, 3.24; N, 5.62.
Found: C, 55.60; H, 3.20; N, 5.47.
Anal. Calcd for C22H14ClF6N3O2 (501.1): C, 52.66; H, 2.81; N, 8.37.
Found: C, 52.66; H, 3.17; N, 8.01.
2,2,2-Trifluoro-1-(3-{[(4-methoxyphenyl)sulfanyl]methyl}-4-
(trifluoromethyl)-1,7-phenanthrolin-6-yl)ethane-1,1-diol (11e)
Mp 122–123 °C (n-hexane–EtOAc).
IR (KBr): 3357 cm–1.
1H NMR (60 MHz, CD3CN–CDCl3): d = 9.43 (dd, J = 2.0, 8.0 Hz,
1 H, H-10), 9.00 (br s, 2 H, OH), 8.83 (dd, J = 2.0, 4.0 Hz, 1 H, H-
8), 8.66 (q, JHF = 2.0 Hz, 1 H, H-5), 8.52 (s, 1 H, H-2), 7.63 (dd,
J = 4.0, 8.0 Hz, 1 H, H-9), 7.13 (d, J = 9.0 Hz, 2 H, Harom), 6.65 (d,
J = 9.0 Hz, 2 H, Harom), 4.32 (q, JHF = 2.0 Hz, 2 H, CH2), 3.67 (s, 3
H, OCH3).
Pyridine-Ring Formation Reaction of 9 with Thiols; General
Procedure
The appropriate thiol R3SH (1.20 or 3.00 mmol) and Et3N (1.20 or
3.00 mmol) were added to a soln of 9 (374 mg, 1.00 mmol) in
MeCN (10 mL), and the mixture was stirred at 50 °C for 2–8 h.
Evaporation of the solvent in vacuo gave a crude mixture which was
subjected to column chromatography (silica gel, n-hexane–EtOAc,
8:1 to 2:1) to give the corresponding 11a–h.
1-{3-[(Ethylsulfanyl)methyl]-4-(trifluoromethyl)-1,7-phenan-
throlin-6-yl}-2,2,2-trifluoroethane-1,1-diol (11a)
Mp 119–120 °C (n-hexane–EtOAc).
IR (KBr): 3317 cm–1.
1H NMR (500 MHz, CDCl3): d = 9.48 (d, J = 8.0 Hz, 1 H, H-10),
9.07 (s, 1 H, H-2), 8.97–7.82 (br, 2 H, OH), 8.79 (s, 1 H, H-5), 8.76
(d, J = 4.0 Hz, 1 H, H-8), 7.56 (dd, J = 4.0, 8.0 Hz, 1 H, H-9), 4.18
(br s, 2 H, CH2), 2.64 (q, J = 7.5 Hz, 2 H, SCH2CH3), 1.33 (t, J = 7.5
Hz, 3 H, CH3).
13C NMR (126 MHz, CDCl3): d = 154.0, 148.6, 145.8, 145.5, 134.8,
132.7, 133.4 (q, JCF = 30.2 Hz), 131.7, 127.8, 126.6, 124.2 (q,
JCF = 278.0 Hz), 123.2 (q, JCF = 289.3 Hz), 122.3, 121.0, 95.6 (q,
JCF = 34.0 Hz), 32.1, 26.5, 14.4.
Anal. Calcd for C23H16F6N2O3S (514.1): C, 53.70; H, 3.13; N, 5.45.
Found: C, 53.77; H, 3.31; N, 5.21.
2,2,2-Trifluoro-1-{3-[(p-tolylsulfanyl)methyl]-4-(trifluorometh-
yl)-1,7-phenanthrolin-6-yl}ethane-1,1-diol (11f)
Mp 135–136 °C (n-hexane–EtOAc).
IR (KBr): 3354 cm–1.
1H NMR (60 MHz, CD3CN–CDCl3): d = 9.77 (dd, J = 2.0, 9.0 Hz,
1 H, H-10), 9.38–7.88 (br, 2 H, OH), 9.12 (dd, J = 2.0, 5.0 Hz, 1 H,
H-8), 9.00–8.87 (m, 2 H, H-2, H-5), 7.88 (dd, J = 5.0, 9.0 Hz, 1 H,
H-9), 7.45–7.12 (m, 4 H, Harom), 4.55 (q, JHF = 2.0 Hz, 2 H, CH2),
2.33 (s, 3 H, CH3).
Anal. Calcd for C23H16F6N2O2S (498.1): C, 55.42; H, 3.24; N, 5.62.
Found: C, 55.02; H, 3.32; N, 5.93.
Anal. Calcd for C18H14F6N2O2S (436.1): C, 49.54; H, 3.23; N, 6.42.
Found: C, 49.24; H, 3.25; N, 6.71.
2,2,2-Trifluoro-1-{3-[(phenylsulfanyl)methyl]-4-(trifluoro-
methyl)-1,7-phenanthrolin-6-yl}ethane-1,1-diol (11g)
Mp 134–135 °C (n-hexane–EtOAc).
IR (KBr): 3328 cm–1.
1-{3-[(Butylsulfanyl)methyl]-4-(trifluoromethyl)-1,7-phenan-
throlin-6-yl}-2,2,2-trifluoroethane-1,1-diol (11b)
Mp 115–116 °C (n-hexane–EtOAc).
IR (KBr): 3357 cm–1.
1H NMR (500 MHz, CDCl3): d = 9.64 (d, J = 8.5 Hz, 1 H, H-10),
8.94 (d, J = 4.0 Hz, 1 H, H-8), 8.86 (s, 1 H, H-5), 8.81 (s, 1 H, H-2),
7.81–7.58 (br, 2 H, OH), 7.73 (dd, J = 4.0, 8.5 Hz, 1 H, H-9), 7.36–
7.29 (m, 5 H, Harom), 4.50 (br s, 2 H, CH2).
1H NMR (60 MHz, DMSO-d6–CD3CN): d = 9.93–8.83 (br, 2 H,
OH), 9.64 (dd, J = 2.0, 9.0 Hz, 1 H, H-10), 9.15–9.05 (m, 2 H, H-
2, H-8), 8.92 (q, JHF = 2.0 Hz, 1 H, H-5), 7.85 (dd, J = 4.0, 9.0 Hz,
1 H, H-9), 4.20 (q, JHF = 2.0 Hz, 2 H, CH2), 2.62 (br t, J = 7.0 Hz, 2
H, SCH2CH2), 1.72–0.75 (m, 7 H, SCH2CH2CH2CH3).
Anal. Calcd for C22H14F6N2O2S (484.1): C, 54.55; H, 2.91; N, 5.78.
Found: C, 54.33; H, 3.16; N, 5.84.
Synthesis 2009, No. 18, 3039–3046 © Thieme Stuttgart · New York

PAPER
Synthetic Method for Fluorine-Containing 1,7-Phenanthrolines
3045
1-(3-{[(4-Chlorophenyl)sulfanyl]methyl}-4-(trifluoromethyl)-
1,7-phenanthrolin-6-yl)-2,2,2-trifluoroethane-1,1-diol (11h)
Mp 126–127 °C (n-hexane–EtOAc).
1-{3-[(Allyloxy)methyl]-4-(trifluoromethyl)-1,7-phenanthrolin-
6-yl}-2,2,2-trifluoroethane-1,1-diol (12e)
Mp 91–92 °C (n-hexane–EtOAc).
IR (KBr): 3362 cm–1.
IR (KBr): 3333 cm–1.
1H NMR (60 MHz, DMSO-d6–CD3CN): d (non-monohydrate
form) = 9.40 (dd, J = 2.0, 8.0 Hz, 1 H, H-10), 8.92 (dd, J = 2.0, 4.0
Hz, 1 H, H-8), 8.77–8.60 (m, 2 H, H-2, H-5), 7.71 (dd, J = 4.0, 8.0
Hz, 1 H, H-9), 7.20 (s, 4 H, Harom), 4.52 (q, JHF = 2.0 Hz, 2 H, CH2).
1H NMR (500 MHz, CDCl3): d = 9.72 (d, J = 8.5 Hz, 1 H, H-10),
9.43 (s, 1 H, H-2), 8.95 (d, J = 4.5 Hz, 1 H, H-8), 8.87 (s, 1 H, H-5),
7.88–7.62 (br, 2 H, OH), 7.75 (dd, J = 4.5, 8.5 Hz, 1 H, H-9), 6.06–
5.98 (m, 1 H, CH2CH=CH2), 5.41 (d, J = 17.0 Hz, 1 H, CH=CH2),
5.30 (d, J = 10.0 Hz, 1 H, CH=CH2), 5.00 (br s, 2 H, CH2), 4.22 (d,
J = 5.5 Hz, 2 H, OCH2CH=CH2).
Anal. Calcd for C22H13ClF6N2O2S (518.0): C, 50.93; H, 2.53; N,
5.40. Found: C, 50.63; H, 2.69; N, 5.54.
Anal. Calcd for C19H14F6N2O3 (432.1): C, 52.79; H, 3.26; N, 6.48.
Found: C, 53.19; H, 3.01; N, 6.33.
Pyridine-Ring Formation Reaction of 9 with Alcohols; General
Procedure
Compound 9 (374 mg, 1.00 mmol) was added to a soln of alcohol
R4OH (10 mL) containing Na (1.20 or 3.00 mmol), and the mixture
was stirred at 50 °C for 1–8 h. The mixture was washed with 1.0 N
aq HCl (20 mL), extracted with EtOAc (80 mL), and dried
(Na2SO4). Evaporation of the solvent in vacuo gave a crude mixture,
which was subjected to column chromatography (silica gel, n-hex-
ane–EtOAc, 13:1 to 2:1); this gave the corresponding 12a–c,e,f.
2,2,2-Trifluoro-1-{3-[(prop-2-ynyloxy)methyl]-4-(trifluoro-
methyl)-1,7-phenanthrolin-6-yl}ethane-1,1-diol (12f)
Mp 106–107 °C (n-hexane–EtOAc).
IR (KBr): 3311, 2121 cm–1.
1H NMR (60 MHz, CD3CN): d = 9.57 (dd, J = 2.0, 8.0 Hz, 1 H, H-
10), 9.34 (s, 1 H, H-2), 9.02 (dd, J = 2.0, 4.0 Hz, 1 H, H-8), 8.82 (q,
JHF = 2.0 Hz, 1 H, H-5), 8.61 (br s, 2 H, OH), 7.80 (dd, J = 4.0, 8.0
Hz, 1 H, H-9), 5.08 (q, JHF = 2.0 Hz, 2 H, CH2), 4.45 (d, J = 2.0 Hz,
2 H, OCH2C≡CH), 2.87 (t, J = 2.0 Hz, 1 H, CH).
2,2,2-Trifluoro-1-[3-(methoxymethyl)-4-(trifluoromethyl)-1,7-
phenanthrolin-6-yl]ethane-1,1-diol (12a)
Mp 113–114 °C (n-hexane–EtOAc).
IR (KBr): 3239 cm–1.
Anal. Calcd for C19H12F6N2O3 (430.1): C, 53.03; H, 2.81; N, 6.51.
Found: C, 53.11; H, 3.12; N, 6.11.
1H NMR (60 MHz, DMSO-d6–CD3CN): d = 9.45–8.50 (br, 2 H,
OH), 9.27 (dd, J = 2.0, 8.0 Hz, 1 H, H-10), 9.01 (s, 1 H, H-2), 8.82
(dd, J = 2.0, 5.0 Hz, 1 H, H-8), 8.63 (br s, 1 H, H-5), 7.57 (dd,
J = 5.0, 8.0 Hz, 1 H, H-9), 4.78 (q, JHF = 2.0 Hz, 2 H, CH2), 3.50 (s,
3 H, CH3).
Pyridine-Ring Formation Reaction of 9 with Potassium
tert-Butoxide
Compound 9 (374 mg, 1.00 mmol) was added to a THF soln (10
mL) of t-BuOK (112 mg, 1.00 mmol), and the mixture was stirred
at 50 °C for 2 h. The mixture was washed with 1.0 N aq HCl (20
mL), extracted with EtOAc (80 mL), and dried (Na2SO4). Evapora-
tion of the solvent in vacuo gave a crude mixture which was subject-
ed to column chromatography (silica gel, n-hexane–EtOAc, 1:1);
this gave 13; yield: 153 mg (39%).
Anal. Calcd for C17H10F6N2O2 (388.1) (non-monohydrate form): C,
52.59; H, 2.60; N, 7.22. Found: C, 52.24; H, 3.00; N, 7.17.
1-[3-(Ethoxymethyl)-4-(trifluoromethyl)-1,7-phenanthrolin-6-
yl]-2,2,2-trifluoroethane-1,1-diol (12b)
Mp 178–179 °C (dec.) (EtOAc).
IR (KBr): 3324 cm–1.
2,2,2-Trifluoro-1-[3-(hydroxymethyl)-4-(trifluoromethyl)-1,7-
phenanthrolin-6-yl]ethane-1,1-diol (13)
Mp 130–131 °C (n-hexane–EtOAc).
IR (KBr): 3384 cm–1.
1H NMR (500 MHz, CD3CN): d = 9.75 (d, J = 8.5 Hz, 1 H, H-10),
9.46 (s, 1 H, H-2), 9.06 (d, J = 4.5 Hz, 1 H, H-8), 8.80 (s, 1 H, H-5),
8.45 (br s, 2 H, OH), 7.90 (dd, J = 4.5, 8.5 Hz, 1 H, H-9), 5.10 (br s,
2 H, CH2), 3.78 (t, J = 6.0 Hz, 1 H, CH2OH).
1H NMR (500 MHz, CDCl3): d = 9.38 (d, 1 H, J = 8.0 Hz, H-10),
9.31 (s, 1 H, H-2), 9.23–7.86 (br, 2 H, OH), 8.71 (br s, 2 H, H-8, H-
5), 7.48 (dd, 1 H, J = 4.0, 8.0 Hz, H-9), 4.95 (br s, 2 H, CH2), 3.75
(q, J = 7.0 Hz, 2 H, OCH2CH3), 1.38 (t, J = 7.0 Hz, 3 H, CH3).
13C NMR (126 MHz, CDCl3): d = 151.7, 148.5, 145.8, 145.8, 134.8,
132.0 (q, JCF = 30.2 Hz), 131.8, 131.6, 127.6, 126.5, 124.2 (q,
JCF = 278.0 Hz), 123.2 (q, JCF = 289.3 Hz), 122.2, 120.4, 95.6 (q,
JCF = 34.0 Hz), 68.1, 67.2, 15.1.
Anal. Calcd for C16H10F6N2O3 (392.1): C, 48.99; H, 2.57; N, 7.14.
Found: C, 49.03; H, 2.49; N, 7.18.
Anal. Calcd for C18H12F6N2O2 (402.1) (non-monohydrate form): C,
53.74; H, 3.01; N, 6.96. Found: C, 53.38; H, 3.04; N, 7.29.
Pyridine-Ring Formation Reaction of 9 with Phenols; General
Procedure
The appropriate phenol R4OH (3.00 or 5.00 mmol) and Et3N (1.50
mmol) were added to a soln of 9 (374 mg, 1.00 mmol) in MeCN (10
mL), and the mixture was stirred at 50 °C for 2 or 24 h. Evaporation
of the solvent in vacuo gave a crude mixture which was purified by
washing with an n-hexane–EtOAc mixture (2:1, 120 mL); this gave
the corresponding 12g–k.
1-[3-(Butoxymethyl)-4-(trifluoromethyl)-1,7-phenanthrolin-6-
yl]-2,2,2-trifluoroethane-1,1-diol (12c)
Mp 109–110 °C (n-hexane–EtOAc).
IR (KBr): 3328 cm–1.
1H NMR (60 MHz, DMSO-d6–CD3CN): d = 9.73 (dd, J = 2.0, 9.0
Hz, 1 H, H-10), 9.50 (s, 2 H, OH), 9.43 (s, 1 H, H-2), 9.18 (dd,
J = 2.0, 5.0 Hz, 1 H, H-8), 8.98 (q, JHF = 2.0 Hz, 1 H, H-5), 7.93 (dd,
J = 5.0, 9.0 Hz, 1 H, H-9), 5.02 (q, JHF = 2.0 Hz, 2 H, CH2), 3.68 (t,
2,2,2-Trifluoro-1-{3-[(4-methoxyphenoxy)methyl]-4-(trifluo-
romethyl)-1,7-phenanthrolin-6-yl}ethane-1,1-diol (12g)
Mp 118–119 °C (n-hexane–EtOAc).
IR (KBr): 3396 cm–1.
J = 6.0 Hz,
2
H, OCH2CH2), 1.78–0.83 (m,
7
H,
OCH2CH2CH2CH3).
1H NMR (500 MHz, CD3CN–CDCl3): d = 9.74 (d, J = 8.5 Hz, 1 H,
H-10), 9.40 (s, 1 H, H-2), 9.00 (d, J = 4.5 Hz, 1 H, H-8), 8.88 (s, 1
H, H-5), 8.13 (br s, 2 H, OH), 7.81 (dd, J = 4.5, 8.5 Hz, 1 H, H-9),
Anal. Calcd for C20H18F6N2O3 (448.1): C, 53.58; H, 4.05; N, 6.25.
Found: C, 53.20; H, 3.80; N, 5.87.
Synthesis 2009, No. 18, 3039–3046 © Thieme Stuttgart · New York

3046
D. Shibata et al.
PAPER
6.98 (d, J = 9.0 Hz, 2 H, Harom), 6.88 (d, J = 9.0 Hz, 2 H, Harom), 5.51
(br s, 2 H, CH2), 3.78 (s, 3 H, CH3).
References
(1) Prado, S.; Michel, S.; Tillequin, F.; Koch, M.; Pfeiffer, B.;
Pierré, A.; Léonce, S.; Colson, P.; Baldeyrou, B.; Lansiauxe,
A.; Bailly, C. Bioorg. Med. Chem. 2004, 12, 3943.
(2) (a) Yapi, A. D.; Mustofa, M.; Valentin, A.; Chavignon, O.;
Teulade, J.-C.; Mallie, M.; Chapat, J.-P.; Blache, Y. Chem.
Pharm. Bull. 2000, 48, 1886. (b) Scheibel, L. W.; Adler, A.
Mol. Pharmacol. 1982, 22, 140.
Anal. Calcd for C23H16F6N2O4 (498.1): C, 55.43; H, 3.24; N, 5.62.
Found: C, 55.74; H, 2.90; N, 5.66.
2,2,2-Trifluoro-1-{3-[(p-tolyloxy)methyl]-4-(trifluoromethyl)-
1,7-phenanthrolin-6-yl}ethane-1,1-diol (12h)
Mp 111–112 °C (n-hexane–EtOAc).
IR (KBr): 3326 cm–1.
(3) (a) Cuesta, J.; Read, M. A.; Neidle, S. Mini Rev. Med. Chem.
2003, 3, 11. (b) Mergny, J.-L.; Lacroix, L.; Teulade-Fichou,
M.-P.; Hounsou, C.; Guittat, L.; Hoarau, M.; Arimondo, P.
B.; Vigneron, J.-P.; Lehn, J.-M.; Riou, J.-F.; Garestier, T.;
Hélène, C. Proc. Natl. Acad. Sci. U.S.A. 2001, 98, 3062.
(4) Pedireddi, V. R. Cryst. Growth Des. 2001, 1, 383.
(5) (a) Zhang, Q.; Chen, Y.; Zheng, Y. Q.; Xia, P.; Xia, Y.;
Yang, Z. Y.; Bastow, K. F.; Morris-Natschke, S. L.; Lee, K.-
H. Bioorg. Med. Chem. 2003, 11, 1031. (b) Mahata, P. K.;
Venkatesh, C.; Kumar, U. K. S.; Ila, H.; Junjappa, H. J. Org.
Chem. 2003, 68, 3966. (c) Graf, G. I.; Hastreiter, D.;
Everson a Silva, L.; Rebelo, R. A.; Montalban, A. G.;
McKillop, A. Tetrahedron 2002, 58, 9095. (d) Bethke, J.;
Margaretha, P. Helv. Chim. Acta 2002, 85, 544. (e)Molock,
F. F.; Boykin, D. W. J. Heterocycl. Chem. 1983, 20, 681.
(6) (a) Kouznetsov, V. V.; Mendez, L. Y. V.; Tibaduiza, B.;
Ochoa, C.; Pereira, D. M.; Ruiz, J. J. N.; Portillo, C. F.;
Serrano, S. M.; Barrio, A. G.; Bahsas, A.; Amaro-Luis, J.
Arch. Pharm. (Weinheim, Ger.) 2004, 337, 127. (b) Jordis,
U.; Sauter, F.; Rudolf, M.; Cai, G. Monatsh. Chem. 1988,
119, 761.
1H NMR (500 MHz, CD3CN): d = 9.73 (d, J = 8.0 Hz, 1 H, H-10),
9.41 (s, 1 H, H-2), 9.07 (d, J = 4.5 Hz, 1 H, H-8), 8.82 (s, 1 H, H-5),
8.45 (br s, 2 H, OH), 7.89 (dd, J = 4.5, 8.0 Hz, 1 H, H-9), 7.15 (d,
J = 8.5 Hz, 2 H, Harom), 6.97 (d, J = 8.5 Hz, 2 H, Harom), 5.54 (br s,
2 H, CH2), 2.28 (s, 3 H, CH3).
Anal. Calcd for C23H16F6N2O3 (482.1): C, 57.27; H, 3.34; N, 5.81.
Found: C, 57.27; H, 3.73; N, 5.93.
2,2,2-Trifluoro-1-[3-(phenoxymethyl)-4-(trifluoromethyl)-1,7-
phenanthrolin-6-yl]ethane-1,1-diol (12i)
Mp 121–122 °C (n-hexane–EtOAc).
IR (KBr): 3313 cm–1.
1H NMR (500 MHz, CD3CN): d = 9.74 (dd, J = 1.5, 8.5 Hz, 1 H, H-
10), 9.43 (s, 1 H, H-2), 9.07 (dd, J = 1.5, 4.5 Hz, 1 H, H-8), 8.83 (s,
1 H, H-5), 8.45 (br s, 2 H, OH), 7.90 (dd, J = 4.5, 8.5 Hz, 1 H, H-9),
7.38–7.34 (m, 2 H, Harom), 7.10–7.02 (m, 3 H, Harom), 5.58 (br s, 2
H, CH2).
Anal. Calcd for C22H14F6N2O3 (468.1): C, 56.42; H, 3.01; N, 5.98.
Found: C, 56.41; H, 3.35; N, 5.62.
(7) (a) Tatibouet, A.; Hancock, R.; Demeunynck, M.; Lhomme,
J. Angew. Chem., Int. Ed. Engl. 1997, 36, 1190.
1-{3-[(4-Chlorophenoxy)methyl]-4-(trifluoromethyl)-1,7-
phenanthrolin-6-yl}-2,2,2-trifluoroethane-1,1-diol (12j)
Mp 153–154 °C (EtOAc).
(b) Nutaitis, C. F.; Smith, K. Org. Prep. Proced. Int. 2007,
39, 611. (c) Jastrzebska-Glapa, M.; Mlochowski, J. Rocz.
Chem. 1976, 50, 987.
(8) (a) Filler, R.; Kobayashi, Y. Biomedicinal Aspects of
Fluorine Chemistry; Kodansha & Elsevier Biomedical:
Tokyo, 1982, 1–240. (b) Welch, J. T. Tetrahedron 1987, 43,
3123. (c) Filler, R.; Kobayashi, Y.; Yagupolskii, L. M.
Organofluorine Compounds in Medicinal Chemistry and
Biomedical Applications; Elsevier: Amsterdam, 1993, 1–
380. (d) Burger, K.; Wucherpfennig, U.; Brunner, E. Adv.
Heterocycl. Chem. 1994, 60, 1.
(9) (a) Hojo, M.; Masuda, R.; Okada, E. Tetrahedron Lett. 1987,
28, 6199. (b) Hojo, M.; Masuda, R.; Okada, E.; Miya, H.
Synthesis 1989, 870.
(10) (a) Okada, E.; Tsukushi, N. Synlett 1999, 210. (b) Okada,
E.; Tsukushi, N.; Shimomura, N. Synthesis 2000, 237.
(11) Okada, E.; Tsukushi, N.; Otsuki, Y.; Nishiyama, S.; Fukuda,
T. Synlett 1999, 126; and references cited therein.
(12) Okada, E.; Tsukushi, N.; Shimomura, N. Synthesis 2000,
1822; and references cited therein.
IR (KBr): 3330 cm–1.
1H NMR (500 MHz, CD3CN): d = 9.75 (d, J = 8.5 Hz, 1 H, H-10),
9.41 (s, 1 H, H-2), 9.08 (d, J = 4.5 Hz, 1 H, H-8), 8.83 (s, 1 H, H-5),
8.45 (br s, 2 H, OH), 7.91 (dd, J = 4.5, 8.5 Hz, 1 H, H-9), 7.35 (d,
J = 8.5 Hz, 2 H, Harom), 7.08 (d, J = 8.5 Hz, 2 H, Harom), 5.56 (br s,
2 H, CH2).
Anal. Calcd for C22H13ClF6N2O3 (502.1): C, 52.55; H, 2.61; N, 5.57.
Found: C, 52.52; H, 2.71; N, 5.56.
2,2,2-Trifluoro-1-{3-[(4-nitrophenoxy)methyl]-4-(trifluoro-
methyl)-1,7-phenanthrolin-6-yl}ethane-1,1-diol (12k)
Mp 221–222 °C (EtOAc).
IR (KBr): 3385 cm–1.
1H NMR (500 MHz, CDCl3): d = 9.77 (d, J = 8.0 Hz, 1 H, H-10),
9.40 (s, 1 H, H-2), 9.03 (d, J = 4.0 Hz, 1 H, H-8), 8.94 (s, 1 H, H-5),
8.29 (d, J = 9.0 Hz, 2 H, Harom), 7.83 (dd, J = 4.0, 8.0 Hz, 1 H, H-9),
7.55 (br s, 2 H, OH), 7.13 (d, J = 9.0 Hz, 2 H, Harom), 5.64 (br s, 2
H, CH2).
(13) Okada, E.; Tone, H.; Tsukushi, N.; Otsuki, Y.; Takeuchi, H.;
Hojo, M. Heterocycles 1997, 45, 339.
(14) Shibata, D.; Okada, E.; Molette, J.; Médebielle, M.
Tetrahedron Lett. 2008, 49, 7161.
(15) Mellor, J. O.; Merriman, G. D. Steroids 1995, 60, 693.
(16) Feller, C.; Renault, J. Bull. Soc. Chim. Fr. 1973, 3, 1112.
Anal. Calcd for C22H13F6N3O5 (513.1): C, 51.47; H, 2.55; N, 8.19.
Found: C, 51.07; H, 2.61; N, 7.95.
Synthesis 2009, No. 18, 3039–3046 © Thieme Stuttgart · New York