Novel furo-pyridine derivatives via sonogashira reactions of functionalized pyridines

Article abstract of DOI:10.1002/ejoc.200800398

A series of 4-pyridyl nonaflates was coupled with several terminal alkynes to efficiently provide new 4-alkynyl-substituted 3-alkoxypyridine derivatives. Apt conditions were developed for their conversion into furo[2,3-c]pyridines. Sonogashira reactions o

Full text of DOI:10.1002/ejoc.200800398

FULL PAPER
DOI: 10.1002/ejoc.200800398
Novel Furo-pyridine Derivatives via Sonogashira Reactions of Functionalized
Pyridines
Tilman Lechel,[a] Jyotirmayee Dash,[a] Irene Brüdgam,[a][‡] and Hans-Ulrich Reißig*[a]
Keywords: Pyridines / Allenes / Palladium catalysis / Furo-pyridines / Fluorescence
A series of 4-pyridyl nonaflates was coupled with several ter-
minal alkynes to efficiently provide new 4-alkynyl-substi-
tuted 3-alkoxypyridine derivatives. Apt conditions were de-
veloped for their conversion into furo[2,3-c]pyridines. Sono-
gashira reactions of 4-alkoxy-substituted 3-pyridyl nona-
flates allowed an access to regioisomeric furo[3,2-c]pyrid-
ines. For both types of alkynyl-substituted alkoxypyridines
an alternative method for cyclization employing iodine mono-
chloride furnished iodinated furo[2,3-c]- or furo[3,2-c]pyrid-
ines, which can undergo a second palladium-catalyzed step.
Iodination of 4-hydroxypyridine derivative 24 with iodine af-
forded a pentasubstituted pyridine which after Sonogashira
reaction immediately undergoes a cyclization to furo-pyr-
idine 25. Thus, three different types of furo-pyridines can be
prepared starting from one precursor. Several compounds
prepared are fluorescent and show strong Stokes shifts.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
fashion at C-3, C-4, and C-5 position of the pyridine deriva-
tives. Subsequent cyclizations of the alkyne moiety with a
neighbouring hydroxy group smoothly provided a series of
highly substituted furo-pyridine derivatives.
Introduction
In recent reports we described the flexible synthesis of 4-
hydroxy-substituted pyridine derivatives by a novel three-
component reaction employing lithiated alkoxyallenes, ni-
triles and carboxylic acids as precursors (Scheme 1).[1,2]
This mechanistically unique process[1a] has a very broad
scope[2] and the resulting pyridine derivatives are of high
synthetic value. Their activation as 4-nonafluorobutanesul-
fonates[3] is easily achieved and the resulting pyridyl nona-
flates 1 are most promising starting materials for palladium-
catalyzed reactions. We have already demonstrated that
Suzuki and Heck reactions can smoothly be performed
affording highly substituted pyridine derivatives.[1,2] In this
communication we want to present a series of Sonogashira
reactions[4] which could be performed in a regioselective
Results and Discussion
6-(Trifluoromethyl)pyridyl nonaflates 1a–1e were treated
with different monosubstituted alkynes 2 under standard
conditions of Sonogashira couplings employing an excess
of diisopropylamine as base. In general, the yields of the
resulting disubstituted alkynes 3 are good to excellent
Table 1. Sonogashira couplings of 4-pyridyl nonaflates with dif-
ferent alkynes.
Precursor[a]
R1
R2
R3
t [h]
T [°C]
3, % yield
1a
1b
1c
1b
1b
1d
1d
1e
Me
Me
Me
Me
Me
Bn
Et
tBu
Ph
tBu
tBu
tBu
tBu
tBu
Ph
Ph
Ph
nBu
CMe2OH
CH2OMe
Ph
17
17
17
7
4
6
r.t.
r.t.
r.t.
70
70
70
70
70
3a, 72
3b, 72[1]
3c, 75
3d, 61
3e, 96
3f, 75
Scheme 1. General route to 2,6-disubstituted 4-pyridyl nonaflates.
[a] Institut für Chemie und Biochemie, Freie Universität Berlin,
Takustr. 3, 14195 Berlin, Germany
Fax: +49-30-838-55367
E-mail: hans.reissig@chemie.fu-berlin.de
[‡] Responsible for the X-ray analysis.
Bn
TMSE
3
3
3g, 99
3h, 78
Ph
[a] Reaction conditions: 5–7 mol-% Pd(OAc)2, 20–24 mol-% PPh3,
5 mol-% CuI, 1.2 equiv. alkyne.
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T. Lechel, J. Dash, I. Brüdgam, H.-U. Reißig
FULL PAPER
(Table 1). We initially performed the coupling at room tem-
perature, but later shifted to 70 °C and shorter reaction
times giving similar yields.
During an attempt to deprotect methoxy-substituted
compound 3b by subsequent treatment with boron tribro-
mide and potassium carbonate we discovered the partial
cyclization to furo[2,3-c]pyridine 4. This transformation
was optimized and hence starting with 3b or 3d products 4
or 5 were isolated in good yields (Scheme 2). Two other
furo-pyridines 6 and 7 were obtained in a similar fash-
ion.[5,6] In the first step 2-(trimethylsilyl)ethoxy-substituted
pyridine 1e was coupled with methyl propargyl ether or
with an imidazolyl-substituted alkyne. The deprotection of
the TMSE group succeeded under milder conditions (tri-
fluoroacetic acid) and subsequent heating with potassium
carbonate delivered products 6 and 7 in moderate overall
yields. Remarkably, the imidazolyl-substituted alkyne intro-
duced for the preparation of 6 also derives from a multi-
component reaction with lithiated alkoxyallenes as crucial
building block.[7] Thus, product 6 contains two C3 subunits
arising from alkoxyallenes.[8]
Scheme 3. Sonogashira reactions of 4-pyridyl nonaflates with TMS
acetylene and 1,4-diethynylbenzene.
Scheme 2. Conversion of 3-alkoxy-4-alkynylpyridines to furo[2,3-c]-
pyridines.
The coupling of pyridyl nonaflate 1e with (trimethylsilyl)-
acetylene provided a mixture of bisalkyne 8 and dipyridyl-
substituted alkyne 9, which was directly converted into
bis(furo-pyridine) derivative 10 (12%) and furo-pyridine de-
rivative 11 (28%) (Scheme 3).[9] The related compound 13
with an inserted central benzene ring was rapidly prepared
starting from nonaflate 1b and 1,4-diethynylbenzene 12.
Here, boron tribromide has to be employed for deprotection
of the methoxy groups. The X-ray analysis of bis(furo[2,3-c]-
pyridyl)benzene derivative 13 proves the constitution and
shows an anti-arrangement of the two furo-pyridine rings
(Figure 1).[10]
Figure 1. X-ray crystal structure of compound 13 (red: O, green: F,
blue: N, yellow: C).
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 3647–3655

Novel Furo-pyridine Derivatives
New options to extend the synthesized heterocyclic π-
systems are offered by an alternative method for furan for-
mation. Heating of benzyloxy-substituted pyridine deriva-
tive 3g with iodine monochloride[11] at 80 °C furnished
iodo-substituted furo-pyridine 14 in 50% yield (23% of 3g
were recovered). This compound was engaged in palladium-
catalyzed reactions which provided the phenyl-, styryl-, and
2-phenylethynyl-substituted products 15, 16, and 17 in good
to excellent yields (Scheme 4).
Scheme 4. ICl-promoted cyclization of 4-alkynyl-3-(benzyloxy)pyr-
idine 3g to iodo-substituted furo-pyridine derivative 14; *Reaction
conditions: a) Pd(OAc)2, PPh3, K2CO3, PhB(OH)2, DMF, 70 °C,
4 h; b) Pd(OAc)2, LiCl, styrene, Et3N, DMF 70 °C, 5 h; c) Pd-
(OAc)2, PPh3, CuI, phenylacetylene, DMF, Et3N, 70 °C, 3 h.
Scheme 5. Synthesis of different furo[3,2-c]pyridine derivatives.
Starting from TMSE-substituted pyridinol derivatives
such as 18 we could also easily approach regioisomeric
furo[3,2-c]pyridines. O-Benzylation, deprotection of the
TMSE group and nonaflation under standard conditions
afforded 3-pyridyl nonaflate 19 in 43% overall yield
(Scheme 5). Coupling with phenylacetylene to 20 and cycli-
zation provided the desired furo[3,2-c]pyridine 21. Alterna-
tively, cyclization in the presence of iodine monochloride
gave the iodinated heterocycle 22 in 64% yield (28% of 20
were recovered). Palladium-catalyzed reaction with phenyl-
acetylene furnished alkyne 23 in 43% yield and as major
component the deiodinated compound 21 (52%). Appar-
ently, the coupling is fairly hindered in 22 due to the bulky
tert-butyl group.
Scheme 6. Preparation of 5-iodopyridine derivative 25 and subse-
quent cyclization to furo[2,3-c]pyridine 26.
Additional options are offered by iodination of com-
pounds such as 24 (Scheme 6), which provides the penta-
substituted pyridine derivative 25 in very good yield. Dur-
ing Sonogashira reaction of 25 with phenylacetylene a
spontaneous cyclization provided furo[2,3-c]pyridine 26 al-
most quantitatively. Thus, three similar furo-pyridines 4, 21,
and 26 differing in the ring annulation position could be
prepared.
The furo-pyridines prepared absorb in the region of 270
to 315 nm (Table 2) and several of these compounds are
highly fluorescent. As expected the Stokes shift strongly de-
pends on the substitution pattern.
Table 2. Absorption and emission of furo-pyridines.
λabs [nm]
λem [nm]
Stokes Shift [nm]
4
6
300
310
315
270
300
280
270
305
310
340
390
355
465
375
415
390
340
370
40
80
40
195
75
135
120
35
10
11
15
16
17
21
26
60
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T. Lechel, J. Dash, I. Brüdgam, H.-U. Reißig
FULL PAPER
Figure 2. Absorption and emission spectra of compound 16.
on Bruker (AC 500) and JOEL (Eclipse 500) instruments. Chemical
shifts are reported relative to TMS (1H: δ = 0.00 ppm), CDCl3 (13C:
δ = 77.0 ppm), or CD3OD (1H: δ = 3.31 ppm, 13C: δ = 49.0 ppm).
Integrals are in accordance with assignments; coupling constants
are given in Hz. All 13C-NMR spectra were proton-decoupled. For
detailed peak assignments 2D spectra were measured (COSY,
HMBC and HMQC). IR spectra were measured with an FT-IRD
spectrometer Nicolet 5 SXC. UV/Vis spectra were measured with a
UV/Vis spectrophotometer Scinco S-3150 PDA. Fluorescence spec-
tra were measured with a spectrofluorometer Jasco FP-6500. For
In Figure 2 we display the absorption and emission of
stilbene-type compound 16 with a Stokes shift of 136 nm.
The largest value was determined for compound 11
(195 nm).
Systematic investigations of the photophysical proper-
ties[12] of these furo-pyridines are required. Our highly mod-
ular synthesis of precursor pyridine derivatives by three-
component cyclization followed by palladium-catalyzed re-
actions will be very helpful for this endeavour. Heterocycles
fused to pyridine derivatives are also of interest in medicinal both techniques a concentration of 10–6  in degassed CH3CN
chemistry.[13] It should be emphasized that trifluoromethyl
and tert-butyl groups, which are present at C-6 and C-2
(1 cm cuvette) at 25 °C was used. MS and HRMS analyses were
performed with Finnigan MAT 711 (EI, 80 eV, 8 kV), MAT CH7A
(EI, 80 eV, 3 kV), CH5DF (FAB, 3 kV), Varian Ionspec QFT-7
position of most of our pyridine derivatives presented here,
(ESI-FT ICRMS) and Agilent 6210 (ESI-TOF) instruments. Ele-
are no prerequisite as demonstrated in our reports describ-
mental analyses were carried out with CHN-Analyzer 2400 (Per-
ing the preparation of starting materials 1.[1,2]
kin–Elmer). Melting points were measured with a Reichert appara-
tus Thermovar and are uncorrected. Single-crystal X-ray data were
collected on a Bruker-XPS diffractometer (CCD area detector, Mo-
Kα radiation, λ = 0.71073 Å, graphite monochromator), empirical
Conclusions
absorption correction using symmetry-equivalent reflections (SAD-
Our new approach to highly functionalized 4-pyridinol
ABS), structure solution and refinement by SHELXS-97 and
SHELXL-97 in the WINGX System.[14,15] The hydrogen atoms
were located by difference Fourier syntheses.
derivatives allows a highly flexible entry to alkynyl-substi-
tuted pyridine derivatives and to furo-pyridines. The key
steps are efficient Sonogashira reactions of the correspond-
ing pyridyl nonaflates and subsequent cyclizations to gener-
ate the furan ring. Of particular value is the fact that three
different types of furo-pyridines can be prepared. Several of
these compounds display interesting photophysical proper-
ties which require further investigations.
Typical Procedure for Sonogashira Coupling Reactions (Method A):
A mixture of pyridyl nonaflate 1d (295 mg, 0.49 mmol), Pd(OAc)2
(8 mg, 0.03 mmol), PPh3 (25 mg, 0.10 mmol), CuI (5 mg,
0.03 mmol), phenylacetylene (57 mg, 0.56 mmol) in DMF (2.0 mL)
and diisopropylamine (1.0 mL) was heated to 70 °C for 3 h under
an argon atmosphere. The mixture was cooled to room tempera-
ture, diluted with brine (5 mL) and extracted with diethyl ether
(3ϫ5 mL). The combined organic phases were dried with Na2SO4
and concentrated to dryness. The residue was purified by column
chromatography on silica gel (hexane/ethyl acetate, 40:1) to give
199 mg (99%) of 3-(benzyloxy)-2-tert-butyl-4-(phenylethynyl)-6-(tri-
Experimental Section
General Methods: Reactions were generally performed under argon
in flame-dried flasks. Solvents and reagents were added by syringes.
Solvents were dried using standard procedures. Reagents were pur-
chased and were used as received without further purification un-
less otherwise stated. Unless otherwise stated, products were puri-
fied by flash chromatography on silica gel (230–400 mesh, Merck
or Fluka) or HPLC (Nucleosil 50–5). Unless otherwise stated,
yields refer to analytical pure samples. NMR spectra were recorded
1
fluoromethyl)pyridine (3g) as a colourless solid; m.p. 54–59 °C. H
NMR (CDCl3, 500 MHz): δ = 1.43 [s, 9 H, C(CH3)3], 5.46 (s, 2 H,
OCH2), 7.28–7.55 (m, 10 H, Ph), 7.66 (s, 1 H, 5-H) ppm. 13C NMR
(CDCl3, 126 MHz): δ = 29.2, 38.6 [q, s, C(CH3)3], 75.0 (t, OCH2),
1
83.7, 99.6 (2 s, CϵC), 121.6 (q, JCF = 273 Hz, CF3), 121.8, 124.9
3
(2 s, C-4, i-Ph), 122.8 (dq, JCF = 2.8 Hz, C-5), 124.9, 127.4, 128.1,
2
128.6, 129.4, 131.7 (6 d, Ph), 140.3 (q, JCF = 35 Hz, C-6), 136.8,
3650
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Eur. J. Org. Chem. 2008, 3647–3655

Novel Furo-pyridine Derivatives
156.9, 162.5 (3 s, C-2, C-3, i-Ph) ppm. IR (KBr): ν = 3090–3030
0.61 mmol), CuI (29 mg, 0.15 mmol), 2-methylbut-3-yn-2-ol
˜
(=C–H), 2960–2870 (C–H), 2230–2205 (CϵC), 1600–1585 (C=C) (309 mg, 3.67 mmol) in D M F (14 mL) and diisopropylamine
cm–1. MS (EI, 80 eV, 70 °C): m/z (%) = 409 (12) [M]+, 394 (14)
[M – CH3]+, 318 (2) [M – C7H7]+, 91 (100) [C7H7]+, 65 (4) [C6H5]+.
HRMS calcd. for C25H22F3NO: 409.16535; found 409.16488.
(7 mL) provided the crude product. Column chromatography on
silica gel (hexane/ethyl acetate, 10:1) afforded 924 mg (96%) of 3e
1
as a colourless solid; m.p. 56–58 °C. H NMR (CDCl3, 500 MHz):
δ = 1.37 [s, 9 H, C(CH3)3], 1.63 (s, 6 H, Me), 4.08 (s, 3 H, OMe),
7.48 (s, 1 H, 5-H) ppm; OH signal could not be detected. 13C NMR
(CDCl3, 126 MHz): δ = 28.9, 38.3 [q, s, C(CH3)3], 31.0 (q, Me),
65.7 (s, C-2Ј), 60.9 (q, OMe), 76.7, 103.8 (2 s, CϵC), 121.4 (q, 1JCF
2-Ethyl-3-methoxy-4-(phenylethynyl)-6-(trifluoromethyl)pyridine
(3a): According to method A, pyridyl nonaflate 1a (100 mg,
0.198 mmol), Pd(OAc)2 (2.3 mg, 0.01 mmol), PPh3 (10.2 mg,
0.039 mmol), CuI (1.9 mg, 0.01 mmol), phenylacetylene (30 mg,
0.29 mmol) in DMF (0.70 mL) and diisopropylamine (0.35 mL)
provided the crude product. Column chromatography on silica gel
(hexane/ethyl acetate, 40:1) afforded 43 mg (72%) of 3a as a light
yellow solid; m.p. 66–68 °C. 1H NMR (CDCl3, 500 MHz): δ = 1.29,
2.91 (t, q, J = 7.5 Hz, 3 H, 2 H, Et), 4.14 (s, 3 H, OMe), 7.38–7.55
(m, 5 H , Ph), 7.59 (s, 1 H , 5-H ) p pm. 13C N M R (CD Cl3,
126 MHz): δ = 12.8, 26.1 (q, t, Et), 61.2 (q, OMe), 83.2, 99.0 (2 s,
3
2
= 274 Hz, CF3), 122.9 (dq, JCF = 2.6 Hz, C-5), 140.1 (q, JCF
=
35 Hz, C-6), 123.8, 157.8, 162.6 (3 s, C-2, C-3, C-4) ppm. IR (KBr):
ν = 3360 (O–H), 3080–3060 (=C–H), 2990–2865 (C–H), 2250–2225
˜
(CϵC), 1600–1585 (C=C) cm–1. C16H20F3NO2 (315.3): calcd. C
60.94, H 6.39, N 4.44; found C 60.93, H 6.43, N 4.46.
3-(Benzyloxy)-2-tert-butyl-4-(3-methoxyprop-1-ynyl)-6-(trifluoro-
methyl)pyridine (3f): According to method A, pyridyl nonaflate 1d
(412 mg, 0.68 mmol), Pd(OAc)2 (8 mg, 0.04 mmol), PPh3 (36 mg,
0.14 mmol), CuI (6 mg, 0.04 mmol), methyl propargyl ether
(56 mg, 0.81 mmol) in D M F (3 mL) and diisopropylamine
(1.5 mL) provided the crude product. Column chromatography on
silica gel (hexane/ethyl acetate, 40:1) afforded 191 mg (75%) of 3f
1
3
CϵC), 121.5 (q, JCF = 274 Hz, CF3), 121.9 (dq, JCF = 2.8 Hz,
C-5), 122.4, 123.6, 128.7, 129.6, 131.7 (2 s, 3 d, C-4, Ph), 141.9 (q,
2JCF = 35.6 Hz, C-6), 156.2, 158.9 (2 s, C-2, C-3) ppm. IR (KBr):
ν = 3000–2870 (=C–H, C–H), 2220 (CϵC), 1600–1540 (C=C)
˜
cm–1. MS (EI, 80 eV, 70 °C): m/z (%) = 305 (100) [M]+, 276 (32)
[M – C2H5]+. C17H14F3NO (305.3): calcd. C 66.88, H 4.62, N 4.59;
found C 66.72, H 4.39, N 4.40.
1
as a colourless oil. H NMR (CDCl3, 500 MHz): δ = 1.41 [s, 9 H,
C(CH3)3], 3.35 (s, 3 H, OMe), 4.23, 5.37 (2 s, 2 H, 2 H, OCH2),
7.33–7.53 (m, 5 H, Ph), 7.57 (s, 1 H, 5-H) ppm. 13C NMR (CDCl3,
126 MHz): δ = 29.1, 38.5 [q, s, C(CH3)3], 58.0 (q, OMe), 60.2, 75.1
2-Phenyl-3-methoxy-4-(phenylethynyl)-6-(trifluoromethyl)pyridine
(3c): According to method A, pyridyl nonaflate 1c (100 mg,
0.181 mmol), Pd(OAc)2 (2.0 mg, 0.009 mmol), PPh3 (9.4 mg,
0.036 mmol), CuI (1.7 mg, 0.009 mmol), phenylacetylene (23 mg,
0.23 mmol) in DMF (0.8 mL) and diisopropylamine (0.4 mL) pro-
vided the crude product. Column chromatography on silica gel
(hexane/ethyl acetate, 40:1) afforded 48 mg (75%) of 3c as a colour-
less solid; m.p. 122 °C. 1H NMR (CDCl3, 500 MHz): δ = 3.91 (s,
3 H, OMe), 7.39–7.50 (m, 6 H, Ph), 7.72 (s, 1 H, 5-H), 7.61–8.01
(m, 4 H, Ph) ppm. 13C NMR (CDCl3, 126 MHz): δ = 61.2 (q,
1
(2 t, OCH2), 80.2, 95.9 (2 s, CϵC), 121.5 (q, JCF = 273 Hz, CF3),
3
122.5 (s, C-4), 123.0 (dq, JCF = 2.8 Hz, C-5), 127.4, 128.2, 128.5
2
(3 d, Ph), 140.5 (q, JCF = 30 Hz, C-6), 136.6, 156.6, 162.9 (3 s, i-
Ph, C-2, C-3) ppm. IR (film): ν = 3095–3030 (=C–H), 2960–2820
˜
(C–H), 2235–2225 (CϵC), 1590–1540 (C=C) cm–1. MS (EI, 80 eV,
80 °C): m/z (%) = 377 (1) [M]+, 362 (1) [M – CH3]+, 346 (2) [M –
OCH3]+, 91 (100) [C7H7]+, 69 (21) [CF3]+, 57 (5) [C4H9]+. HRMS
calcd. for C21H22F3NO2: 377.16026; found 377.16144.
3
OMe), 83.2, 99.0 (2 s, CϵC), 121.8 (dq, JCF = 2.9 Hz, C-5), 123.3
2-tert-Butyl-4-(phenylethynyl)-6-(trifluoromethyl)-3-[2-(trimethylsil-
yl)ethoxy]pyridine (3h): According to method A, pyridyl nonaflate
1e (212 mg, 0.35 mmol), Pd(OAc)2 (7 mg, 0.02 mmol), PPh3
(18 mg, 0.07 mmol), CuI (4 mg, 0.02 mmol), phenylacetylene
(42 mg, 0.42 mmol) in D M F (2.0 mL) and diisopropylamine
(1.0 mL) provided the crude product. Column chromatography on
silica gel (hexane/ethyl acetate, 40:1) afforded 115 mg (78%) of 3h
as a colourless solid; m.p. 61 °C. 1H NMR (CDCl3, 500 MHz): δ
= 0.02 (s, 9 H, TMS), 1.34 (t, J = 9.0 Hz, 2 H, CH2), 1.44 [s, 9 H,
C(CH3)3], 4.51 (t, J = 9.0 Hz, 2 H, OCH2), 7.35–7.56 (m, 5 H, Ph),
7.60 (s, 1 H, 5-H) ppm. 13C NMR (CDCl3, 126 MHz): δ = –1.4 (q,
TMS), 19.1 (t, CH2), 29.2, 38.6 [q, s, C(CH3)3], 71.8 (t, OCH2),
1
(q, JCF = 275 Hz, CF3), 126.1, 128.4, 128.7, 129.4, 129.5, 129.7,
2
131.9, 136.2, 138.6 (2 s, 6 d, s, C-4, Ph), 142.6 (q, JCF = 35.5 Hz,
C-6), 152.8, 156.5 (2 s, C-2, C-3) ppm. IR (KBr): ν = 3000–2940
˜
(= C–H , C–H), 2220 (CϵC), 1600–1580 (C=C) cm–1. MS (EI,
80 eV, 80 °C): m/z (%) = 353 (100) [M]+, 352 (64) [M – H]+. HRMS
calcd. for C21H14F3NO: 353.10275; found 353.10377.
2-tert-Butyl-4-(hex-1-ynyl)-3-methoxy-6-(trifluoromethyl)pyridine
(3d): According to method A, pyridyl nonaflate 1b (100 mg,
0.188 mmol), Pd(OAc)2 (2.5 mg, 0.013 mmol), PPh3 (10 mg,
0.037 mmol), CuI (1.8 mg, 0.009 mmol), 1-hexyne (46 mg,
0.56 mmol) in DMF (0.8 mL) and diisopropylamine (0.4 mL) pro-
vided the crude product. Column chromatography on silica gel
(hexane/ethyl acetate, 40:1) afforded 36 mg (61%) of 3d as a light
1
84.2, 98.5 (2 s, CϵC), 121.7 (q, JCF = 274 Hz, CF3), 122.1, 124.3
3
(2 s, C-4, i-Ph), 122.8 (qd, JCF = 2.8 Hz, C-5), 128.6, 129.4, 131.6
2
1
(3 d, Ph), 139.8 (q, JCF = 37 Hz, C-6), 156.6, 162.6 (2 s, C-2, C-
yellow oil. H NMR (CDCl3, 500 MHz): δ = 0.94 (t, J = 7.4 Hz, 3
3) ppm. IR (KBr): ν = 3090–3070 (=C–H), 3000–2870 (C–H),
˜
H, Me), 1.39 [s, 9 H, C(CH3)3], 1.43–1.53, 1.60–1.66 (2 m, 2 H
each, CH2), 2.49 (t, J = 7.5 Hz, 2 H, CH2), 4.01 (s, 3 H, OMe),
7.47 (s, 1 H, 5-H) ppm. 13C NMR (CDCl3, 126 MHz): δ = 13.6,
19.5, 22.1, 29.1 (q, 3 t, Bu), 30.4, 38.3 [q, s, C(CH3)3], 60.8 (q,
2235–2210 (CϵC), 1600–1540 (C=C) cm–1. MS (EI, 80 eV, 50 °C):
m/z (%) = 419 (1) [M ]+ , 404 (1) [M – CH 3]+ , 391 (32) [M –
C2H 4]+ , 101 (10) [C2H 4SiC3H 9]+ , 73 (100) [C3H 9Si]+ , 69 (2)
[CF3]+, 57 (6) [C4H9]+. C23H28F3NOSi (419.6): calcd. C 65.84, H
6.73, N 3.34; found C 65.89, H 6.68, N 3.29.
1
OMe), 75.4, 101.5 (2 s, CϵC), 121.6 (q, JCF = 273.5 Hz, CF3),
3
2
123.3 (dq, JCF = 2.9 Hz, C-5), 140.1 (q, JCF = 34.5 Hz, C-6),
125.3, 157.9, 162.4 (3 s, C-2, C-3, C-4) ppm. IR (KBr): ν = 2960–
˜
Typical Procedure for the Preparation of Furo-pyridine Derivatives
(Method B): To a solution of pyridine 3b (200 mg, 0.60 mmol) in
dichloromethane (6 mL) under argon atmosphere was added BBr3
(1  in CH2Cl2, 0.90 mL, 0.90 mmol) dropwise at 0 °C and warmed
up to room temperature. The reaction mixture was monitored by
TLC; upon completion, ice/water was added and the mixture was
extracted with dichloromethane (3ϫ5 mL). The combined organic
layers were washed with water and brine, dried with Na2SO4 and
2870 (=C–H, C–H), 2230 (CϵC), 1590–1540 (C=C) cm–1. MS (EI,
80 eV, 80 °C): m/z (%) = 313 (69) [M]+, 298 (100) [M – CH3]+, 57
(17) [C4H9]+. HRMS: calcd. for C17H22F3NO: 313.16534; found
313.16488.
4-[2-tert-Butyl-3-methoxy-6-(trifluoromethyl)pyridin-4-yl]-2-methyl-
but-3-yn-2-ol (3e): According to method A, pyridyl nonaflate 1b
(1.63 g, 3.06 mmol), Pd(OAc)2 (48 mg, 0.21 mmol), PPh3 (159 mg,
Eur. J. Org. Chem. 2008, 3647–3655
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3651

T. Lechel, J. Dash, I. Brüdgam, H.-U. Reißig
(q, JCF = 34.4 Hz, C-5), 150.8, 153.8, 158.1 (3 s, C-3a, C-7, C-7a)
FULL PAPER
2
evaporated under reduced pressure. The residue was dissolved in
DMF (5 mL) and K2CO3 (243 mg, 1.80 mmol) was added. After
stirring at 80 °C for 12 h, the mixture was diluted with water
(12 mL) and extracted with diethyl ether (3ϫ10 mL). The com-
bined organic phases were dried with Na2SO4 and concentrated to
dryness. Column chromatography on silica gel (hexane/ethyl ace-
tate, 10:1) afforded 139 mg (73%) of 7-tert-butyl-2-phenyl-5-(tri-
fluoromethyl)furo[2,3-c]pyridine (4) as a colourless solid; m.p. 88–
89 °C. 1H NMR (CDCl3, 500 MHz): δ = 1.61 [s, 9 H, C(CH3)3],
7.06 (s, 1 H, 3-H), 7.44–7.92 (m, 5 H, Ph), 7.77 (s, 1 H, 4-H) ppm.
13C NMR (CDCl3, 126 MHz): δ = 29.0, 37.7 [q, s, C(CH3)3], 100.7
ppm. IR (film): ν = 3120 (=C–H), 2975–2830 (C–H), 1610–1580
˜
(C=C) cm–1. MS (EI, 80 eV, 80 °C): m/z (%) = 287 (20) [M]+, 272
(83) [M – CH3]+, 242 (9) [M – C2H5O]+, 69 (10) [CF3]+, 57 (36)
[C4H9]+, 45 (45) [C2H5O]+, 41 (100), 31 (6) [OCH3]+. HRMS calcd.
for C14H16F3NO2: 287.11299; found 287.11331.
7-tert-Butyl-2-(2-methyl-1,5-diphenyl-1H-imidazol-4-yl)-5-(trifluoro-
methyl)furo[2,3-c]pyridine (6): According to method C, pyridyl non-
aflate 1e (311 mg, 0.504 mmol), Pd(OAc)2 (8 mg, 0.035 mmol),
PPh3 (28 mg, 0.106 mmol), CuI (6 mg, 0.025 mmol), 4-ethynyl-2-
methyl-1,5-diphenylimidazole (156 mg, 0.604 mmol) in D MF
(2.4 mL) and diisopropylamine (1.2 mL), TFA/CH2Cl2 (4 mL, 1:7),
K2CO3 (209 mg, 1.51 mmol) and D MF (3.0 mL) provided the
crude product. Column chromatography on silica gel (hexane/ethyl
acetate, 5:1) afforded 70 mg (29%) of 6 as a colourless solid; m.p.
241–243 °C. 1H N M R (CD Cl3, 500 M H z): δ = 1.14 [s, 9 H ,
C(CH3)3], 2.37 (s, 3 H, Me), 7.10 (s, 1 H, 3-H), 7.09–7.37 (m, 10
H, Ph), 7.72 (s, 1 H, 4-H) ppm. 13C NMR (CDCl3, 126 MHz): δ =
14.1 (q, Me), 28.5, 37.0 [q, s, C(CH3)3], 100.9 (d, C-3), 111.4 (d, C-
3
1
(d, C-3), 111.7 (dq, JCF = 2.7 Hz, C-4), 122.3 (q, JCF = 278 Hz,
2
CF 3), 121.2, 125.7, 129.2, 130.1 (3 d, s, Ph), 140.2 (q, JCF
34.4 Hz, C-5), 136.3, 150.4, 153.6, 159.0 (4s, C-2, C-3a, C-7, C-7a)
=
ppm. IR (KBr): ν = 3120 (=C–H), 2970–2870 (C–H), 1600–1570
˜
(C=C) cm–1. MS (EI, 80 eV, 60 °C): m/z (%) = 319 (59) [M]+, 304
(100) [M – CH3]+, 277 (64) [M – C(CH3)2]+, 57 (9) [C(CH3)3]+.
HRMS: calcd. for C18H16F3NO: 319.11841; found 319.11793.
2-Butyl-7-tert-butyl-5-(trifluoromethyl)furo[2,3-c]pyridine (5): Ac-
cording to method B, pyridine 3d (156 mg, 0.50 mmol), BBr3 (1 
in CH2Cl2, 0.75 mL, 0.75 mmol) in dichloromethane (4 mL) pro-
vided the crude product, which was treated with K2CO3 (203 mg,
1.50 mmol) in DMF (6 mL) at 80 °C for 12 h. Column chromatog-
raphy on silica gel (hexane/ethyl acetate, 4:1) afforded 127 mg
1
2
4), 122.3 (q, JCF = 275 Hz, CF3), 139.7 (q, JCF = 34 Hz, C-5),
127.8, 128.1, 128.4, 128.5, 128.9, 129.4, 129.5, 130.9 (3 d, s, 3 d, s,
Ph), 132.8, 135.8, 136.1 (3 s, C-3a, C-4Ј, C-5Ј), 146.6 (s, C-2Ј),
150.0, 153.1, 155.7 (3 s, C-2, C-7a, C-7) ppm. IR (KBr): ν = 3060–
˜
3010 (=C–H), 2985–2850 (C–H), 1635–1590 (C=C) cm–1. HRMS:
(ESI-TOF ) calcd. for C28H 25F 3N 3O [M H ]+ : 476.1965; found
476.1944. C28H24F3N3O (475.5): calcd. C 70.72, H 5.09, N 8.84;
found C 71.01, H 4.82, N 8.59.
1
(85%) of 5 as a light yellow liquid. H NMR (CDCl3, 500 MHz):
δ = 0.98 (t, J = 7.7 Hz, 3 H, Me), 1.55 [s, 9 H, C(CH3)3], 1.43–
1.48, 1.75–1.82 (2 m, 2 H each, CH2), 2.86 (t, J = 7.7 Hz, 2 H,
CH2), 6.47 (s, 1 H, 3-H), 7.68 (s, 1 H, 4-H) ppm. 13C NMR (CDCl3,
126 MHz): δ = 13.7, 22.3, 28.3, 28.8 (q, 3 t, Bu), 29.6, 37.5 [q, s,
C(CH3)3], 101.9 (d, C-3), 111.4 (dq, JCF = 2.6 Hz, C-4), 123.6 (q,
1JCF = 275 Hz, CF3), 139.7 (q, JCF = 35.5 Hz, C-5), 136.3, 150.5,
7-tert-Butyl-2-{4-[7-tert-butyl-5-(trifluoromethyl)furo[2,3-c]pyridin-
2-yl]phenyl}-5-(trifluoromethyl)furo[2,3-c]pyridine (13): According
to method C, pyridyl nonaflate 1b (120 mg, 0.226 mmol), Pd-
(OAc)2 (2.5 mg, 0.011 mmol), PPh3 (11.8 mg, 0.045 mmol),
CuI (1.9 mg, 0.01 mmol), 1,4-diethynylbenzene (12) (34 mg,
0.271 mmol) in DMF (1.0 mL) and diisopropylamine (0.50 mL),
BBr3 (1  in CH2Cl2, 0.51 mL, 0.51 mmol) in dichloromethane
(2 mL) provided the crude product, which was subjected with
K2CO3 (135 mg, 1.00 mmol) in DMF (6 mL) at 80 °C for 12 h.
Column chromatography on silica gel (hexane/ethyl acetate, 1:1)
afforded 88 mg (69%) of 13 as a colourless solid; m.p. 302–304 °C.
1H NMR (CDCl3, 500 MHz): δ = 1.63 [s, 18 H, C(CH3)3], 7.18 (s,
2 H, 3-H), 7.81 (s, 2 H, 4-H), 8.05 (s, 4 H, Ar) ppm. 13C NMR
(CDCl3, 126 MHz): δ = 29.0, 37.7 [q, s, C(CH3)3], 101.8 (d, C-3),
3
2
152.9, 163.5 (4s, C-2, C-3a, C-7, C-7a) ppm. IR (film): ν = 3120
˜
(=C–H), 2960–2870 (C–H), 1600–1590 (C=C) cm–1. MS (EI, 80 eV,
30 °C): m/z (%) = 299 (37) [M]+, 284 (100) [M – CH3]+, 257 (37)
[M – C(CH3)2]+, 57 (7) [C(CH3)3]+. C16H20F3NO (299.3): calcd. C
64.20, H 6.73, N 4.68; found C 63.68, H 6.41, N 4.24.
Typical Procedure for the Preparation of Furo-pyridine Derivatives
Starting from Pyridyl Nonaflates (Method C): A mixture of pyridyl
nonaflate 1e (365 mg, 0.59 mmol), Pd(OAc)2 (9 mg, 0.04 mmol),
PPh3 (31 mg, 0.12 mmol), CuI (6 mg, 0.04 mmol), methyl propargyl
ether (50 mg, 0.71 mmol) in DMF (2.6 mL) and diisopropylamine
(1.3 mL) was heated to 70 °C for 3 h under an argon atmosphere.
The mixture was cooled to room temperature, diluted with brine
(10 mL) and extracted with diethyl ether (3ϫ10 mL). The com-
bined organic phases were dried with Na2SO4 and concentrated to
dryness. The crude product was dissolved in a 1:7 mixture of TFA
and dichloromethane (4 mL). After stirring for 2 h at room tem-
perature the reaction mixture was quenched with water (10 mL)
and extracted with dichloromethane (3ϫ10 mL). The combined
organic phases were dried with Na2SO4 and concentrated to dry-
ness. The resulting crude product was dissolved in DMF (2.7 mL)
and K2CO3 (245 mg, 1.77 mmol) was added. After heating for 3 h
at 80 °C, the mixture was quenched at room temperature with water
(10 mL) and extracted with diethyl ether (3ϫ10 mL). The com-
bined organic phases were dried with Na2SO4 and concentrated to
dryness. Column chromatography on silica gel (hexane/ethyl ace-
tate, 10:1) afforded 75 mg (44%) of 7-tert-butyl-2-(methoxymethyl)-
5-(trifluoromethyl)furo[2,3-c]pyridine (7) as light yellow oil. 1H
NMR (CDCl3, 500 MHz): δ = 1.53 [s, 9 H, C(CH3)3], 3.48 (s, 3 H,
OMe), 4.63 (s, 2 H, OCH2), 6.76 (s, 1 H, 3-H), 7.75 (s, 1 H, 4-H)
3
1
111.9 (dq, JCF = 2.8 Hz, C-4), 122.3 (q, JCF = 243 Hz, CF3),
2
126.3, 130.4 (d, s, Ar), 140.5 (q, JCF = 35 Hz, C-5), 136.3, 150.5,
153.9, 157.8 (4s, C-2, C-3a, C-7, C-7a) ppm. IR (KBr): ν = 3115
˜
(=C–H), 2975–2870 (C–H), 1600–1585 (C=C) cm–1. MS (EI, 80 eV,
60 °C): m/z (%) = 560 (100) [M]+, 545 (80) [M – CH3]+, 541 (11)
[M – F]+, 503 (5) [M – C(CH3)3], 57 (8) [C(CH3)3]+. C30H26F6N2O2
(560.5): calcd. C 64.28, H 4.68, N 5.00; found C 64.17, H 4.30, N
4.70.
7,7Ј-Di(tert-butyl)-5,5Ј-bis(trifluoromethyl)-2,2Ј-bifuro[2,3-c]pyrid-
ine (10) and 2-tert-Butyl-4-[7-tert-butyl-5-(trifluoromethyl)furo-
[2,3-c]pyridin-2-yl]-6-(trifluoromethyl)pyridin-3-ol (11): According
to method C, pyridyl nonaflate 1e (618 mg, 1.00 mmol), Pd(OAc)2
(16 mg, 0.07 mmol), PPh3 (60 mg, 0.23 mmol), CuI (10 mg,
0.05 mmol), trimethylsilylacetylene (118 mg, 1.20 mmol) in DMF
(4.6 mL) and diisopropylamine (2.3 mL) provided the crude 1:1
mixture of 8 and 9 which was not separated. TFA/CH2Cl2 (4 mL,
1:7), K2CO3 (829 mg, 6.00 mmol) and DMF (5 mL) provided the
crude product. Column chromatography on silica gel (hexane/ethyl
acetate, 20:1Ǟ10:1) afforded 30 mg (12%) of 10 as a colourless
solid and 65 mg (28%) of 11 as a light yellow solid.
ppm. 13C NMR (CDCl3, 126 MHz): δ = 28.8, 37.5 [q, s, C(CH3)3],
3
58.8 (q, OMe), 67.0 (t, OCH2), 104.8 (d, C-3), 112.0 (dq, JCF
=
Data for 10: M.p. 210–214 °C. 1H NMR (CDCl3, 500 MHz): δ =
1.61 [s, 18 H, C(CH3)3], 7.36 (s, 2 H, 3-H), 7.85 (s, 2 H, 4-H) ppm.
1
2.9 Hz, C-4), 122.3 (q, JCF = 273 Hz, CF3), 135.3 (s, C-2), 140.0
3652
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 3647–3655

Novel Furo-pyridine Derivatives
13C NMR (CDCl3, 126 MHz): δ = 28.8, 37.8 [q, s, C(CH3)3], 104.9
7-tert-Butyl-2-phenyl-3-(2-phenylethenyl)-5-(trifluoromethyl)-
furo[2,3-c]pyridine (16): A mixture of furo-pyridine 14 (43 mg,
0.097 mmol), Pd(OAc)2 (1.5 mg, 0.006 mmol), LiCl (20 mg,
0.485 mmol) and styrene (61 mg, 0.582 mmol) in DMF (0.44 mL)
and Et3N (0.22 mL) was heated to 70 °C for 5 h under an argon
atmosphere. The mixture was cooled to room temperature and di-
luted with brine (5 mL) and extracted with diethyl ether (3ϫ5 mL).
The combined organic phases were dried with Na2SO4 and concen-
trated to dryness. The residue was purified by column chromatog-
raphy on silica gel (hexane/ethyl acetate, 40:1) to give 34 mg (83%)
of 16 as a colourless solid; m.p. 123 °C. 1H N M R (CD Cl3,
500 MHz): δ = 1.62 [s, 9 H, C(CH3)3], 7.26, 7.31 (2 d, J = 16.6 Hz,
1 H each, HC=CH), 7.29–7.89 (m, 10 H, Ph), 8.08 (s, 1 H, 4-H)
ppm. 13C NMR (CDCl3, 126 MHz): δ = 28.6, 37.6 [q, s, C(CH3)3],
3
1
(d, C-3), 112.3 (dq, JCF = 2.4 Hz, C-4), 122.0 (q, JCF = 273 Hz,
2
CF3), 135.2 (s, C-2), 140.9 (q, JCF = 34.5 Hz, C-5), 148.9, 150.8,
154.5 (3 s, C-7, C-7a, C-3a) ppm. 19F NMR (CDCl3, 470 MHz): δ
= –66.7 (s, CF ) ppm. IR (KBr): ν = 2980–2845 (=C–H, C–H),
˜
3
1740–1580 (C = C ) cm – 1 . H R M S: (E SI -T O F ) ca lcd . fo r
C24H23F6N2O2 [MH]+: 485.1658; found 485.1635.
Data for 11: M.p. 126–129 °C. 1H NMR (CDCl3, 500 MHz): δ =
1.53, 1.61 [2 s, 9 H each, C(CH3)3], 7.35 (br. s, 1 H, OH), 7.42 (s,
1 H, 3-H), 7.84 (s, 1 H, 4Ј-H), 7.86 (s, 1 H, 4-H) ppm. 13C NMR
(CDCl3, 126 MHz): δ = 28.5, 29.1, 37.7, 38.4 [2q, 2 s, C(CH3)3],
3
106.6 (d, C-3), 112.3, 116.4 (2 dq, both JCF = 2.8 Hz each, C-4),
1
1
121.7 (s, C-4Ј), 121.6, 122.0 (2q, JCF = 273, JCF = 274 Hz, CF3),
2
2
135.2 (s, C-2), 138.8, 141.2 (2q, JCF = 34.6, JCF = 35.5 Hz, C-5,
C-6Ј), 149.5, 149.9, 154.0, 154.1, 158.4 (5s, C-2Ј, C-7, C-4Ј, C-7a,
C-3Ј) ppm. 19F NMR (CDCl3, 470 MHz): δ = –67.2, –66.7 (2 s,
3
111.5 (dq, JCF = 3 Hz, C-4), 114.1 (s, C-3), 118.1 (d, HC=), 122.3
1
(q, JCF = 274 Hz, CF3), 126.5, 128.1, 128.2, 128.9, 129.1, 129.7,
2
129.9, 135.1 (6 d, 2 s, Ph), 132.9 (d, HC=), 140.3 (q, JCF = 34 Hz,
CF ) ppm. IR (KBr): ν = 3615, 3530 (O–H, N–H), 2970–2850 (=C–
˜
3
C-5), 137.0, 149.9, 154.0, 155.4 (4s, C-7, C-7a, C-3a, C-2) ppm. IR
H, C–H), 1725–1580 (C=C) cm–1. HRMS: (ESI-TOF) calcd. for
(K Br): ν = 3110–3025 (= C–H), 2990–2865 (C–H ), 1650–1600
˜
C22H23F6N2O2 [MH]+: 461.1658; found 461.1670.
(C=C) cm–1. MS (EI, 80 eV, 50 °C): m/z (%) = 421 (100) [M]+, 406
(53) [M – CH3]+, 77 (2) [C6H5]+, 69 (1) [CF3]+. HRMS calcd. for
C26H22F3NO: 421.16534; found 421.16501.
7-tert-Butyl-3-iodo-2-phenyl-5-(trifluoromethyl)furo[2,3-c]pyridine
(14): To a solution of pyridine 3g (150 mg, 0.367 mmol) in 1,2-
dichloroethane (2 mL) was added dropwise ICl (1.10 mL, 1  in
CH2Cl2, 1.10 mmol). After heating to 80 °C in a sealed tube for
1 d the reaction mixture was diluted with satd. aq. Na2S2O5 solu-
tion (5 mL) and extracted with dichloromethane (3ϫ5 mL). The
combined organic phases were dried with Na2SO4 and concen-
trated to dryness. The residue was purified by column chromatog-
raphy on silica gel (hexane/ethyl acetate, 40:1) to give 82 mg (50%)
7-tert-Butyl-2-phenyl-3-(phenylethynyl)-5-(trifluoromethyl)furo[2,3-c]-
pyridine (17): A mixture of furo-pyridine 14 (30 mg, 0.067 mmol),
Pd(OAc)2 (1 mg, 0.005 mmol), PPh3 (5 mg, 0.02 mmol), CuI (1 mg,
0.005 mmol) and phenylacetylene (8 mg, 0.08 mmol) in D MF
(0.3 mL) and diisopropylamine (0.15 mL) was heated to 70 °C for
3 h under an argon atmosphere. The mixture was cooled to room
temperature, diluted with brine (5 mL) and extracted with diethyl
ether (3ϫ5 mL). The combined organic phases were dried with
Na2SO4 and concentrated to dryness. The residue was purified by
column chromatography on silica gel (hexane/ethyl acetate, 40:1)
to give 28 mg (99%) of 17 as a colourless solid; m.p. 112 °C. 1H
NMR (CDCl3, 500 MHz): δ = 1.62 [s, 9 H, C(CH3)3], 7.40–7.65
(m, 8 H, Ph), 7.92 (s, 1 H, 4-H), 8.31–8.37 (m, 2 H, Ph) ppm. 13C
NMR (CDCl3, 126 MHz): δ = 28.9, 37.9 [q, s, C(CH3)3], 79.2, 97.9
1
of 14 as a colourless solid and 35 mg (23%) of 3g; m.p. 176 °C. H
NMR (CDCl3, 500 MHz): δ = 1.58 [s, 9 H, C(CH3)3], 7.49–8.21 (m,
5 H, Ph), 7.64 (s, 1 H, 4-H) ppm. 13C NMR (CDCl3, 126 MHz): δ
3
= 28.9, 37.5 [q, s, C(CH3)3], 59.6 (s, C-3), 112.7 (dq, JCF = 2.7 Hz,
1
C-4), 122.1 (q, JCF = 274 Hz, CF3), 127.9, 128.8, 128.9, 130.5 (3
2
d, s, Ph), 140.0 (q, JCF = 30 Hz, C-5), 140.1, 150.0, 153.9, 155.9
(4s, C-2, C-3a, C-7, C-7a) ppm. IR (KBr): ν = 3060–3050 (=C–H),
˜
2990–2865 (C–H), 1605–1530 (C=C) cm–1. MS (EI, 80 eV, 100 °C):
m/z (%) = 445 (100) [M]+, 430 (97) [M – CH3]+, 318 (2) [M – I]+,
126 (5) [I]+, 77 (5) [C6H5]+, 69 (11) [CF3]+, 57 (11) [C4H9]+. HRMS:
ca lcd . fo r C 1 8 H 1 5 F 3 I N O : 445.01505; fo u n d 445. 01622.
3
(2 s, CϵC), 99.2 (s, C-3), 111.3 (dq, JCF = 3 Hz, C-4), 121.1 (q,
1JCF = 273 Hz, CF3), 122.6, 126.6, 128.6, 128.9, 129.0, 130.6, 131.7,
2
133.5 (s, 6 d, s, Ph), 140.8 (q, JCF = 36 Hz, C-5), 137.4, 149.1,
153.8, 158.6 (4s, C-7, C-7a, C-3a, C-2) ppm. IR (KBr): ν = 3090–
˜
3030 (= C–H ), 3000–2870 (C–H ), 1610–1560 (C= C ) cm–1
26H20F3NO (419.4): calcd. C 74.45, H 4.81, N 3.34; found C
74.35, H 4.59, N 3.25.
.
C
18H15F3INO (445.2): calcd. C 48.56, H 3.40, N 3.15; found C
48.87, H 3.46, N 3.10.
C
7-tert-Butyl-2,3-diphenyl-5-(trifluoromethyl)furo[2,3-c]pyridine (15):
A mixture of furo-pyridine 14 (35 mg, 0.078 mmol), Pd(OAc)2
(1 mg, 0.005 mmol), PPh3 (5 mg, 0.02 mmol), K2CO3 (11 mg,
0.078 mmol) and phenylboronic acid (11 mg, 0.094 mmol) in DMF
(0.36 mL) was heated to 70 °C for 4 h under an argon atmosphere.
The mixture was cooled to room temperature, diluted with brine
(5 mL) and extracted with diethyl ether (3ϫ5 mL). The combined
organic phases were dried with Na2SO4 and concentrated to dry-
ness. The residue was purified by column chromatography on silica
gel (hexane/ethyl acetate, 40:1) to give 24 mg (78%) of 15 as a
colourless solid; m.p. 194 °C. 1H NMR (CDCl3, 500 MHz): δ =
1.64 [s, 9 H, C(CH3)3], 7.35–7.71 (m, 10 H, Ph), 7.66 (s, 1 H, 4-H)
ppm. 13C NMR (CDCl3, 126 MHz): δ = 29.0, 37.6 [q, s, C(CH3)3],
4-(Benzyloxy)-2-tert-butyl-6-(trifluoromethyl)pyridin-3-yl-
1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (19): To a solution of
pyridinol 18 (2.53 g, 7.53 mmol) in THF (15 mL) were added NaH
(904 mg, 60 % in mineral oil, 22.6 mmol) and benzyl bromide
(2.69 mL, 22.6 mmol) at room temperature and stirred for 3 d. The
mixture was slowly diluted with water (15 mL) and extracted with
diethyl ether (3ϫ15 mL), dried with Na2SO4 and concentrated to
dryness. The residue was diluted in dichloromethane (10 mL) and
TFA (5 mL) was added. The reaction mixture was stirred at room
temperature for 8 h and quenched with water (20 mL), extracted
with dichloromethane (3ϫ20 mL), dried with Na2SO4 and concen-
trated to dryness. The crude product was dissolved in THF (15 mL)
and NaH (904 mg, 60% in mineral oil, 22.6 mmol) was added. Af-
ter dropwise addition of nonafluorobutanesulfonyl fluoride
(4.07 mL, 22.6 mmol) the mixture was stirred at room temperature
for 3 d and quenched by slow addition of water (20 mL). It was
extracted with ethyl acetate (3ϫ20 mL), dried with Na2SO4 and
concentrated to dryness. The residue was purified by column
3
1
110.8 (dq, JCF = 2.6 Hz, C-4), 117.1 (s, C-3), 122.2 (q, JCF
=
274 Hz, CF3), 127.4, 128.4, 128.7, 129.36, 129.43, 129.5, 129.7,
2
131.2 (6 d, 2 s, Ph), 140.6 (q, JCF = 34 Hz, C-5), 137.3, 153.5,
153.7, 156.4 (4s, C-7a, C-7, C-3a, C-2) ppm. IR (KBr): ν = 3115–
˜
3030 (=C–H), 2990–2850 (C–H), 1750–1690 (C=C) cm–1. MS (EI,
80 eV, 120 °C): m/z (%) = 395 (32) [M]+, 380 (78) [M – CH3]+, 77
(36) [C6H5]+, 69 (18) [CF3]+, 57 (41) [C4H9]+, 41 (100). HRMS chromatography on silica gel (hexane/ethyl acetate, 40:1) to afford
1
calcd. for C24H20F3NO: 395.14969; found 395.14922.
1.97 g (43%) of 19 as a colourless solid; m.p. 90–92 °C. H NMR
Eur. J. Org. Chem. 2008, 3647–3655
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3653

T. Lechel, J. Dash, I. Brüdgam, H.-U. Reißig
FULL PAPER
(CDCl3, 500 MHz): δ = 1.48 [s, 9 H, C(CH3)3], 5.24 (s, 2 H, OCH2),
7.21 (s, 1 H, 5-H), 7.35–7.41 (m, 5 H, Ph) ppm. 13C NMR (CDCl3,
6), 158.1, 160.4, 164.6 (3 s, C-2, C-4, C-7a) ppm. IR (KBr): ν =
˜
3090–3060 (=C–H), 3005–2865 (C–H), 1605–1545 (C=C) cm–1. MS
126 MHz): δ = 29.4, 38.7 [q, s, C(CH3)3], 72.2 (t, OCH2), 105.1 (EI, 80 eV, 70 °C): m/z (%) = 445 (90) [M ]+ , 430 (100) [M –
(dq, 3JCF = 3 Hz, C-5), 120.7 (q, 1JCF = 275 Hz, CF3), 128.1, 128.9,
CH3]+, 426 (7) [M – F]+, 318 (19) [M – I]+, 77 (22) [C6H5]+, 69 (12)
[CF 3]+ , 57 (29) [C4H 9]+ . H R M S calcd. for C18H 15F 3IN O:
445.01505; found 445.01433. C18H15F3INO (445.2): calcd. C 48.56,
H 3.40, N 3.15; found C 48.07, H 2.92, N 3.07.
2
129.1, 133.6 (3 d, s Ph), 146.2 (q, JCF = 35 Hz, C-6), 136.1, 157.5,
163.0 (3 s, C-2, C-3, C-4) ppm. 19F NMR (CDCl3, 470 MHz): δ =
–68.2 (s, CF3), –80.6 (m, 4Ј-F), –105.4 (m, 3Ј-F), –120.7 (m, 2Ј-F),
–125.6 (m, 1Ј-F) ppm. IR (KBr): ν = 3105–3025 (=C–H), 3010–
˜
4-tert-Butyl-2-phenyl-3-(phenylethynyl)-6-(trifluoromethyl)furo[3,2-c]-
pyridine (23): A mixture of furo-pyridine 22 (62 mg, 0.139 mmol),
Pd(OAc)2 (2 mg, 0.010 mmol), PPh3 (7 mg, 0.028 mmol), CuI
(1 mg, 0.005 mmol) and phenylacetylene (17 mg, 0.167 mmol) in
DMF (0.6 mL) and diisopropylamine (0.3 mL) was heated to 70 °C
for 4 h under an argon atmosphere. The mixture was cooled to
room temperature and diluted with brine (5 mL) and extracted with
diethyl ether (3ϫ5 mL). The combined organic phases were dried
with Na2SO4 and concentrated to dryness. The residue was purified
by column chromatography on silica gel (hexane/ethyl acetate, 40:1)
to give 25 mg (43%) of 23 as a colourless solid and 23 mg (52%)
2850 (C–H), 1605–1560 (C=C) cm–1. C21H17F12NO4S (607.4):
calcd. C 41.52, H 2.82, N 2.31, S 5.28; found C 41.49, H 2.52, N
2.31, S 5.04.
4-(Benzyloxy)-2-tert-butyl-3-(phenylethynyl)-6-(trifluoromethyl)pyr-
idine (20): According to method A, pyridyl nonaflate 19 (278 mg,
0.458 mmol), Pd(OAc)2 (7 mg, 0.032 mmol), PPh3 (24 mg,
0.092 mmol), CuI (4 mg, 0.023 mmol), phenylacetylene (55 mg,
0.550 mmol) in DMF (2.2 mL) and diisopropylamine (1.1 mL) pro-
vided the crude product. Column chromatography on silica gel
(hexane/ethyl acetate, 40:1) afforded 127 mg (68 %) of 20 as a
colourless solid; m.p. 120 °C. 1H NMR (CDCl3, 500 MHz): δ =
1.62 [s, 9 H, C(CH3)3], 5.24 (s, 2 H, OCH2), 7.14 (s, 1 H, 5-H),
7.37–7.56 (m, 10 H, Ph) ppm. 13C NMR (CDCl3, 126 MHz): δ =
29.0, 39.7 [q, s, C(CH3)3], 70.6 (t, OCH2), 83.2, 104.2 (2 s, CϵC),
1
of 21; m.p. 112 °C. H NMR (CDCl3, 500 MHz): δ = 1.72 [s, 9 H,
C(CH3)3], 7.48–8.39 (m, 10 H, Ph), 7.74 (s, 1 H, 7-H) ppm. 13C
NMR (CDCl3, 126 MHz): δ = 30.0, 39.4 [q, s, C(CH3)3], 84.3, 98.4,
98.5 (3 s, C-3, CϵC), 103.1 (dq, 3JCF = 3.9 Hz, C-7), 121.9 (q, 1JCF
= 274 Hz, CF3), 122.9, 124.8, 128.6, 128.7, 128.9, 129.1, 130.3,
3
1
101.7 (dq, JCF = 3 Hz, C-5), 121.4 (q, JCF = 274 Hz, CF3), 145.7
2
131.1 (s, 6 d, s, Ph), 141.5 (q, JCF = 35 Hz, C-6), 127.1, 159.0,
2
(q, JCF = 34 Hz, C-6), 123.3, 127.0, 128.2, 128.5, 128.7, 128.8,
159.5, 165.2 (4s, C-2, C-3a, C-4, C-7a) ppm. IR (film): ν = 3085–
˜
131.1, 135.4 (s, 6 d, s, Ph), 110.1, 166.9, 171.2 (3 s, C-2, C-3, C-4)
3030 (=C–H), 2960–2850 (C–H), 2195 (CϵC), 1600–1560 (C=C)
cm–1. MS (EI, 80 eV, 130 °C): m/z (%) = 419 (56) [M]+, 404 (7)
[M – CH3]+, 342 (15) [M – C6H5]+, 101 (7) [C8H5]+, 77 (31) [C6H5],
69 (32) [CF3]+, 57 (100) [C4H9]+. HRMS calcd. for C18H16F3NO:
419.14969; found 419.14862.
ppm. IR (KBr): ν = 3080–3010 (=C–H), 2985–2860 (C–H), 2210–
˜
2200 (CϵC), 1600–1545 (C=C) cm–1. MS (EI, 80 eV, 150 °C): m/z
(%) = 409 (19) [M]+, 394 (6) [M – CH3]+, 318 (8) [M – C7H7]+, 91
(100) [C7H7]+, 69 (3) [CF3]+, 57 (8) [C4H9]+. C25H22F3NO (409.4):
calcd. C 73.34, H 5.42, N 3.42; found C 73.01, H 5.17, N 3.37.
2-tert-Butyl-5-iodo-3-methoxy-6-(trifluoromethyl)pyridin-4-ol (25):
A mixture of pyridine 24 (229 mg, 0.919 mmol), K2CO3 (381 mg,
2.76 mmol), I2 (700 mg, 2.76 mmol) in MeCN (5 mL) was heated
to 70 °C for 3 d in a sealed tube. The mixture was cooled to room
temperature and diluted with satd. aq. Na2S2O5 solution (5 mL)
and extracted with dichloromethane (3ϫ5 mL). The combined or-
ganic phases were dried with Na2SO4 and concentrated to dryness.
The residue was purified by column chromatography on silica gel
(hexane/ethyl acetate, 10:1) to give 280 mg (81%) of 25 as a colour-
4-tert-Butyl-2-phenyl-6-(trifluoromethyl)furo[3,2-c]pyridine (21): Ac-
cording to method B, pyridine 20 (120 mg, 0.29 mmol), BBr3 (1 
in CH2Cl2, 0.88 mL, 0.88 mmol) in dichloromethane (3 mL) pro-
vided the crude product, which was treated with K2CO3 (122 mg,
0.88 mmol) in DMF (5 mL) at 80 °C for 12 h. Column chromatog-
raphy on silica gel (hexane/ethyl acetate, 10:1) afforded 52 mg
(56%) of 21 as a colourless solid; m.p. 94–95 °C. 1H NMR (CDCl3,
500 MHz): δ = 1.54 [s, 9 H, C(CH3)3], 7.27 (s, 1 H, 3-H), 7.41–7.90
(m, 5 H , Ph), 7.70 (s, 1 H , 7-H ) p pm. 13C N M R (CD Cl3,
126 MHz): δ = 29.8, 39.2 [q, s, C(CH3)3], 100.8 (d, C-3), 102.7 (dq,
1
less oil. H NMR (CDCl3, 500 MHz): δ = 1.38 [s, 9 H, C(CH3)3],
3.91 (s, 3 H, OMe), 6.38 (br. s, 1 H, OH) ppm. 13C NMR (CDCl3,
1
3JCF = 3.3 Hz, C-7), 122.2 (q, JCF = 273 Hz, CF3), 124.8 125.4,
126 MHz): δ = 29.0, 37.9 [q, s, C(CH3)3], 60.9 (q, OMe), 80.0 (s,
2
129.0, 129.1, 129.7 (s, 3 d, s, C-3a, Ph), 141.3 (q, JCF = 34.8 Hz,
1
2
C-5), 121.1 (q, JCF = 275 Hz, CF3), 142.3 (q, JCF = 34 Hz, C-6),
144.0, 155.8, 160.3 (3 s, C-2, C-3, C-4) ppm. IR (film): ν = 3430–
C-6), 157.3, 159.8, 163.8 (3 s, C-2, C-4, C-7a) ppm. IR (KBr): ν =
˜
˜
3090–3040 (=C–H), 2990–2850 (C–H), 1605–1560 (C=C) cm–1. MS
(EI, 80 eV, 70 °C): m/z (%) = 319 (55) [M ]+ , 304 (100) [M –
CH3]+, 284 (24) [M – CH3 – HF]+, 77 (4) [C6H5]+. HRMS calcd.
for C18H16F3NO: 319.11840; found 319.11808.
3420 (O–H ), 2960–2860 (C –H ), 1705–1690 (C = C ) cm– 1
.
C11H13F3INO2 (375.1): calcd. C 35.22, H 3.49, N 3.73; found C
35.40, H 3.24, N 3.75.
6-tert-Butyl-7-methoxy-2-phenyl-4-(trifluoromethyl)furo[3,2-c]pyrid-
4-tert-Butyl-3-iodo-2-phenyl-6-(trifluoromethyl)furo[3,2-c]pyridine ine (26): According to method A, pyridine 25 (207 mg,
(22): To a solution of pyridine 20 (230 mg, 0.562 mmol) in 1,2-
dichloroethane (2 mL) was added dropwise ICl (1.68 mL, 1  in
CH2Cl2, 1.68 mmol). After heating to 80 °C in a sealed tube for
1 d the reaction mixture was diluted with satd. aq. Na2S2O5 solu-
tion (5 mL) and extracted with dichloromethane (3ϫ5 mL). The
combined organic phases were dried with Na2SO4 and concen-
trated to dryness. The residue was purified by column chromatog-
0.552 mmol), Pd(OAc)2 (9 mg, 0.039 mmol), PPh3 (29 mg,
0.110 mmol), CuI (5 mg, 0.028 mmol), phenylacetylene (66 mg,
0.662 mmol) in DMF (2.54 mL) and diisopropylamine (1.27 mL)
provided the crude product. Column chromatography on silica gel
(hexane/ethyl acetate, 30:1) afforded 192 mg (99%) of 26 as a
colourless solid; m.p. 140 °C. 1H NMR (CDCl3, 500 MHz): δ =
1.47 [s, 9 H, C(CH3)3], 4.36 (s, 3 H, OMe), 7.12 (s, 1 H, 3-H), 7.42–
raphy on silica gel (hexane/ethyl acetate, 40:1) to give 159 mg (64%) 7.88 (m, 5 H, Ph) ppm. 13C NMR (CDCl3, 126 MHz): δ = 29.1,
1
of 22 as a colourless solid and 64 mg (28%) of 20; m.p. 108–110 °C.
38.3 [q, s, C(CH3)3], 98.4 (d, C-3), 122.2 (q, JCF = 274 Hz, CF3),
1H NMR (CDCl3, 500 MHz): δ = 1.71 [s, 9 H, C(CH3)3], 7.50–7.94 125.3, 125.4, 128.9, 129.0, 129.8 (s, 3 d, s, C-3a, Ph), 131.3 (q, JCF
2
(m, 5 H , Ph), 7.72 (s, 1 H , 7-H ) p pm. 13C N M R (CD Cl3,
= 35.5 Hz, C-4), 141.8, 151.1, 153.9, 157.9 (4s, C-6, C-7, C-7a, C-
2) ppm. IR (KBr): ν = 3000–2840 (C–H), 1620–1560 (C=C) cm–1
126 MHz): δ = 32.0, 39.6 [q, s, C(CH3)3], 59.0 (s, C-3), 103.3 (dq,
.
˜
3JCF = 2.9 Hz, C-7), 106.4 (s, C-3a), 122.9 (q, 1JCF = 273 Hz, CF3),
C19H18F3NO2 (349.3): calcd. C 65.32, H 5.19, N 4.01; found C
2
127.2, 128.4, 129.8, 130.3 (3 d, s, Ph), 140.8 (q, JCF = 35 Hz, C- 65.17, H 5.00, N 4.06.
3654
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 3647–3655

Novel Furo-pyridine Derivatives
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Acknowledgments
Generous support of this work by the Deutsche Forschungsgemein-
schaft (DFG) (SFB 765), the Alexander von Humboldt foundation
(research fellowship for J. D.), the Fonds der Chemischen Industrie,
and the Bayer Schering Pharma AG is gratefully acknowledged.
We also thank Dr. R. Zimmer for his help during the preparation
of this manuscript.
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Published Online: June 6, 2008
Eur. J. Org. Chem. 2008, 3647–3655
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3655