Synthesis of highly functionalized biaryls by condensation of 2-fluoro-1,3-bis(silyloxy) 1,3-dienes with 3-cyanochromones and subsequent domino "retro-Michael/aldol/fragmentation"

Article abstract of DOI:10.1021/jo1018443

The Me₃SiOTf-mediated condensation of 1-ethoxy-2-fluoro-1,3- bis(trimethylsilyloxy) 1,3-dienes with 3-cyanochromones afforded 3-cyano-2-(4-ethoxy-3-fluoro-2,4-dioxobutyl)chroman-4-ones. Their reaction with triethylamine afforded fluorinated azaxanthones or biaryls. The product distribution depends on the structure of the diene. The formation of the biaryls can be explained by an unprecedented domino "retro-Michael/aldol/ fragmentation" reaction.

Full text of DOI:10.1021/jo1018443

pubs.acs.org/joc
compounds are used as ligands3 in catalytic reactions and as
Synthesis of Highly Functionalized Biaryls by
Condensation of 2-Fluoro-1,3-bis(silyloxy)
organocatalysts.4
Aryl fluorides are available by reaction of arenes with fluorine,
xenon fluorides, or related strong electrophilic reagents.5 How-
ever, these methods are often not practical because the reagents
are difficult to handle, dangerous, or expensive. Selectfluor
represents a very useful, commercially available electrophilic
fluorination agent.6 However, direct fluorinations of arenes
using Selectfluor suffer from low o/p regioselectivity.6,7 In
addition, only highly reactive (electron-rich) arenes can be
successfully used as substrates.7 The synthesis of heavily sub-
stituted fluorinated arenes is particularly difficult because of the
low reactivity of sterically hindered starting materials which are
not readily available.
An alternative approach to aryl fluorides relies on a building
block strategy.8 In recent years, we studied the chemistry of
1,3-bis(silyloxy)-1,3-butadienes9 and their application to or-
ganofluorine chemistry.10 We have also studied the reaction of
1,3-bis(silyloxy)-1,3-butadienes with chromone derivatives.11
In this context, we developed a new synthesis of azaxanthones
by condensation of 1,3-bis(silyloxy)-1,3-butadienes with 3-cy-
anochromones and the subsequent base-mediated domino12
“retro-Michael/nitrile-addition/heterocyclization” reaction.13
We have also reported a synthetic approach to biaryl lactones
1,3-Dienes with 3-Cyanochromones and Subsequent
Domino “Retro-Michael/Aldol/Fragmentation”
Muhammad Farooq Ibad,† Obaid-ur-Rahman Abid,†
Muhammad Adeel,†,‡ Muhammad Nawaz,† Verena Wolf,†
Alexander Villinger,† and Peter Langer*,†,§
†Institut fu€r Chemie der Universita€t Rostock, Albert-Einstein-
Strasse 3a, D-18059 Rostock, Germany, ‡Department of
Chemistry, Gomal University, Dera Ismail Khan, K.P.K.,
Pakistan, and §Leibniz Institut fu€r Katalyse e.V. an der
Universita€t Rostock, Albert-Einstein-Strasse 29a, D-18059
Rostock, Germany
peter.langer@uni-rostock.de
Received September 17, 2010
(3) (a) Schmidbaur, H.; Kumberger, O. Chem. Ber. 1993, 126, 3. (b)
Dinger, M. B.; Henderson, W. J. Organomet. Chem. 1998, 560, 233. (c)
€
Liedtke, J.; Loss, S.; Widauer, C.; Grutzmacher, H. Tetrahedron 2000, 56,
143. (d) Schneider, S.; Tzschucke, C. C.; Bannwarth, W. In Multiphase
Homogeneous Catalysis; Cornils, B., Herrmann, W. A., Horvath, I. T.,
Leitner, W., Mecking, S., Olivier-Booubigou, H., Vogt, D., Eds.; Wiley-
VCH: New York, 2005; Chapter 4, p 346. (e) Clarke, D.; Ali, M. A.; Clifford,
A. A.; Parratt, A.; Rose, P.; Schwinn, D.; Bannwarth, W.; Rayner, C. M.
Curr. Top. Med. Chem. 2004, 7, 729.
(4) Reviews: (a) Wittkopp, A.; Schreiner, P. R. The Chemistry of Dienes
and Polyenes; John Wiley & Sons Ltd.: New York, 2000; Vol. 2. (b) Schreiner,
P. R. Chem. Soc. Rev. 2003, 32, 289. See also: (c) Wittkopp, A.; Schreiner,
P. R. Chem.;Eur. J. 2003, 9, 407. (d) Kleiner, C. M.; Schreiner, P. R. Chem.
Commun. 2006, 4315. (e) Kotke, M.; Schreiner, P. R. Synthesis 2007, 5, 779.
Review: Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701.
(5) Reviews: (a) Tredwell, M.; Gouverneur, V. Org. Biomol. Chem. 2006,
4, 26. (b) Ma, J.-A.; Cahard, D. Chem. Rev. 2004, 104, 6119. (c) Singh, R. P.;
Shreeve, J. M. Synthesis 2002, 17, 2561. (d) Taylor, S. D.; Kotoris, C. C.;
Hum, G. Tetrahedron 1999, 55, 12431. (e) Purrington, S. T.; Kagen, B. S.;
Patrick, T. B. Chem. Rev. 1986, 86, 997.
(6) Reviews: (a) Nyffeler, P. T.; Duron, S. G.; Burkart, M. D.; Vincent,
S. P.; Wong, C.-H. Angew. Chem. 2005, 117, 196. Angew. Chem., Int. Ed.
2005, 44, 192. (b) Singh, R. P.; Shreeve, J. M. Acc. Chem. Res. 2004, 37, 31.
Banks, R. E.; Besheesh, M. K.; Mohialdin-Khaffaf, S. N.; Sharif, I. J. Chem.
Soc., Perkin Trans. 1 1996, 2069.
(7) Stavber, S.; Jereb, M.; Zupan, M. Synlett 1999, 9, 1375. For a recent
example of a Fries rearrangement of 4-fluorophenol, see: Sebille, S.; de
Tullio, P.; Becker, B.; Antoine, M.-H.; Boverie, S.; Pirotte, B.; Lebrun, P, P.
J. Med. Chem. 2005, 48, 614.
(8) For examples, see: (a) Shi, G.-q.; Cottens, S.; Shiba, S. A.; Schlosser,
M. A. Tetrahedron 1992, 48, 10569. (b) Shi, G.-q.; Schlosser, M. Tetrahedron
1993, 49, 1445. (c) Patrick, T. B.; Rogers, J.; Gorrell, K. Org. Lett. 2002, 4,
3155. Lefebvre, O.; Brigaud, T.; Portella, C. Tetrahedron 1998, 54, 5939.
(9) For a review of 1,3-bis(silyloxy)-1,3-butadienes in general, see: Langer,
P. Synthesis 2002, 441.
The Me3SiOTf-mediated condensation of 1-ethoxy-2-fluoro-
1,3-bis(trimethylsilyloxy) 1,3-dienes with 3-cyanochromones
afforded 3-cyano-2-(4-ethoxy-3-fluoro-2,4-dioxobutyl)-
chroman-4-ones. Their reaction with triethylamine afforded
fluorinated azaxanthones or biaryls. The product distribu-
tion depends on the structure of the diene. The formation of
the biaryls can be explained by an unprecedented domino
“retro-Michael/aldol/fragmentation” reaction.
Organofluorine compounds are of considerable importance
in medicinal chemistry.1 The fluorine atom combines a high
electronegativity with a small size which often results in an
improvement of drug-receptor interactions. Undesired meta-
bolic transformations are rare because of the chemical and
biological stability of the carbon-fluorine bond. The transport
of the drug is facilitated by the high lipophilicity of organo-
fluorine compounds. Fluorinated arenes and heteroarenes
are also versatile building blocks in transition-metal-catalyzed
cross-coupling reactions.2 Last but not least, organofluorine
(1) (a) Fluorine in Bioorganic Chemistry; Filler, R., Kobayasi, Y.,
Yagupolskii, L. M., Eds.; Elsevier: Amsterdam, 1993. (b) Filler, R. Fluorine
Containing Drugs in Organofluorine Chemicals and Their Industrial
Application; Pergamon: New York, 1979; Chapter 6. (c) Hudlicky, M.
Chemistry of Organic Compounds; Ellis Horwood: Chichester, 1992.
(d) Kirsch, P. Modern Fluoroorganic Chemistry; VCH: Weinheim, 2004.
(e) Chambers, R. D. Fluorine in Organic Chemistry; Blackwell Publishing
CRC Press: Boca Raton, 2004.
(10) For a review of applications of 1,3-bis(silyloxy)-1,3-butadienes in
fluorine chemistry, see: Langer, P. Synlett 2009, 2205.
(11) For a review of reactions of chromones with 1,3-bis(silyloxy)-1,
3-butadienes, see: Langer, P. Synlett 2007, 1016.
(12) For reviews of domino reactions, see: (a) Tietze, L. F.; Beifuss, U.
Angew. Chem. 1993, 105, 137; Angew. Chem., Int. Ed. Engl. 1993, 32, 131. (b)
Tietze, L. F. Chem. Rev. 1996, 96, 115.
(13) (a) Langer, P.; Appel, B. Tetrahedron Lett. 2003, 5133. (b) Rashid,
M. A.; Rasool, N.; Appel, B.; Adeel, M.; Karapetyan, V.; Mkrtchyan, S.;
Reinke, H.; Fischer, C.; Langer, P. Tetrahedron 2008, 64, 5416.
(2) Metal-Catalyzed Cross-Coupling Reactions; de Meijere, A., Diederich,
F., Eds.; Wiley-VCH: Weinheim, 2004.
DOI: 10.1021/jo1018443
r
Published on Web 11/09/2010
J. Org. Chem. 2010, 75, 8315–8318 8315
2010 American Chemical Society

Ibad et al.
JOCNote
SCHEME 1. Synthesis of 1b-ia
SCHEME 2. Synthesis of 3a-ia
aConditions: (i) 1) LDA (2.3 equiv), THF, -78 °C, 1 h; (2) BnBr or
R-I, -78 f þ20 °C, 14 h; (3) HCl (10%).
TABLE 1. Synthesis of 1b-i
1
R
% yielda
aConditions: (i) Me3SiCl, NEt3, benzene, 20 °C, 48 h; (ii) (1) LDA,
THF, -78 °C, 1 h, (2) Me3SiCl, -78 f þ20 °C, 14 h.
b
c
d
e
f
g
h
i
Bn
Me
n-Pr
n-Bu
n-Pent
n-Hex
n-Oct
n-Dec
60
59
59
63
74
64
62
61
TABLE 2. Synthesis of 3a-f
2, 3
R
2a (%)
3a (%)
a
b
c
d
e
f
g
h
i
H
Bn
Me
n-Pr
n-Bu
n-Pent
n-Hex
n-Oct
n-Dec
81
83
67
82
80
65
77
84
81
94
91
88
90
93
89
87
94
92
aYields of isolated products.
by condensation of 1,3-bis(silyloxy)-1,3-butadienes with chro-
mones and subsequent base-mediated domino “retro-Mi-
chael/aldol/lactonization” reaction.14 Herein, we report, for
the first time, the reaction of 3-cyanochromones with 2-fluoro-
1,3-bis(silyloxy) 1,3-dienes which give rise to the unexpected
formation of highly functionalized fluorinated biaryls. The
formation of the products can be explained by an hitherto
unprecedented domino “retro-Michael/aldol/fragmentation”
reaction. These reactions are preparatively useful as they
provide a convenient approach to highly substituted fluori-
nated biaryls which are not readily available by other methods.
For our studies, there was the need to develop a new and
general method for the synthesis of various 2-fluoro-3-oxoesters.
The reaction of 1,3-dicarbonyl dianions with alkyl halides has
been widely used for the synthesis of β-ketoesters.15 The applica-
tion of this methodology to the synthesis of fluorinated deriva-
tives has, to the best of our knowledge, not been reported to date.
We were pleased to find that the reaction of the dianion of com-
mercially available ethyl 2-fluoroacetoacetate (1a) with benzyl
bromide and various alkyl iodides afforded the 2-fluoro-3-oxo
esters 1b-i(Scheme 1, Table 1). The yields (59-74%) are typical
for dianion reactions, and the experiments thus show that the
fluorine substituent is compatible with the reaction conditions.
The silylation of 1a-i afforded silyl enol ethers 2a-i. The
latter were transformed, by deprotonation (LDA) at -78 °C
and subsequent addition of trimethylchlorosilane, into the
1-ethoxy-2-fluoro-1,3-bis(trimethylsilyloxy) 1,3-dienes 3a-i
(Scheme 2, Table 2). The fluorine substituent again proved to
be compatible with the reaction conditions. The synthesis of
3a has been previously reported.16 Dienes 3a-i can be stored
at -20 °C under inert atmosphere for several weeks.
aYields of isolated products.
reaction gave intermediate A, which underwent a nitrile addition
to give intermediate C. Heterocyclization of the latter af-
forded 5a. A completely different product, fluorinated biaryl 6b
(72% yield), was obtained when 4a was reacted with diene 3b
(Scheme 3). The isomeric azaxanthone 5b was isolated in only
14% yield. The formation of 6b can be explained by a domino
“retro-Michael/aldol/1,5-ester-shift” reaction (path B). A pro-
ton shift of intermediate A afforded B, which underwent an
intramolecular aldol reaction to give D. An intramolecular ester
shift (intermediate E) and subsequent aromatization gave rise to
the formation of 6b. This process is related to the formation of
biaryl lactones by condensation of 1,3-bis(silyloxy)-1,3-buta-
dienes with simple chromones and subsequent base-mediated
domino “retro-Michael/aldol/lactonization” reaction.14 In con-
trast to this process, a direct aromatization during the intramo-
lecular aldol reaction is not possible in the present reaction
because a quaternary carbon atom is involved. However, the
aromatization can take place because of the fragmentation.
The experiments described above suggest that the product
distribution depends on the chain length of the diene. To prove
this assumption, the substituents of the diene and of the
chromone were systematically varied (Scheme 4, Table 3). The
reaction of parent 3-cyanochromone (4a) with substituted dienes
3c-i mainly afforded the biaryls 6b-h. Azaxanthones were
isolated as side products or not at all. The reaction of unsub-
stituted diene 3a with 3-cyanochromone 4c, containing two
electron-donating methyl groups, exclusively afforded azax-
anthone 5j. In contrast, biaryls 6k,l were the main products in
the reaction of 4c with substituted dienes 3d,g.
The Me3SiOTf-mediated reaction of 3a with 3-cyanochro-
mone (4a) afforded 3-cyano-2-(4-ethoxy-3-fluoro-2,4-dioxo-
butyl)chroman-4-one 7a. The reaction of an ethanol solution
of the crude product of 7a with triethylamine afforded the
fluorinated azaxanthone 5a in 56% yield (Scheme 3). Its forma-
tion can be explained by a domino “retro-Michael/nitrile-addi-
tion/heterocyclization” reaction (path A). The retro-Michael
The reaction of 3a with 3-cyanochromones 4f and 4g,
containing electron-withdrawing halogen substituents, ex-
clusively afforded the azaxanthones 5w and 5ab. In contrast,
fluorinated biaryls were formed in the reaction of 4e-g with
substituted dienes. The structures of 5ab and 6d were in-
dependently confirmed by X-ray crystal structure analyses
(see the Supporting Information).
(14) Appel, B.; Saleh, N. N. R.; Langer, P. Chem.;Eur. J. 2006, 12, 1221.
(15) Weiler, L. J. Am. Chem. Soc. 1970, 92, 6702.
(16) Adeel, M.; Reim, S.; Wolf, V.; Yawer, M. A.; Hussain, I.; Villinger,
A.; Langer, P. Synlett 2008, 2629.
8316 J. Org. Chem. Vol. 75, No. 23, 2010

Ibad et al.
JOCNote
SCHEME 3. Possible Mechanisms of the Formation of 5a and 6b
SCHEME 4. Synthesis of 5a-ai and 6a-aia
aKey: (i) (1) Me3SiOTf, 1 h, 20 °C, (2) CH2Cl2, 0 f 20 °C, 12 h, (3) HCl
(10%); (ii) (1) NEt3, EtOH, 20 °C, 12 h, (2) HCl (10%).
TABLE 3. Synthesis of 5a-ai and 6a-ai
3
4
5, 6
R1
R2
R3
R4
5a (%)
6a (%)
a
c
d
e
f
g
h
i
g
a
d
g
f
a
a
a
a
a
a
a
a
b
c
c
c
d
d
d
e
e
e
e
e
e
e
f
f
f
f
f
g
g
g
g
g
g
h
h
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
H
Me
n-Pr
n-Bu
n-Pent
n-Hex
n-Oct
n-Dec
n-Hex
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
H
H
H
H
H
H
H
Cl
Cl
Cl
Cl
Cl
H
H
H
H
H
H
H
H
56
14
17
0
13
11
20
13
13
46
14
9
12
10
18
0
14
13
0
12
10
0
35
9
13
21
0
33
11
16
11
7
0
72
71
71
72
69
63
76
70
0
71
73
70
66
63
68
77
73
72
70
70
77
0
79
73
63
76
0
73
75
77
73
77
72
70
Me
Me
Me
Me
Me
Me
Me
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
F
n-Pr
n-Hex
n-Pent
n-Hex
n-Dec
Bn
g
i
b
c
d
e
f
g
h
a
c
d
h
i
a
c
d
f
g
i
Me
n-Pr
s
t
u
v
w
x
y
n-Bu
n-Pen
n-Hex
n-Oct
H
Me
n-Pr
n-Oct
n-Dec
H
Me
n-Pr
n-Pent
n-Hex
n-Dec
Me
z
aa
ab
ac
ad
ae
af
ag
ah
ai
F
F
F
F
F
Et
Et
In conclusion, we have reported the Me3SiOTf-mediated
condensation of 1-ethoxy-2-fluoro-1,3-bis(trimethylsilyloxy)
1,3-dienes with 3-cyanochromones to give 3-cyano-2-(4-ethoxy-
3-fluoro-2,4-dioxobutyl)chroman-4-ones. Their reaction with
triethylamine afforded fluorinated azaxanthones or biaryls.
The use of unsubstituted 2-fluoro-1,3-bis(trimethylsilyloxy)-
1,3-butadiene 3a generally resulted in exclusive formation of
fluorinated azaxanthones 5 by a domino “retro-Michael/
nitrile-addition/heterocyclization” reaction. In contrast, the
employment of substituted homologues gave rise to the for-
mation of fluorinated biaryls as the main products. Their
formation can be explained by an unprecedented domino
“retro-Michael/aldol/fragmentation” reaction. In some reac-
tions, the corresponding azaxanthones were isolated as side
products. Thus, the product distribution is influenced by the
chain length of the diene. An influence of the structure of
the diene on the product distribution has been previously
0
10
12
c
g
n-Hex
aYields of isolated products.
observed in our study related to the reaction of 1,3-bis(silyloxy)
1,3-dienes with 3-cyanochromones.13 For specific dienes,
containing a substituent located at carbon atom C-4 but no
substituent at C-2, the formation of biaryl lactones by domino
“retro-Michael/aldol/lactonization” reactions was observed.
But this transformation was not general, and in most cases,
azaxanthones were formed. Therefore, the fluorine atom at-
tached to carbon atom C-2 of dienes 3 must have an important
influence on the mechanism and biaryl formation. The steric
influence of the fluorine atom and of the substituent R1 may
result in a conformation which facilitates the intramolecular
aldol reaction at the expense of the nitrile addition. Preliminary
J. Org. Chem. Vol. 75, No. 23, 2010 8317

Ibad et al.
JOCNote
results suggest that reactions of dienes containing a chlorine
instead of a fluorine atom exclusively afford azaxanthones and
not chlorinated biaryls.
From a preparative viewpoint, the reactions reported are
useful as they allow for a convenient approach to highly
substituted fluorinated biaryls which are not readily avail-
able by other methods.
1H), 7.53 (d, J=8.1 Hz, 1H), 7.72 (dt, J=7.8 Hz, 1.7 Hz, 1H), 8.24
(d, J=8.1 Hz, 1H), 8.53 (s, 1H); 13C NMR (62.90 MHz, CDCl3) δ=
13.2, 14.1, 24.6, 32.5, 62.3, 87.9 (d, 1JFC=188 Hz), 117.0 (d, 4J=
1.8 Hz), 118.5, 121.5, 124.7, 126.7, 135.1, 135.8, 138.9, 155.6 (d,
2JF,C=18.8 Hz), 155.8, 157.8, 167.0 (d, 2JF,C=25.6 Hz), 177.3; 19
F
NMR (282 MHz, CDCl3) δ=-182.15; IR (ATR, cm-1) ν=3359
(w), 3054 (w), 3071 (w), 2964 (w), 2920 (w), 2850 (w), 1762 (s), 1663
(s), 1601 (s), 1562 (w), 1469 (m), 1438 (m), 1423 (s), 1374 (m), 1312
(m), 1201 (m), 1099 (m), 1054 (s), 1014 (m), 754 (s), 665 (m), 595
(w); MS (GC, 70 eV) m/z 345 (Mþ þ 2, 2), 344 (Mþ þ 1), 343 (Mþ,
75), 328 (100), 315 (15), 294 (7), 270 (17), 254 (39), 210 (7), 139 (3),
121 (3), 76 (4), 51 (1); HRMS (EI) calcd for C19H18FNO4 [Mþ]
343.12144, found 343.121662. 6c: mp 110-112 °C; 1H NMR (300
MHz, CDCl3) δ=0.90 (t, 3J=7.5 Hz, 3H), 1.13 (t, 3J=7.0 Hz, 3H),
1.52-1.64 (m, 2H), 2.57 (dt, 3JHH=7.5 Hz, 4JFH=1.5 Hz, 2H), 4.08
(q, 3J=7.1 Hz, 2H), 7.25 (s, 1H), 7.27-7.35 (m, 3H), 7.41 (dt, 3J=
7.2 Hz, 4J = 2.1 Hz, 1H);13C NMR (62.90 MHz, CDCl3) δ= 13.8,
13.9, 22.8, 31.4 (d, 4JFC=2.3 Hz), 65.0, 104.2 (d, 3JF,C=4.6 Hz),
117.4 (d, 4JC,F=3.7 Hz), 122.3, 124.0, 126.0 (d, 2JF,C=18 Hz), 126.3,
130.3 (d, 4JF,C = 3.0), 130.7, 131.4, 132.2 (d, 4JF,C = 2.7 Hz), 146.1
Experimental Section
General Procedure for the Synthesis of Azaxanthones 5 and
Biaryls 6. To neat 3-cyanochromone 4 (1.0 equiv) were added
Me3SiOTf (1.3 equiv) and CH2Cl2 (1 mL) at 20 °C. After the mix-
ture was stirred for 1 h, CH2Cl2 (10 mL) and 1,3-bis(trimethyl-
silyloxy)-1,3-butadiene 3(1.3 equiv) were added at 0 °C. The mixture
was stirred for 12 h at 20 °C and subsequently poured into hydro-
chloric acid (10%). The organic and the aqueous layer were sepa-
rated, and the latter was extracted with CH2Cl2 (3 ꢀ 100 mL). The
combined organic layers were washed with water, dried (Na2SO4),
and filtered, and the filtrate was concentrated in vacuo. The residue
was dissolved in ethanol (10 mL), NEt3 (2.0 equiv) was added, and
the solution was stirred for 12 h at 20 °C. To the solution were sub-
sequently added an aqueous solution of hydrochloric acid (1 M) and
ether (50 mL). The organic and the aqueous layer were separated,
and the latter was extracted with ether (3 ꢀ 100 mL). The combined
organic layers were washed with water, dried (Na2SO4), and filtered,
and the filtrate was concentrated in vacuo. The residue was purified
by column chromatography (silica gel, EtOAc/hexane).
2
1
(d, JF,C =15.8 Hz), 149.8, 150.7 (d, JC,F =260 Hz); IR (ATR,
cm-1) ν=3305(b),2962(w),2932(w), 2872(w),2225(w), 1762(m),
1617 (m), 1480 (s), 1433 (m), 1369 (m), 1242 (s), 1203 (s), 1152 (m),
1094 (m), 996 (m), 900 (w), 767 (m), 665 (w), 579 (w); MS (GC,
70 eV) m/z 343 (Mþ, 2), 326 (1), 299 (5), 284 (35), 271 (35), 254 (7),
243 (26), 242 (100), 228 (7), 207 (6), 177 (3), 158 (3), 139 (3), 94 (1),
44 (7), 32 (32); HRMS (EI) calcd for C19H18FNO4 [Mþ] 343.12144,
found 343.12230.
Ethyl 2-Fluoro-2-(5-oxo-3-propyl-5H-chromeno[2,3-b]pyridine-
2-yl)acetate (5c) and 6-Cyano-2-fluoro-3-hydroxy-4-propyl-20-ethox-
ycarbonyloxybiphenyl (6c). Starting with 3-cyanochromone 4a
(171 mg, 1.0 mmol), Me3SiOTf (288 mg, 0.23 mL, 1.3 mmol), 3d
(435 mg, 1.3 mmol), CH2Cl2 (9.0 mL), EtOH (10 mL), and triethyl-
amine (202 mg, 0.28 mL, 2.0 mmol), 5c (244 mg, 17%) and 6c (58mg,
71%) were isolated as slightly yellow solids. 5c: mp 97-99 °C; 1H
Acknowledgment. Financial support by the DAAD
(stipends for M.F.I., O.-u.-R.A., and M.N.) and by the State
of Pakistan (HEC scholarships for M.N. and O.-u.-R.A.) is
gratefully acknowledged.
Supporting Information Available: Synthetic procedures,
compound characterization, copies of NMR spectra, and X-ray
structures. This material is available free of charge via the
Internet at http://pubs.acs.org.
3
NMR (300 MHz, CDCl3) δ=0.97 (t, J=7.3 Hz, 3H), 1.23 (t,
3J=6.9 Hz, 3H), 1.60-1.77 (m, 2H), 2.70-2.86 (m, 2H), 4.19-
4.35(m, 3J=6.9 Hz, 2H), 6.07 (d, 2JFH=47.7 Hz), 7.36 (t, J=7.5 Hz,
8318 J. Org. Chem. Vol. 75, No. 23, 2010