Synthesis of gem-difluorinated 1,6-naphthyridine-5,7-diones

Article abstract of DOI:10.1016/j.tet.2012.05.122

A synthetic route toward new 8,8-difluoro-1,6-naphthyridine-5,7-diones, which are of interest as new building blocks in pharmaceutical chemistry, is described. The key steps include a copper-mediated cross-coupling of ethyl bromodifluoroacetate and 2-bromo-3-cyanopyridine, followed by hydrolysis of the nitrile function and subsequent cyclization.

Full text of DOI:10.1016/j.tet.2012.05.122

Tetrahedron 68 (2012) 6941e6947
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of gem-difluorinated 1,6-naphthyridine-5,7-diones
,
Karel Piron a, Sara Kenis a, Guido Verniest a y, Riccardo Surmont a, Jan Willem Thuring b, Peter ten Holte b,
,
Frederik Deroose b, Norbert De Kimpe a
*
a Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium
b Janssen Research and Development, Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340 Beerse, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 17 April 2012
Received in revised form 23 May 2012
Accepted 29 May 2012
Available online 15 June 2012
A synthetic route toward new 8,8-difluoro-1,6-naphthyridine-5,7-diones, which are of interest as new
building blocks in pharmaceutical chemistry, is described. The key steps include a copper-mediated
cross-coupling of ethyl bromodifluoroacetate and 2-bromo-3-cyanopyridine, followed by hydrolysis of
the nitrile function and subsequent cyclization.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
our knowledge, compounds containing the 8,8-difluoro-1,6-
naphthyridine moiety 5 are even unknown in literature. In this
Site-selective fluorination has become an important strategy for
developing new bioactive compounds, which is reflected by the
numerous papers in the area of organofluorine chemistry in the last
decade.1 The intensified research dealing with the synthesis of new
fluorinated organic compounds has resulted in numerous new
commercial applications in pharmaceutical chemistry and agro-
chemistry.2 In particular, heterocycles containing a gem-difluoro-
methylene group in their ring structure or bearing an exocyclic
difluoromethylenated substituent, have been the subject of intense
research for developing new bioactive compounds.3 Due to the
high electronegativity of the fluorine atom, the introduction of
a CF2-group can strongly influence the electronic nature of the
molecule and therefore alter its bioactivity. Furthermore, CF2/CH2
transposition has been recognised as a valuable tool in blocking
metabolic oxidation.4 For example, this strategy of replacing
a methylene by a difluoromethylene group has been successfully
applied to synthesize antifungal agents, such as 1,2,4-triazoles 15
and thrombin inhibitors (e.g., 2, Fig. 1).6 Moreover, several gem-
difluorinated bicyclic heterocycles are known as compounds with
interesting bioactive properties. Isoquinoline-1,3-dione 3 possesses
nitric oxide synthase (NOS) inhibiting activity and is promising for
treating diabetes,7 while compounds 4 are recognised as HSP90
inhibitors, which are useful in the treatment of diseases of the
cardiovascular and central nervous system.8
paper, we describe the successful preparation of 8,8-difluoro-1,6-
naphthyridine-5,7-diones 5 (X, Y: C]O), which are of specific in-
terest in medicinal chemistry.
2. Results and discussion
Among the variety of methods available to introduce a CF2-group
in organic compounds,4 the copper-mediated coupling reaction of
ethyl bromodifluoroacetate and halogenated heteroaromatics is
well-established and has resulted in useful heterocycles bearing an
exocyclic difluoromethylene susbstituent.5,9 In this respect, it was
believed that this strategy could be suitable for synthesizing
new gem-difluorinated bicyclic compounds. In a first attempt to
reach precursors for the construction of the envisaged bicyclic
ring structures, 2-chloro-3-cyanopyridine 6 was stirred in the
presence of copperand ethylbromodifluoroacetatein DMSO at 50 ꢀC
(Scheme 1). After reaction for 15 h, the obtained mixture contained
only 50% of ethyl pyridin-2-yldifluoroacetate 8, which was accom-
panied by starting material and decomposition products of the in
situ generated organocopperreagent. Because the obtained pyridine
8 was isolated from the mixture in a disappointing 12% yield, and
because 2-bromopyridines are known to be more reactive
substrates for the cross-coupling reactions as compared to
2-chloropyridines,9,10 the corresponding 2-bromopyridine 7 was
evaluated as a substrate for the reaction with ethyl bromodi-
fluoroacetate in the presence of copper. 2-Chloropyridine 6 was
treated with bromotrimethylsilane to give 2-bromo-3-
cyanopyridine 7 in excellent yield.11 Subsequently, the copper-
Despite these interesting properties, gem-difluorinated bicyclic
azaheterocycles are scarcely described in literature. To the best of
* Corresponding author. Tel.: þ32 (0) 9 264 59 51; fax: þ32 (0) 9 294 62 43;
mediated cross-coupling of 2-bromo-3-cyanopyridine
7 and
e-mail address: nobert.dekimpe@UGent.be (N. De Kimpe).
y
ethyl bromodifluoroacetate proceeded smoothly, affording ethyl
(3-cyanopyridin-2-yl)difluoroacetate 8 in 83% yield.
Current address: Faculty of Science and Bio-engineering Sciences. Vrije Uni-
versiteit Brussel, Pleinlaan 2, B-1050 Brussels, Belgium.
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.05.122

6942
K. Piron et al. / Tetrahedron 68 (2012) 6941e6947
F
F
HO
O
F
F
Heteroaryl
R
H
N
H
N
H
N
NH2
NH
N
O
N
N
N
O
N
α
2 human -thrombin inhibitor
1 fungicides
F
F
F
F
O
R1
F
F
N
H2N
N
N
Y
N
NH
R1
N
R2
O
X
N
OR2
3
4
5
NOS inhibitor
HSP90 inhibitors
8,8-difluoro-1,6-naphtyridine
moiety (X, Y: CH2 or C=O)
Fig. 1. Examples of gem-difluorinated bioactive compounds.
1.1 equiv CF2BrCOOEt
2.3 equiv Cu
F
F
N
X
N
OEt
DMSO, 50°C, 15 h
O
CN
CN
2 equiv TMSBr
6
7
X = Cl
X = Br (92%)
8 (12% from 6 ,
83% from 7)
Δ
CH3CH2CN, , 70 h
conc. H2SO4
rt, 24 h
a) 1.1 equiv RBr
1.2 equiv NaH
F
F
F
F
N
O
R
N
O
DMF, 60°C, 2 h
10a c
(
- )
N
NH
O
or
O
b) 3 equiv CH2N2
Et2O, rt, 15 h
10d
10a R = Bn (54%)
9 (93%)
10b
R = 4-BrBn (47%)
(
)
10c
R = 4-NO2Bn (50%)
10d R = CH3 (100%)
8 equiv BH3.SMe2
THF, 0°C, 6 h
(R = H)
F
F
8 equiv BH3.SMe2
N
OH
THF, 0°C, 6 h
(R = Bn)
N
R
O
11a R = H (71%)
11b R = Bn (79%)
Scheme 1.
In a next step toward the desired 1,6-naphtyridines, it was
attempted to reduce the nitrile function of pyridine 8 via catalytic
hydrogenation over Pd/C, PtO2 or Raney nickel, via borane re-
duction or via LiAlH4 reduction. Unfortunately, the corresponding
3-aminomethylpyridine could not be obtained. Therefore, it was
decided to hydrolyze the cyano group as an alternative strategy.
Treatment of ethyl (3-cyanopyridin-2-yl)difluoroacetate 8 with an
excess of sulfuric acid at room temperature for 24 h nicely gave rise
N-functionalization. The reaction of 9 with (substituted) benzyl
bromides resulted in new N-substituted imides 10aec in moderate
yields, while treating the N-unsubstituted imide with an ethereal
diazomethane solution afforded the N-methylated derivative 10d
quantitatively.
As fused bicyclic piperidines are known to possess interesting
bioactivities,12 the reduction of both carbonyl functions of the im-
ide moiety of compounds 9 and 10a using borane, LiAlH4 or mon-
ochloroalane (AlH2Cl) was evaluated. In contrast to the complex
reaction mixtures obtained by using LiAlH4 or monochloroalane
(AlH2Cl), the reaction of imides 9 and 10a with 8 equiv of BH3.SMe2
in tetrahydrofuran for 6 h at 0 ꢀC gave rise to stable hemiaminals
11a and 11b. Increasing the temperature or using more equivalents
to 8,8-difluoro-1,6-naphthyridine-5,7(6H,8H)-dione
9 in 93%
yield (100 mg scale). It should be noted that applying this method
on a larger scale (0.50 g), somewhat lower yields of 65e80%
were obtained. Nevertheless, 8,8-difluoro-1,6-naphthyridine-
5,7(6H,8H)-dione 9 could be used as a starting material for further

K. Piron et al. / Tetrahedron 68 (2012) 6941e6947
6943
of the borane reagent in order to obtain full reduction of the car-
bonyl group resulted in decomposition of the product. Indeed, it is
pharmacological activities.17 Although a plethora of reaction
conditions was evaluated in order to obtain the ring-closed
products (e.g., (para)formaldehyde in the presence of HCl, AcOH,
H2SO4, TFA, pyrophosphoric acid or Lewis acids, in a broad range
of solvents, including CH2Cl2, ClCH2CH2Cl, benzene, toluene or
xylenes), the bicyclic compounds 22 and 24 were never detected.
In this respect, it should be mentioned that treatment of amine 23
with an aqueous solution of formaldehyde (37%) for 16 h under
reflux afforded 1,3,5-triazinane 25 (24%) and dioxazinane 26 (4%).
Although it is known that compounds bearing an aromatic ring,
which is activated by electron-donating substituents, easily un-
dergo PicteteSpengler cyclization reactions, compounds 21 and
23 proved to be unsuitable substrates for cyclization, most prob-
known that a hydroxyl group at b-position of a CF2-group is quite
stable and generally difficult to reduce.13
Having in hand a straightforward method for the synthesis of
imide 9, the above described methodology was extended toward
the synthesis of other fluorinated bicyclic aromatics. Based on
known cross-coupling procedures of ethyl bromodifluoroacetate
and aryl iodides,13,14 commercially available 5-chloro-2-
iodobenzonitrile 12 was treated with 2.5 equiv of ethyl bromodi-
fluoroacetate and 5.2 equiv of copper in DMSO at 65 ꢀC for 6 h
afforded the cross-coupled product 13 in 82% yield after chro-
matographic purification on silica gel (Scheme 2). The use of less
F
F
F
F
2.5 equiv CF2BrCOOEt
I
O
OEt
conc. H2SO4
rt, 24 h
5.2 equiv Cu
NH
O
DMSO, 65°C, 6 h
Cl
Cl
CN
Cl
CN
O
12
13 (82%)
14 (49%)
F
F
F
F
1.1 equiv CF2BrCOOEt
2.3 equiv Cu
N
N
O
conc. H2SO4
N
X
N
N
OEt
X
NH
O
DMSO, 50°C, 3 h
rt, 24 h or
0°C, 1 h
N
CN
CN
O
15 X = Cl
16 X = Br (79%)
17 (41%)
18
2 equiv TMSBr
CH3CH2CN, rt, 16 h
Scheme 2.
equivalents of copper and ethyl bromodifluoroacetate resulted in
an incomplete conversion, while applying more equivalents
(3 equiv CF2BrCOOEt, 6.6 equiv Cu) considerably increased the
formation of unidentified side products. Stirring the difluorinated
ester 13 in sulfuric acid for 24 h at room temperature subsequently
gave rise to the desired 7-chloro-4,4-difluoroisoquinoline-
1,3(2H,4H)-dione 14 in moderate yield. It should be noted that due
to the presence of the CF2-moiety, the acidity of the imidic proton of
N-unsubstituted isoquinoline-1,3-diones, such as 14, is significantly
increased (typically pKa 4e5), which makes this type of compounds
of interest as carboxylic acid bioisosteres.15 In addition, the de-
veloped cyclization methodology was also applied using a suitably
substituted pyrazine 17, which was obtained in 41% yield from 2-
bromo-3-cyanopyrazine 16. However, in this case, the hydrolysis
of the nitrile function proved to be much more difficult, since only
decomposition products were obtained after treatment with sul-
furic acid.
In an alternative strategy toward interesting fluorinated iso-
quinolines or tetrahydroisoquinolines, a PicteteSpengler reaction
of suitable fluorinated amines or amides was evaluated. Toward
this end, 1-iodo-3-methoxybenzene 19 was cross-coupled with
ethyl bromodifluoroacetate, affording ethyl 2,2-difluoro-2-(3-
methoxyphenyl)acetate 20 (Scheme 3). The latter was treated
with ammonia in methanol to obtain quantitatively the
corresponding amide 21, which was subsequently reduced using
borane to yield 2,2-difluoro-2-(3-methoxyphenyl)ethylamine
23. Finally, the transformation of amide 21 and amine
23 into 1,4-dihydroisoquinoline-3-one 22 and 1,2,3,4-
tetrahydroisoquinoline 24, respectively, via a PicteteSpengler
reaction was assessed. This type of reaction is an important tool
for creating tetrahydroisoquinoline ring systems,16 which are the
core structural units of many organic compounds with interesting
ably due to the strong electron-withdrawing effect of the CF2-
substituent.
In conclusion, a straightforward synthetic pathway toward new
bicyclic difluorinated azaheterocyclic compounds was developed. A
copper-mediated cross-coupling of ethyl bromodifluoroacetate and
(hetero)aryl halides, followed by hydrolysis of the nitrile group and
subsequent ring closure were the key steps in the synthesis of new
8,8-difluoro-1,6-naphthyridine-5,7(6H,8H)-diones 9, 10 and 7-
chloro-4,4-difluoroisoquinoline-1,3-(2H,4H)-dione 14, which are
of interest as new building blocks for medicinal chemistry
purposes.
3. Experimental part
3.1. General
1H NMR spectra were recorded at 300 MHz (JEOL ECLIPSEþ) with
CDCl3 as solvent and tetramethylsilane as internal standard. 13C
NMR spectra were recorded at 75 MHz (JEOL ECLIPSEþ) with CDCl3
as solvent and tetramethylsilane as internal standard. 19F NMR
spectra were recorded at 282 MHz (JEOL ECLIPSEþ) with CDCl3 as
solvent and CFCl3 as internal standard. Electron spray (ES) mass
spectra were obtained with an Agilent 1100 Series MS (ES, 4000 V)
mass spectrometer. Electron impact (EI) mass spectrawere recorded
by using a HP 6890 GC coupled to a HP 5973 MSD (mass selective
detector). IR spectra were measured with a Spectrum One FTIR
spectrophotometer. Elemental analysis of new compounds was
performed using a CHN-elemental analyser (tin combustion cap-
sules were used for both solids and sticky oils). Diethyl ether and
tetrahydrofuranwere dried over sodium benzophenone ketyl. Other
solvents were used as received from the supplier. Melting points of
crystalline compounds were measured with a Buchi 540 apparatus.

6944
K. Piron et al. / Tetrahedron 68 (2012) 6941e6947
F
F
1.5 equiv CF2BrCOOEt
MeO
O
MeO
MeO
I
2.5 equiv Cu
OEt
DMSO, 55°C, 6 h
20 (69%)
19
excess NH3
(7 M in MeOH)
MeOH, rt, 1.5 h
F
F
F
F
Pictet-Spengler
MeO
O
O
cyclization
X
NH2
NH
21 (100%)
22
3 equiv BH3.SMe2
CH2Cl2, Δ, 40 h
F
F
F
F
37% aq. CH2O
MeO
MeO
Δ, 16 h
X
NH
NH2
23 (85%)
24
OMe
F
F
F
F
F
MeO
+
OMe
N
N
F
F
F
MeO
N
N
O
O
25 (24%)
26 (4%)
Scheme 3.
3.2. Ethyl (3-cyanopyridin-2-yl)difluoroacetate 8
3.3. 8,8-Difluoro-1,6-naphthyridine-5,7(6H,8H)-dione 9
To a solution of 4.52 g (22.25 mmol, 1.1 equiv) of ethyl
bromodifluoroacetate and 3.70 g (20.23 mmol, 1 equiv) of 2-
bromo-3-cyanopyridine 7 in DMSO (40 mL) was added 2.95 g
(46.53 mmol, 2.3 equiv) of copper powder, and the resulting
mixture was stirred at 50 ꢀC for 15 h. Afterward, the
reaction mixture was cooled to room temperature, diluted with
EtOAc (40 mL) and poured in an aqueous solution of
1.27 M KH2PO4 (60 mL). After 30 min of stirring, the resulting
suspension was filtered through a pad of CeliteÒ, after which
the copper salts were washed with EtOAc (40 mL).
Subsequently, the organic phase of the filtrate was washed
with water (2ꢁ40 mL), dried (MgSO4), concentrated and
purified by flash chromatography (hexane/EtOAc 4:1, Rf¼0.07)
In a flask of 10 mL, 185 mg (0.817 mmol, 1 equiv) of ethyl (3-
cyanopyridin-2-yl)difluoroacetate 8 was dissolved in 0.5 mL of
sulfuric acid. After stirring vigorously for 24 h at room temperature,
the mixture was poured onto 1 g of ice and the product was
extracted with EtOAc (4ꢁ5 mL). Drying (MgSO4) of the organic
phases, evaporation of the solvent and recrystallisation from
methanol, afforded 150 mg (0.757 mmol, 93% yield) of 8,8-difluoro-
1,6-naphthyridine-5,7(6H,8H)-dione
9
as
white
crystals
(mp¼257 ꢀC). 1H NMR (acetone-d6):
d
7.92 (1H, dd, J¼8.0 Hz, 4.8 Hz,
NCHCHCH); 8.57 (1H, dd, J¼8.0 Hz, 1.5 Hz, NCHCHCH); 9.07 (1H, dd,
J¼4.8 Hz, 1.5 Hz, NCHCHCH); 11.17 (1H, s(broad), NH). 19F NMR
(acetone-d6):
d
ꢂ101.0 (2F, s, CF2). 13C NMR (acetone-d6):
d 104.2 (t,
J¼243.5 Hz, CF2); 122.7 (t, J¼4.6 Hz, CarCO); 127.4 (NCHCHCH);
136.5 (NCHCHCH); 149.0 (t, J¼21.9 Hz, CarCF2); 155.3 (NCHCHCH);
161.3 (CarC]O); 162.3 (t, J¼29.4 Hz, CF2C]O). IR (ATR, cmꢂ1):
to afford 3.79
g (16.79 mmol, 83% yield) of ethyl (3-
cyanopyridin-2-yl)difluoroacetate
8
as
orange
crystals
(mp¼41.6 ꢀC). 1H NMR (CDCl3):
d
1.37 (3H, t, J¼7.2 Hz, CH3);
n
¼3442 (NH); 3168; 3032; 2923; 2829; 1745 (C]O); 1720 (C]O);
4.44 (2H, q, J¼7.2 Hz, OCH2); 7.61 (1H, dd, J¼8.0 Hz, 4.7 Hz,
NCHCHCH); 8.19 (1H, dd, J¼8.0 Hz, 1.4 Hz, NCHCHCH); 8.82
(1H, dd, J¼4.7 Hz, 1.4 Hz, NCHCHCH). 19F NMR (CDCl3):
1597; 1450; 1377; 1301; 1269; 1160; 1133; 1087; 1069; 1051; 1014;
863; 834; 794; 710; 667. MS (ESþ) m/z (%): 217 (MþH3Oþ, 100).
GCeMS (EI) m/z (%): 198 (Mþ, 11); 179 (MþꢂF, 1); 155 (MþꢂCONH,
100); 127 (MþꢂCONHCO, 97). Anal. Calcd for C8H4F2N2O2: C, 48.50;
H, 2.03; N, 14.14. Found: C, 48.25; H, 2.13; N, 13.98.
d
ꢂ101.7 (2F, s, CF2). 13C NMR (CDCl3):
d 13.8 (CH3); 63.6
(OCH2); 107.9 (CarCN); 111.9 (t, J¼255.0 Hz, CF2); 113.9 (CN);
125.4 (NCHCHCH); 142.5 (NCHCHCH); 151.6 (NCHCHCH); 153.2
(t, J¼28.3 Hz, NCq,ar); 162.0 (t, J¼31.2 Hz, C]O). IR (ATR, cmꢂ1):
3.4. 6-Benzyl-8,8-difluoro-1,6-naphthyridine-5,7(6H,8H)-
dione 10a
n
¼2237 (CN); 1771 (C]O); 1585; 1468; 1444; 1393; 1373;
1316; 1285; 1270; 1236; 1181; 1132; 1106; 1058; 1015; 845;
813; 782; 722; 662. MS (ESþ) m/z (%): 227 (MþHþ, 100). Anal.
Calcd for C10H8F2N2O2: C, 53.10; H, 3.57; N, 12.39. Found: C,
53.28; H, 3.65; N, 12.36.
To a solution of 1.00 g (5.05 mmol, 1 equiv) of 8,8-difluoro-1,6-
naphthyridine-5,7(6H,8H)-dione 9 in DMF (10 mL) at 0 ꢀC was
added 0.24 g of sodium hydride (60% in mineral oil, 6.06 mmol,

K. Piron et al. / Tetrahedron 68 (2012) 6941e6947
6945
1.2 equiv). After stirring for 20 min at 0 ꢀC, 0.95 g (5.55 mmol,
1.1 equiv) of benzyl bromide was added dropwise at 0 ꢀC, and the
resulting mixture was stirred at 60 ꢀC for 2 h. Subsequently, the
reaction mixture was cooled to 0 ꢀC and quenched with aq satd
NaHCO3 (5 mL), after which, water (10 mL) was added and the
aqueous phase was extracted with EtOAc (4ꢁ20 mL). The combined
organic phases were washed with brine (3ꢁ20 mL), dried (MgSO4)
and concentrated to afford the crude product, which was dissolved
in CH3CN and extracted with hexane to remove the residual min-
eral oil (from the used NaH dispersion). After evaporation of the
CH3CN in vacuo, the product was recrystallized from MeOH to
afford 0.79 g (2.74 mmol, 54% yield) of 6-benzyl-8,8-difluoro-1,6-
d
43.8 (CH2); 103.7 (t, J¼245.8 Hz, CF2); 121.9 (t, J¼4.0 Hz, CarCO);
124.0 (2ꢁCHnitrobenzyl); 127.5 (NCHCHCH); 130.1 (2ꢁCHnitrobenzyl);
137.6 (NCHCHCH); 142.2 (Cq,nitrobenzyl); 147.8 (CNO2); 148.0 (t,
J¼21.9 Hz, CarCF2); 155.9 (NCHCHCH); 160.9 (CarC]O); 162.7 (t,
J¼30.0 Hz, CF2C]O). IR (ATR, cmꢂ1):
¼3069; 2359; 1743 (C]O);
n
1693 (C]O); 1613; 1598; 1545 (NO2); 1428; 1383; 1349; 1335;
1309; 1291; 1250; 1226; 1162; 1145; 1111; 1090; 1076; 1060; 1030;
1014; 975; 958, 863; 846; 803; 796; 745; 738; 721; 696; 660.
GCeMS (EI) m/z (%): 333 (Mþ, 45); 305 (8); 277 (5); 258 (11); 249
(13); 207 (9); 155 (18); 129 (100); 127 (52); 100 (17); 89 (28); 77
(15); 63 (15); 51 (10); 50 (10). Anal. Calcd for C15H9F2N3O4: C, 54.06;
H, 2.72; N, 12.61. Found: C, 54.01; H, 2.69; N, 12.75.
naphthyridine-5,7(6H,8H)-dione
10a
as
white
crystals
(mp¼145.5 ꢀC). 1H NMR (CDCl3):
d
5.21 (2H, s, CH2); 7.28e7.36 (3H,
3.7. 8,8-Difluoro-6-methyl-1,6-naphthyridine-5,7(6H,8H)-
dione 10d
m, 3ꢁCHbenzyl); 7.44e7.49 (2H, m, 2ꢁCHbenzyl); 7.72 (1H, dd,
J¼8.0 Hz, 4.9 Hz, NCHCHCH); 8.56 (1H, dd, J¼8.0 Hz, 1.7 Hz,
NCHCHCH); 9.03 (1H, dd, J¼4.9 Hz, 1.7 Hz, NCHCHCH). 19F NMR
To a solution of 30 mg (0.14 mmol, 1 equiv) of 8,8-difluoro-1,6-
naphthyridine-5,7(6H,8H)-dione 9 in Et2O (5 mL) was added
0.42 mmol (3 equiv) of a diazomethane solution in Et2O (standard
preparation according to literature procedures18). The resulting
mixture was stirred at room temperature for 15 h, after which the
solvent was evaporated in vacuo, yielding 32 mg (0.14 mmol, 100%
yield) of 8,8-difluoro-6-methyl-1,6-naphthyridine-5,7(6H,8H)-
dione 10d as white crystals (mp¼107.8 ꢀC, Et2O). 1H NMR (acetone-
(CDCl3):
d
ꢂ98.6 (2F, s, CF2). 13C NMR (CDCl3):
d 44.4 (CH2); 103.6 (t,
J¼245.2 Hz, CF2); 122.1 (t, J¼4.6 Hz, Cq,arCO); 127.3 (NCHCHCH);
128.2 (CHbenzyl); 128.7 (2ꢁCHbenzyl); 129.1 (2ꢁCHbenzyl); 135.2
(Cq,benzyl); 137.3 (NCHCHCH); 148.0 (t, J¼22.0 Hz, CarCF2); 155.4
(NCHCHCH); 160.8 (CarC]O); 162.5 (t, J¼29.4 Hz, CF2C]O). IR (ATR,
cmꢂ1):
n
¼2926; 1741 (C]O), 1693 (C]O), 1584, 1492; 1455; 1432;
1389; 1360; 1340; 1312; 1299; 1250; 1224; 1207; 1156; 1138; 1113;
1070; 1029; 954; 848; 824; 794; 759; 724,699; 666; 658; 620.
GCeMS (EI) m/z (%): 288 (Mþ, 100); 260 (11); 232 (20); 231 (10);
212 (14); 204 (18); 155 (11); 132 (10); 129 (99); 127 (33); 100 (12);
91 (C7Hþ7, 29); 77 (13); 65 (12). Anal. Calcd for C15H10F2N2O2: C,
62.50; H, 3.50; N, 9.72. Found: C, 62.02; H, 3.72; N, 9.48.
d6):
d
3.38 (3H, s, CH3); 7.91 (1H, dd, J¼8.0 Hz, 4.6 Hz, NCHCHCH);
8.60 (1H, dd, J¼8.0 Hz, 1.4 Hz, NCHCHCH); 9.05 (1H, dd, J¼4.6 Hz,
1.4 Hz, NCHCHCH). 19F NMR (acetone-d6):
NMR (acetone-d6):
d
ꢂ99.5 (2F, s, CF2). 13
C
d
26.9 (CH3); 104.0 (t, J¼242.9 Hz, CF2); 122.8 (t,
J¼4.6 Hz, CarCO); 127.6 (NCHCHCH); 136.8 (NCHCHCH); 148.1 (t,
J¼21.9 Hz, CarCF2); 155.2 (NCHCHCH); 161.5 (CarC]O); 162.9 (t,
3.5. 6-(4-Bromobenzyl)-8,8-difluoro-1,6-naphthyridine-
5,7(6H,8H)-dione 10b
J¼29.4 Hz, CF2C]O). IR (ATR, cmꢂ1):
¼3083; 2925; 1743 (C]O);
n
1678 (C]O); 1596; 1424; 1372; 1306; 1280; 1218; 1165; 1083;
1064; 1046; 952; 834; 795; 720. MS (ESþ) m/z (%): 231 (MþH3Oþ,
100). Anal. Calcd for C9H6F2N2O2: C, 50.95; H, 2.85; N, 13.20. Found:
C, 50.85; H, 2.79; N, 13.28.
The same procedure as described for the synthesis of 6-benzyl-
8,8-difluoro-1,6-naphthyridine-5,7(6H,8H)-dione 10a was applied.
Since 4-bromobenzyl bromide is a solid, it was first dissolved in
DMF and the solution was added dropwise to the reaction mixture.
Yield¼47%. Mp¼138.6 ꢀC (methanol). White crystals. 1H NMR
3.8. 8,8-Difluoro-7,8-dihydro-7-hydroxy-1,6-naphthyridine-
5(6H)-one 11a
(CDCl3):
d
5.16 (2H, s, CH2); 7.36 (2H, d, J¼8.5 Hz, CHCH); 7.46 (2H, d,
J¼8.5 Hz, CHCH); 7.73 (1H, dd, J¼8.0 Hz, 5.0 Hz, NCHCHCH); 8.56
(1H, dd, J¼8.0 Hz, 1.7 Hz, NCHCHCH); 9.04 (1H, dd, J¼5.0 Hz, 1.7 Hz,
To a solution of 0.25 g (1.26 mmol, 1 equiv) of 8,8-difluoro-1,6-
naphthyridine-5,7(6H,8H)-dione 9 in dry THF (4 mL) at 0 ꢀC was
added 0.77 g (0.96 ml, 10.09 mmol, 8 equiv) of BH3.SMe2 dropwise.
After 6 h stirring at 0 ꢀC, 5 mL of MeOH was slowly added at 0 ꢀC,
after which the solvents were evaporated in vacuo and the product
was recrystallized from MeOH to afford 0.18 g (0.90 mmol, 71%
yield) of 8,8-difluoro-7,8-dihydro-7-hydroxy-1,6-naphthyridine-
5(6H)-one 11a as gray crystals (mp¼184.3 ꢀC). 1H NMR (acetone-
NCHCHCH). 19F NMR (CDCl3):
d
ꢂ98.6 (2F, s, CF2). 13C NMR (CDCl3):
d
43.9 (CH2); 103.6 (t, J¼245.8 Hz, CF2); 122.1 (t, J¼4.0 Hz, CarCO);
122.6 (CBr); 127.3 (NCHCHCH); 131.1 (2ꢁCHbromobenzyl); 132.0
(2ꢁCHbromobenzyl); 134.2 (Cq, bromobenzyl); 137.5 (NCHCHCH); 148.1
(t, J¼22.5 Hz, CarCF2); 155.7 (NCHCHCH); 160.9 (CarC]O); 162.6 (t,
J¼30.0 Hz, CF2C]O). IR (ATR, cmꢂ1):
¼1740 (C]O); 1680 (C]O);
n
1593; 1488; 1434; 1394; 1340; 1314; 1302; 1252; 1222; 1146; 1088;
1070; 1057; 1032; 1014; 963; 830; 794; 728; 664; 635. GCeMS (EI)
m/z (%): 366/368 (Mþ, 26); 338/340 (3); 310/312 (4); 282/284 (7);
259 (6); 231 (5); 207(10); 184 (5); 169/171 (11); 155 (10); 129 (100);
127 (28); 109 (8); 100 (10); 90(16); 89 (19); 77 (9); 63 (7); 50 (7).
Anal. Calcd for C15H9BrF2N2O2: C, 49.07; H, 2.47; N, 7.63. Found: C,
49.05; H, 2.56; N, 7.54.
d6):
d
5.38 (1H, s(broad), CHOH); 6.21 (1H, d, J¼5.0 Hz, OH);
7.73e7.78 (1H, m, NCHCHCH); 8.39 (1H, dd, J¼7.9 Hz, 1.7 Hz,
NCHCHCH); 8.39 (1H, s(broad), NH); 8.89 (1H, dd, J¼5.0 Hz, 1.7 Hz,
NCHCHCH). 19F NMR (acetone-d6):
d
ꢂ99.9 (1F, dd, J¼268.3 Hz,
6.6 Hz, CFaFb); ꢂ127.9 (1F, d, J¼268.3 Hz, CFaFb). 13C NMR (acetone-
d6):
d
76.5 (dd, J¼36.9 Hz, J¼30.0 Hz, CHOH); 113.0 (dd, J¼257.3 Hz,
233.1 Hz, CF2); 124.5 (CarC]O); 126.7 (NCHCHCH); 136.1
(NCHCHCH); 149.0 (t, J¼23.7 Hz, CarCF2); 153.4 (NCHCHCH); 162.2
3.6. 8,8-Difluoro-6-(4-nitrobenzyl)-1,6-naphthyridine-
5,7(6H,8H)-dione 10c
(C]O). IR (ATR, cmꢂ1):
n
¼3206; 3118; 2932; 1686 (C]O); 1592;
1491; 1469; 1455; 1432; 1393; 1356; 1315; 1257; 1228; 1197; 1160;
1128; 1094; 1080; 1061; 1017; 822; 788; 693; 636. MS (ESꢂ) m/z
(%): 199 (MꢂHꢂ, 100). Anal. Calcd for C8H5F2N2O2: C, 48.01; H, 3.02;
N, 14.00. Found: C, 47.93; H, 2.95; N, 14.11.
The same procedure as described for the synthesis of 6-(4-
bromobenzyl)-8,8-difluoro-1,6-naphthyridine-5,7(6H,8H)-dione
10b was applied.
Yield¼50%. Mp¼147.1 ꢀC (ethanol). White crystals. 1H NMR
3.9. 6-Benzyl-8,8-difluoro-7,8-dihydro-7-hydroxy-1,6-
naphthyridine-5(6H)-one 11b
(CDCl3):
d
5.30 (2H, s, CH2); 7.64 (2H, d, J¼8.3 Hz, CHCH); 7.76 (1H,
dd, J¼7.9 Hz, 4.7 Hz, NCHCHCH); 8.21 (2H, d, J¼8.3 Hz, CHCH); 8.58
(1H, dd, J¼7.9 Hz, 1.7 Hz, NCHCHCH); 9.07 (1H, dd, J¼4.7 Hz, 1.7 Hz,
To a solution of 0.20 g (0.69 mmol, 1 equiv) of 6-benzyl-8,8-
difluoro-1,6-naphthyridine-5,7(6H,8H)-dione 10a in dry THF
NCHCHCH). 19F NMR (CDCl3):
d
ꢂ98.5 (2F, s, CF2). 13C NMR (CDCl3):

6946
K. Piron et al. / Tetrahedron 68 (2012) 6941e6947
(4 mL) at 0 ꢀC was added dropwise 0.42 g (0.52 ml, 5.55 mmol,
8 equiv) of BH3$SMe2. After 6 h stirring at 0 ꢀC, 5 mL of MeOH was
slowly added at 0 ꢀC, followed by evaporation of the solvents in
vacuo. Subsequently, the crude product was redissolved in CH2Cl2
(10 mL), after which the organic phase was washed with water
Subsequently, the reaction mixture was cooled to 0 ꢀC and quenched
with an aqueous solution of 2 M NaOH (10 mL). Afterward, the
aqueous phase was extracted with EtOAc (3ꢁ10 mL), and the com-
bined organic phases were washed with brine (2ꢁ10 mL). After
drying (MgSO4) and evaporation of the solvents in vacuo, the product
was recrystallized from Et2O to afford 1.56 g (8.49 mmol, 79% yield) of
3-bromo-2-cyanopyrazine 16 as white crystals (mp¼43.5 ꢀC). 1H
(2ꢁ5 mL), dried (MgSO4) and concentrated to yield 0.16
g
(0.55 mmol, 79% yield) of 6-benzyl-8,8-difluoro-7,8-dihydro-7-
hydroxy-1,6-naphthyridine-5(6H)-one 11b as yellow crystals
NMR (CDCl3):
13C NMR (CDCl3):
147.0 (CH). IR (ATR, cmꢂ1):
d
8.61 (1H, d, J¼2.2 Hz, CH); 8.71 (1H, d, J¼2.2 Hz, CH).
(mp¼134.1 ꢀC). 1H NMR (CDCl3):
d
2.89 (1H, s(broad), OH); 4.53 (1H,
d
114.7 (CN); 133.3 (CCN); 143.3 (CBr); 143.4 (CH);
d, J¼15.1 Hz, CHaHb); 5.23 (1H, dd, J¼6.5 Hz, 3.6 Hz, CHOH); 5.33
(1H, d, J¼15.1 Hz, CHaHb); 7.28e7.41 (5H, m, 5ꢁCHbenzyl); 7.61e7.65
(1H, m, NCHCHCH); 8.52 (1H, dd, J¼7.7 Hz, 1.7 Hz, NCHCHCH); 8.88
n¼3101; 2243 (CN); 1958; 1538; 1515;
1425; 1364; 1336; 1249; 1184; 1161; 1071; 1048; 945; 870; 839; 824;
668; 653. GCeMS (EI) m/z (%): 183/185 (Mþ, 58); 129/131 (13); 104
(MþꢂBr, 100); 77 (23); 52 (28). Anal. Calcd for C5H2BrN3: C, 32.64; H,
1.10; N, 22.84. Found: C, 32.78; H, 1.15; N, 22.67.
(1H, dd, J¼5.0 Hz, 1.7 Hz, NCHCHCH). 19F NMR (CDCl3):
ꢂ98.5 (1F,
d
dd, J¼273.6 Hz, 6.5 Hz, CFaFb); ꢂ127.5 (1F, d, J¼273.6 Hz, CFaFb). 13
C
NMR (CDCl3):
d
48.6 (CH2); 80.5 (dd, J¼38.1 Hz, J¼31.2 Hz, CHOH);
112.4 (dd, J¼249.2 Hz, 242.3 Hz, CF2); 124.6 (CarC]O); 126.7
(NCHCHCH); 128.1, 128.3, and 129.0 (5ꢁCHbenzyl); 135.8 (Cq,benzyl);
137.2 (NCHCHCH); 147.8 (t, J¼23.1 Hz, CarCF2); 153.3 (NCHCHCH);
3.13. Ethyl (3-cyanopyrazin-2-yl)difluoroacetate 17
The synthetic procedure for compound 17 is analogous to the
synthesis of ethyl (3-cyanopyridin-2-yl)difluoroacetate 8.
Flash chromatography (hexane/EtOAc 9:1, Rf¼0.05). Yield¼41%.
161.7 (C]O). IR (ATR, cmꢂ1):
n
¼3300 (OH); 1659 (C]O); 1592;
1428; 1359; 1288; 1232; 1200; 1152; 1068; 944; 910; 832; 797;
767; 728; 698. MS (ESþ) m/z (%): 291 (MþHþ, 100). MS (ESꢂ) m/z
(%): 289 (MꢂHꢂ, 100). Anal. Calcd for C15H12F2N2O2: C, 62.07; H,
4.17; N, 9.65. Found: C, 62.19; H, 4.03; N, 9.88.
Yellow oil. 1H NMR (CDCl3):
d
1.38 (3H, t, J¼7.2 Hz, CH3); 4.45 (2H, q,
J¼7.2 Hz, OCH2); 8.83 (1H, d, J¼1.9 Hz, CHar); 8.91 (1H, d, J¼1.9 Hz,
CHar). 19F NMR (CDCl3):
d
ꢂ103.0 (2F, s, CF2). 13C NMR (CDCl3):
d 13.9
(CH3); 64.3 (OCH2); 111.2 (t, J¼255.6 Hz, CF2); 113.2 (CN); 128.8
(CCN); 145.4 (CH); 146.7 (CH); 150.1 (t, J¼28.9 Hz, CarCF2); 161.5 (t,
3.10. Ethyl (4-chloro-2-cyanophenyl)difluoroacetate 13
J¼31.2 Hz, C¼O). IR (ATR, cmꢂ1):
¼2987; 2336 (CN); 1774 (C¼O);
n
The synthetic procedure for compound 13 is analogous to the
synthesis of ethyl (3-cyanopyridin-2-yl)difluoroacetate 8.
Flash chromatography (petroleum ether/EtOAc 8:1, Rf¼0.22).
1561; 1469; 1447; 1409; 1372; 1309; 1286; 1244; 1117; 1061; 1012;
874; 854; 820; 784; 724; 660. GCeMS (EI) m/z (%): 227 (Mþ, 0.1); 198
(MþꢂC2H5, 0.1); 155 (100); 154 (MþꢂCOOEt, 25); 128 (18); 100 (37).
Yield¼82% (purity: 87%). Colorless oil. 1H NMR (CDCl3):
d 1.36 (3H, t,
J¼7.2 Hz, CH3); 4.39 (2H, q, J¼7.2 Hz, OCH2); 7.69 (1H, dd, J¼8.5 Hz,
3.14. 2,2-Difluoro-2-(3-methoxyphenyl)acetamide 21
1.7 Hz, CHar); 7.73 (1H, d, J¼8.5 Hz, CHar); 7.79 (1H, s(broad), CHar).
19F NMR (CDCl3):
d
ꢂ101.3 (2F, s, CF2). 13C NMR (CDCl3):
d
13.8
In a flask of 25 mL, 0.50 g (2.17 mmol) of ethyl 2,2-difluoro-2-(3-
methoxyphenyl)acetate 20 was dissolved in a 7 M solution of NH3 in
MeOH (10 mL). The mixture was stirred at room temperature for
90 min, followed by evaporation of the solvent in vacuo to yield
0.44 g (2.17 mmol,100% yield) of 2,2-difluoro-2-(3-methoxyphenyl)
(CH3); 64.2 (OCH2); 112.0 (t, J¼255.0 Hz, CF2); 112.1 (t, J¼4.0 Hz,
CarCN); 114.8 (CN); 128.6 (t, J¼7.5 Hz, CHar); 133.3 (CHar); 134.0
(t, J¼25.4 Hz, CarCF2); 134.4 (CHar); 137.8 (CCl); 162.2 (t, J¼34.0 Hz,
C]O). IR (ATR, cmꢂ1):
n
¼2988; 2236 (CN); 1761 (C]O); 1597;
1567; 1474; 1448; 1391; 1372; 1274; 1250; 1217; 1192; 1111; 1087;
1013; 992; 887; 856; 830; 768; 734; 684; 637. MS (ESþ) m/z (%):
277/279 (MþNHþ4 , 100).
acetamide 21 as white crystals (mp¼76.8 ꢀC).1H NMR (CDCl3):
d 3.84
(3H, s, CH3O); 6.43 (1H, s(broad), NHaHb); 6.59 (1H, s(broad),
NHaHb); 7.03 (1H, dd, J¼8.3 Hz, 2.2 Hz, CH3OCq,arCHCH); 7.15e7.21
(2H, m, CHCq,ar(CF2)CH); 7.38 (1H, t, J¼8.3 Hz, CHCHCH). 19F NMR
3.11. 7-Chloro-4,4-difluoroisoquinoline-1,3(2H,4H)-dione 14
(CDCl3):
(t, J¼6.3 Hz,
d
ꢂ102.8 (2F, s, CF2). 13C NMR (CDCl3):
d 55.3 (CH3O); 110.8
q,arCHCq,ar); 114.3 (t, J¼253.3 Hz, CF2); 116.7
C
The synthetic procedure for compound 14 is analogous to the
synthesis of 8,8-difluoro-1,6-naphthyridine-5,7(6H,8H)-dione 9.
Flash chromatography (petroleum ether/EtOAc 9:1, Rf¼0.13).
(CHCHCq,arOCH3); 117.5 (t, J¼5.8 Hz, CHCHCq,arCF2); 129.8
(CHCHCH); 133.9 (t, J¼25.4 Hz, Cq,arCF2); 159.6 (Cq,arOCH3); 166.9 (t,
J¼31.7 Hz, C]O). IR (ATR, cmꢂ1):
¼3394 (NH); 3182 (NH); 1678
n
Yield¼49%. White crystals (mp¼137.0 ꢀC). 1H NMR (CDCl3):
d
7.83
(C]O); 1602; 1464; 1421; 1283; 1217; 1179; 1141; 1083; 1075; 1046;
1022; 864; 805; 790; 701; 659. MS (ESþ) m/z (%): 219 (MþNHþ4 ,100).
MS (ESꢂ) m/z (%): 200 (MꢂHþ, 100). Anal. Calcd for C9H9F2NO2: C,
53.73; H, 4.51; N, 6.96. Found: C, 53.92; H, 4.13; N, 7.33.
(1H, dd, J¼8.4 Hz, 1.7 Hz, CHar); 7.88 (1H, d, J¼8.4 Hz, CHar); 8.24
(1H, d, J¼1.7 Hz, CHar); 8.40 (1H, s(broad), NH). 19F NMR (CDCl3):
d
ꢂ92.5 (2F, s, CF2). 13C NMR (CDCl3):
d
105.6 (t, J¼242.9 Hz, CF2);
126.4 (t, J¼5.8 Hz, CarCO); 127.9 (CHar); 129.1 (CHar); 130.1 (t,
J¼24.8 Hz, CarCF2); 135.6 (CHar); 139.6 (CCl); 160.8 (C]O); 161.7 (t,
3.15. 2,2-Difluoro-2-(3-methoxyphenyl)ethylamine 23
J¼31.2 Hz, CF2CO). IR (ATR, cmꢂ1):
¼3214 (NH); 3123; 2844; 1744
n
(C]O); 1706 (C]O); 1598; 1584; 1429; 1358; 1307; 1290; 1251;
1158; 1136; 1101; 1076; 1039; 994; 935; 838; 808; 718; 688; 672.
GCeMS (EI) m/z (%): 231/233 (Mþ, 20); 188/190 (MþꢂCONH, 61);
160/162 (MþꢂCONHCO, 100); 125 (MþꢂCONHCOeCl, 48); 75 (20).
Anal. Calcd for C9H4ClF2NO2: C, 46.68; H, 1.47; N, 6.05. Found: C,
46.60; H, 1.18; N, 5.96.
To an ice cooled solution of 4.10 g (20.38 mmol, 1 equiv) of 2,2-
difluoro-2-(3-methoxyphenyl)acetamide 21 in CH2Cl2 (90 mL) was
added dropwise 4.64 g (5.79 ml, 61.14 mmol, 3 equiv) of BH3.SMe2.
After stirring for 40 h at reflux temperature, the reaction mixture
was quenched by carefully adding water/MeOH 1:1 (20 mL) at 0 ꢀC.
After extraction with CH2Cl2 (3ꢁ50 mL), the combined organic
phases were dried (MgSO4) and concentrated in vacuo to afford
3.12. 3-Bromo-2-cyanopyrazine 16
3.24
methoxyphenyl)ethylamine 23 as a yellow oil. 1H NMR (CDCl3):
1.31 (2H, s(broad), NH2); 3.12 (2H, t, J¼14.9 Hz, CH2); 3.84 (3H, s,
g
(17.32 mmol, 85% yield) of 2,2-difluoro-2-(3-
To a solution of 1.50 g (10.75 mmol, 1 equiv) of 2 chloro-3-
cyanopyrazine 15 in propanenitrile (10 mL) was added 3.30 g
(21.50 mmol, 2 equiv) of bromotrimethylsilane dropwise, and the
resulting mixture was stirred for 16 h at room temperature.
d
CH3O); 6.95e7.08 (3H, m, 3ꢁCH); 7.36 (1H, t, J¼8.0 Hz, CHCHCH).
19F NMR (CDCl3):
d
ꢂ105.6 (2F, t, J¼14.9 Hz, CF2). 13C NMR (CDCl3):
d
49.0 (t, J¼30.6 Hz, CH2); 54.9 (CH3O); 110.7 (t, J¼6.3 Hz,

K. Piron et al. / Tetrahedron 68 (2012) 6941e6947
6947
C
q,arCHCq,ar); 115.1 (CHCHCq,arOCH3); 117.1 (t, J¼5.8 Hz,
Research and Development, a Division of Janssen Pharmaceutica
NV, for financial support.
CHCHCq,arCF2); 121.3 (t, J¼242.9 Hz, CF2); 129.4 (CHCHCH); 136.6 (t,
J¼26.0 Hz, Cq,arCF2); 159.4 (Cq,arOCH3). IR (ATR, cmꢂ1):
¼3395
n
(NH); 1606; 1589; 1491; 1455; 1435; 1320; 1292; 1281; 1219; 1164;
1034; 1004; 858; 836; 782; 697. GCeMS (EI) m/z (%): 187 (Mþ, 100);
158 (41); 157 (MþꢂCH2NH2, 36); 127 (37); 125 (11); 114 (53); 109
(12); 77 (15); 75 (13); 63 (14).
References and notes
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Deroose, F.; De Kimpe, N. Org. Biomol. Chem. 2010, 8, 4514e4517; (b) Surmont,
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Verniest, G.; Surmont, R.; Van Hende, E.; Deweweire, A.; De Kimpe, N. J. Org.
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Giardino, E. C.; Patel, S.; Huang, H.; Xu, G.; Fitzgerald, M.; Haertlein, B. J.; Mohan, V.;
Crysler, C.; Eisennagel, S.;Dasgupta, M.;McMillan, M.;Spurlino, J.C.;Huebert, N.D.;
Maryanoff, B. E.; Tomczuk, B. E.; Damiano, B. P.; Player, M. R. Bioorg. Med. Chem. Lett.
2008, 18, 2865e2870; (h) Amel Diab, S.; Hienzch, A.; Lebargy, C.; Guillarme, S.;
Pfund, E.; Lequeux, T. Org. Biomol. Chem. 2009, 7, 4481e4490.
3.16. 1,3,5-Tris[2,2-trifluoro-2-(3-methoxyphenyl)ethyl]-1,3,5-
triazinane 25 and 5-[2,2-difluoro-2-(3-methoxyphenyl)ethyl]-
1,3,5-dioxazinane 26
In a flask of 10 mL, 0.40 g (2.14 mmol, 1 equiv) of 2,2-difluoro-2-
(3-methoxyphenyl)ethylamine 23 was dissolved in 1 mL of an
aqueous 37% formaldehyde-solution and stirred for 16 h at reflux
temperatures. Afterward, the reaction mixture was cooled to room
temperature and extracted with toluene (3ꢁ5 mL). Washing of the
organic phase with water (2ꢁ5 mL), drying (K2CO3) and evapora-
tion of the solvent afforded the crude product, which was purified
by flash chromatography (hexane/EtOAc/Et3N 80:10:10) to yield
0.11 g (0.506 mmol, 24% yield) of 1,3,5-tris[2,2-trifluoro-2-(3-
methoxyphenyl)ethyl]-1,3,5-triazinane 25 (Rf¼0.02) and 20 mg
(0.077 mmol, 4% yield) of 5-[2,2-difluoro-2-(3-methoxyphenyl)
ethyl]-1,3,5-dioxazinane 26 (Rf¼0.16), both as yellow oils.
3.17. 1,3,5-Tris[2,2-trifluoro-2-(3-methoxyphenyl)ethyl]-1,3,5-
triazinane 25
1H NMR (CDCl3):
d
2.89 (6H, t, J¼13.8 Hz, 3ꢁCH2CF2); 3.42 (6H, s,
3ꢁNCH2N); 3.79 (9H, s, 3ꢁCH3O); 6.91e6.99 (9H, m, 9ꢁCHar); 7.30
(3H, t, J¼8.0 Hz, 3ꢁCHCHCH). 19F NMR (CDCl3):
d
ꢂ100.4 (6F, t,
J¼13.8 Hz, 3ꢁCF2). 13C NMR (CDCl3):
d
55.2 (3ꢁCH3O); 57.9 (t,
4. (a) Tozer, M. J.; Herpin, T. F. Tetrahedron 1996, 52, 8619e8683 and references
cited therein; (b) Tarui, A.; Sato, K.; Omote, M.; Kumadaki, I.; Ando, A. Adv.
Synth. Catal. 2010, 352, 2733e2744.
5. (a) Eto, H.; Kaneko, Y.; Sakamoto, T. Chem. Pharm. Bull. 2008, 48, 982e990; (b)
Taguchi, T.; Kitagawa, O.; Morikawa, T.; Nishiwaki, T.; Uehara, H.; Endo, H.;
Kobayashi, Y. Tetrahedron Lett. 1986, 27, 6103e6106.
6. Lu, T.; Markotan, T.; Ballentine, S. K.; Giardino, E. C.; Spurlino, J.; Brown, K.;
Maryanoff, B. E.; Tomczuk, B. E.; Damiano, B. P.; Shukla, U.; End, D.; Andrade-
Gordon, P.; Bone, R. F.; Player, M. R. J. Med. Chem. 2010, 53, 1843e1856.
7. Shimazawa, R.; Sano, H.; Tanatani, A.; Miyachi, H.; Hashimoto, Y. Chem. Pharm.
Bull. 2004, 52, 498e499.
J¼30.0 Hz, 3ꢁCH2CF2); 74.9 (3ꢁNCH2N); 110.1 (t, J¼6.3 Hz,
3ꢁCq,arCHCq,arCF2); 115.3 (3ꢁCHCHCq,arOCH3); 117.6 (t, J¼6.3 Hz,
3ꢁCHCHCq,arCF2); 121.4 (t, J¼244.6 Hz, 3ꢁCF2); 129.4 (3ꢁCHCHCH);
137.3 (t, J¼25.4 Hz, 3ꢁCq,arCF2); 159.4 (3ꢁCq,arOCH3). IR (ATR,
cmꢂ1):
n¼1606, 1589, 1491, 1455, 1436, 1327, 1292, 1279, 1225, 1180,
1138, 1110, 1067, 1039, 1009, 986, 931, 911, 880, 846, 857, 846, 783,
730, 709, 697. MS (ESþ) m/z (%): 620 (MþNaþ, 10), 200 (100).
3.18. 5-[2,2-Difluoro-2-(3-methoxyphenyl)ethyl]-1,3,5-
8. Chen, Y. K.; Co, E. W.; Guntupalli, P.; Lawson, J. D.; Notz, W. R. L.; Stafford J. A.;
Ton-Nu, H. eT. PCT Int. Appl. 2009, WO 2009097578 A1.
9. Ashwood, M. S.; Cottrell, I. F.; Cowden, C. J.; Wallace, D. J.; Davies, A. J.; Kennedy,
D. J.; Dolling, U. H. Tetrahedron Lett. 2002, 43, 9271e9273.
10. Verniest, G.; Wang, X.; De Kimpe, N.; Padwa, A. J. Org. Chem. 2010, 75, 424e433.
11. Schlosser, M.; Cottet, F. Eur. J. Org. Chem. 2002, 4181e4184.
12. (a) Winters, G.; Sala, A.; Barone, D.; Baldoli, E. J. J. Med. Chem. 1985, 28,
934e940; (b) Fukui, H.; Inoguchi, K.; Nakano, J. Heterocycles 2002, 56,
257e264; (c) Thurmond, R.; Beavers, M. P.; Cai, H.; Meduna, S. P.; Gustin, D. J.;
Sun, S.; Almond, H. J.; Karlsson, L.; Edwards, J. P. J. Med. Chem. 2004, 47,
4799e4801; (d) Appell, M.; Dunn, W. J., III; Reith, M. E.; Miller, L.; Flippen-
Anderson, J. L. Bioorg. Med. Chem. 2002, 10, 1197e1206.
dioxazinane 26
1H NMR (CDCl3):
d
3.64 (2H, t, J¼13.8 Hz, CH2CF2); 3.83 (3H, s,
CH3O); 4.56 (4H, s(br), CH2NCH2); 5.15 (2H, s, OCH2O); 6.94e7.06
(3H, m, 3ꢁCHar); 7.33 (1H, t, J¼7.7 Hz, CHCHCH). 19F NMR (CDCl3):
d
ꢂ100.5 (2F, t, J¼13.8 Hz, CF2). 13C NMR (CDCl3):
d 55.3 (CH3O); 57.3
(t, J¼30.0 Hz, CH2CF2); 84.9 (CH2NCH2); 94.9 (OCH2O); 111.0 (t,
J¼6.3 Hz,
Cq,arCHCq,arCF2); 115.5 (CHCHCq,arOCH3); 117.6 (t,
J¼6.3 Hz, CHCHCq,arCF2); 121.2 (t, J¼243.5 Hz, CF2); 129.5
(CHCHCH); 137.1 (t, J¼26.0 Hz, Cq,arCF2); 159.5 (Cq,arOCH3). IR (ATR,
13. Sato, K.; Nishimoto, T.; Tamoto, K.; Omote, M.; Ando, A.; Kumadaki, I. Hetero-
cycles 2002, 56, 403e412.
cmꢂ1):
n
¼2933; 2877; 2840; 1745; 1683; 1606; 1589; 1492; 1456;
14. (a) Sato, K.; Kawata, R.; Ama, F.; Omote, M.; Ando, A.; Kumadaki, I. Chem. Pharm.
Bull. 1999, 47, 1013e1016; (b) Sato, K.; Omote, M.; Ando, A.; Kumadaki, I. J.
Fluorine Chem. 2004, 125, 509e515.
15. Pan, Y.; Holmes, C. P.; Tumelty, D. J. Org. Chem. 2005, 70, 4897e4900.
16. (a) Cox, E. D.; Cook, J. M. Chem. Rev. 1995, 95, 1797e1842; (b) Youn, S. W. Org.
Prep. Proced. Int. 2006, 38, 505e591.
17. (a) Dalence-Guzman, M. F.; Berglund, M.; Skogvall, S.; Sterner, O. Bioorg. Med.
Chem. 2008, 16, 2499e2512; (b) Torrens Jover, A.; Yenes Minguez, S.; Prio, J. M.;
Romero Alonso, L.; Dordal Zueras, A.; Buschmann, H. H. U.S. Patent Appl. Publ.
2006, U.S. 20,060,142,332 A1. (c) Villani F. J.; Zhong, H. U.S. Patent Appl. Publ.
2008, U.S. 20080033177 A1. (d) Yang, L.; Mills, S. G.; Morriello, G. J.; Guiadeen
D.; Shankaran, K. PCT Int. Appl. 2005, WO 2005110409 A2.
1436; 1331; 1292; 1280; 1234; 1219; 1175; 1151; 1074; 1030; 960;
931; 880; 859; 846; 788; 732; 709; 698; 662. GCeMS (EI) m/z (%):
259 (Mþ, 12); 229 (15); 212 (43); 199 (36); 198 (33); 157 (53); 127
(21); 114 (23); 102 (99); 72 (25); 42 (100).
Acknowledgements
The authors are indebted to Ghent University (GOA), the Re-
search Foundation-Flanders (FWO-Vlaanderen) and Janssen
18. Black, T. H. Aldrichim. Acta 1983, 16, 3e10.