Selective synthesis of fluorinated furan derivatives via AgNO 3-catalyzed activation of an electronically deficient triple bond

Article abstract of DOI:10.1021/jo701616c

(Chemical Equation Presented) The transition metal-catalyzed direct activation of electron deficient triple bonds was investigated by using the combined electron withdrawing effects of two fluorine atoms to modulate the electronic density of the triple bo

Full text of DOI:10.1021/jo701616c

mediated triple bond activation: either through the formation
of a vinylidene complex or through the direct activation of the
π-bond. Because both activation methods are initiated from the
metal-alkyne complex,5 the coordination of an electron-rich
triple bond with a Lewis acid is regarded as the keystone of
this methodology.6 Conversely, the activation of electronically
deficient triple bonds with Lewis acids is hardly known.3d We
now report the activation of an electronically deficient triple
bond in gem-difluorohomopropargyl alcohol 1 using AgNO3
as a Lewis acid. This discovery has resulted in new syntheses
of fluorinated furan derivatives 2, 3, and 4.
We decided to choose gem-difluorohomopropargyl alcohol7
as a model because we envisaged a localized deactivation
through inductive effects, of which the gem-difluoropropargyl
group is capable of. As demonstrated by DFT calculations
(Figure 1), the two fluorine atoms modulate the electronic
density of the triple bond as compared with its nonfluorinated
counterpart.
Selective Synthesis of Fluorinated Furan
Derivatives via AgNO3-Catalyzed Activation of an
Electronically Deficient Triple Bond
Satoru Arimitsu and Gerald B. Hammond*
Department of Chemistry, UniVersity of LouisVille,
LouisVille, Kentucky 40292
gb.hammond@louisVille.edu
ReceiVed July 27, 2007
Another rationale for using fluorine is its impact on the
biological activities of furan systems. The anti-HIV agents 3,3-
gem-difluoromethylenated nucleoacids8 and the anticancer drug
Gemcitabine (2′-deoxy-2′-difluorocytidine), recently approved
for the treatment of pancreatic cancer,9 are cases in point.
Notwithstanding their potential usefulness, syntheses of
fluorofurans and fluorohydrofurans are still tedious and there
are no practical reactions that can generate substrate diversity.
Furthermore, there are no reports of catalytic synthesis of these
compounds.10
The transition metal-catalyzed direct activation of electron
deficient triple bonds was investigated by using the combined
electron withdrawing effects of two fluorine atoms to
modulate the electronic density of the triple bond. With use
of catalytic amounts of AgNO3 (10 mol %) the synthesis of
substituted 3,3-difluoro-4,5-dihydrofurans from gem-difluo-
rohomopropargyl alcohols occurred in excellent NMR yields.
Treatment of these dihydrofurans with SiO2 or Pd/H2 yielded
the corresponding 3-fluorinated furans and 3,3-difluorotet-
rahydrofurans.
(4) (a) Hashmi, A. S. K. Chem. ReV. 2007, 107, 3180-3211. (b) Hashmi,
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L.; Rieger, P. H.; Shaw, M. J. J. Am. Chem. Soc. 1995, 117, 12202-12208.
(d) Nevado, C.; Echavarren, A. M. Synthesis 2005, 2, 167-182. (e) Bruneau,
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During the past decade there has been a concerted effort to
develop transition metals capable of activating the triple bond
to form new carbon-carbon bonds and carbon-heteroatom
bonds.1 It is well-known that complexes of group 11 metals
(Cu,2 Ag,3 Au4) can activate electron-rich triple bonds; especially
gold complexes have shown exceptional alkynophilicity under
mild conditions. There are two types of transition metal-
(7) (a) Arimitsu, S.; Hammond, G. B. J. Org. Chem. 2006, 71, 8665-
8668. (b) Kirihara, M.; Takuwa, T.; Takizawa, S.; Momose, T.; Nemoto,
H. Tetrahedron 2000, 56, 8275-8280. (c) Hanzawa, Y.; Inazawa, K.; Kon,
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Chem. 1987, 53, 2406-2409. (b) Patel, V. F.; Hardin, J. N.; Mastro, J. M.;
Law, K. L.; Zimmermann, J. L.; Ehlhardt, W. J.; Woodland, J. M.; Starling,
J. J. Bioconj. Chem. 1996, 7, 497-510. (c) Zhang, X.; Xia, H.; Dong, X.;
Jin, J.; Meng, W.-D.; Qing, F.-L. J. Org. Chem. 2003, 68, 9026-9033. (d)
Zhou, W.; Gumina, G.; Chong, Y.; Wang, J.; Schinazi, R. F.; Chu, C. K.
J. Med. Chem. 2004, 47, 3399-3408.
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(2, Suppl. 6), S26-S32.
(10) Noncatalytic versions are reported: For 3,3-difluorotetrahydro-
furane, see ref 7. For 3-fluorofurans, see: (a) Sham, H. L.; Betebenner, D.
A. J. Chem. Soc., Chem. Commun. 1991, 1134-1135. (b) Lee, K.; Zhou,
W.; Kelley, L.-L. C.; Momany, C.; Chu, C. K. Tetrahydron: Asymmetry
2002, 13, 1589-1598. (c) Moon, H. R.; Kim, H. O.; Jeong, L. S. J. Chem.
Soc., Perkin Trans. 1 2002, 1800-1804. (d) Xu, W.; Chen, Q.-Y. Org.
Biomol. Chem. 2003, 1, 1151-1156.
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UK, 2002. ComprehensiVe Organometallic Chemistry II; Abel, E. W., Stone,
F. G. A., Wilkinson, G., Eds.; Pergamon: Oxford, UK, 1995; Vol. 12.
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, UK, 1991; Vol. 4. For Recent reviews on transition
metal catalyzed reaction with alkynes, see: Ojima, I.; Tzamarioudaki, M.;
Li, Z.; Donovan, R. J. Chem. ReV. 1996, 96, 635-662. (b) Muller, T. E.;
Beller, M. Chem. ReV. 1998, 98, 675-703. Aubert, C.; Buisine, O.;
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5804-5812. (b) Xu, L.; Lewis, I. R.; Davidsen, S. K.; Summers, J. B.
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10.1021/jo701616c CCC: $37.00 © 2007 American Chemical Society
Published on Web 10/02/2007
J. Org. Chem. 2007, 72, 8559-8561
8559

TABLE 2. Synthesis of 3,3-Difluoro-4,5-dihydrofuran 2 and
3-Fluorofuran 3
entry
R
R′
yields of products,a %
1
2
3
4
5
6
7
8
9
H
Ph (1a)
94 (2a)
70 (2b)
>99 (2c)
>99 (2d)
55 (3a)
55 (3b)
65 (3c)
79 (3d)
62 (3e)
32 (3f)
52 (3g)
49 (3h)
68 (3i)
20 (3j)
no rxn
4-Me-C6H4 (1b)
4-MeO-C6H4 (1c)
3-MeO-C6H4 (1d)
2,4-(MeO)2-C6H3 (1e) >99 (2e)
4-Cl-C6H4 (1f)
4-CF3-C6H4 (1g)
2-F-C6H4 (1h)
BnOCH2 (1i)
Ph
>99 (2f)
>99 (2g)
91 (2h)
81 (2i)
10b
11
12
13
Ph (1j)
FIGURE 1. Comparison of the electronic states of the triple bond of
gem-difluorohomopropargyl alcohol 1a (A) and its nonfluorinated
counterpart (B) [b3lyp/6-311g(d,p)5d].
TIPS (1k)
n-Hex (1l)
BnOCH2 (1m)
58 (3l)
65 (3m)
a Yields of 2 were determined by 19F NMR; yields of 3 were calculated
TABLE 1. Screening of Metal Complexes of Group 11 Metals
after isolation of pure product. b Reaction time was 24 h.
TABLE 3. Synthesis of 3,3-Difluorotetrahydrofuran 4
entry
cat. X (mol %)
solvent
time,a h
yields of 2/3,b %
1
2
3
4
5
6
7
8
AuBr3 (5)
CH2 Cl2
24
24
12
24
24
24
24
24
0/34
no rxn
0/34
60/11
45/31
no rxn
0/34
Me3PAuCl (5)
AgOTf (5)
AgNO3 (5)
AgNO3 (10)
Ag2 CO3 (5)
CuI (5)
entry
R′
yields of 4,a,b
%
1
2
3
4
5
6
7
8
Ph (1a)
74 [81] (4a)
41 [52] (4b)
63 [71] (4d)
52 [68] (4e)
49 [53] (4f)
68 [92] (4g)
67 [73] (4h)
50 [57] (4i)
4-Me-C6H4 (1b)
3-MeO-C6H4 (1d)
2,4-(MeO)2-C6H3 (1e)
4-Cl-C6H4 (1f)
4-CF3-C6H4 (1g)
2-F-C6H4 (1h)
CuOTf (5)
no rxn
9
10
11
AgNO3 (10)
THF
Et2O
benzene
6
6
6
94/0
no rxn
72/5
BnOCH2 (1i)
a The reaction time was determined by consumption of 1 as monitored
a Isolated yields. b The values in brackets correspond to 19F NMR yields.
by TLC. b Yields were determined by 19F NMR.
We proceeded to screen group 11 metals that would cat-
alyze the cyclization of 1 to 2 (Table 1). In striking contrast to
nonfluorinated systems,11 gold(I) or -(III) complexes did not
give satisfactory results (Table 1, entries 1 and 2). Instead,
we found that AgNO3 was the best catalyst for obtaining 3,3-
difluoro-4,5-dihydrofuran 2a (Table 1, entries 4 and 5). This
reaction exhibited a remarkable solvent effect, THF being
the best solvent for obtaining 2a selectively (Table 1, entry 9).
Product 2a could not be isolated by silica gel chromato-
graphy or distillation, both purification methods yielded 3--
fluorofuran 3a.12 Interestingly, our attempts to obtain 3a by
inducing aromatization of 2a using basic (NaOH, t-BuOK, and
NaH) or acidic (BF3‚Et2O and BCl3) conditions failed com-
pletely.
To explore the scope and limitations of the new Ag(I)-
catalyzed cyclization, various gem-difluorohomopropargyl
alcohols 1 were treated with AgNO3 (10 mol %) in THF
(Table 2).
In all cases 19F NMR showed an excellent conversion to 4,5-
dihydrofurans 2 regardless of the type of substrate R′ used
[electron-donating (Table 2, entries 2-5), electron-withdrawing
(Table 2, entries 6-8), and aliphatic substituents (Table 2, entry
9)]. After eluting through a silica gel column, 4,5-dihydrofurans
2 furnished the corresponding 3-fluorofurans 3 in good isolated
yields (Table 2, entries 1-5 and 9); electron-withdrawing
substituents (entries 6-8) produced 3 in moderate to low yields.
In the case of internal alkynes, the Ag(I)-catalyzed cyclization
funishes 3-fluorofuran 3, albeit in low to moderate yields (Table
2, entries 10, 12, and 13). The reaction did not take place when
R ) TIPS (Table 2, entry 11).
(11) (a) For further references, see ref 4a. (b) Belting, V.; Krause, N.
Org. Lett. 2006, 8, 4489-4492. (c) Liu, B.; Brabander, J. K. D. Org. Lett.
2006, 8, 4907-4910. (d) Liu, Y.; Song, F.; Song, Z.; Liu, M.; Yan, B.
Org. Lett. 2005, 7, 5409-5412. (e) Antoniotti, S.; Genin, E.; Michelet, V.;
Genet, J.-P. J. Am. Chem. Soc. 2005, 127, 9976-9977. (f) Hashmi, A. S.
K.; Schwarz, L.; Choi, J.-H.; Frost, T. M. Angew. Chem., Int. Ed. 2000,
39, 2285-2288.
Although 3,3-difluoro-4,5-dihydrofurans 2 could not be
isolated, we were in the position to readily prepare 3,3-
fluorotetrahydrofuran 4 by catalytic hydrogenation of 2 with a
simple one-step synthesis of 2 in hand (Table 3, entries 1-8).
This reaction gave high 19F NMR yields and satisfactory isolated
(12) A similar aromatization on silica gel has been reported; see ref 3a.
8560 J. Org. Chem., Vol. 72, No. 22, 2007

19F NMR (CDCl3) δ -165.29 (s, 1F); 13C NMR (CDCl3) δ 104.7
(d, J ) 20.2 Hz), 123.7 (d, J ) 4.8 Hz), 127.3, 128.9, 129.2 (d, J
) 4.8 Hz), 136.8 (d, J ) 21.1 Hz), 140.0 (d, J ) 9.5 Hz), 149.5
(d, J ) 253.1 Hz); IR (neat) 3155, 3056, 1633, 1432 cm-1; MS
m/z (%) 162 (100, M+), 133 (27), 105 (6). Anal. Calcd: C, 74.07;
H, 4.35. Found: C, 73.90; H, 4.36.
yields with all substrates tested. The reaction mechanism
proposed for the cyclization of 1 to 2 contemplates activation
of the triple bond through coordination with AgNO3, followed
by a 5-endo-dig cyclization and proton shift to produce 4,5-
dihydrofuran 2.
In conclusion, AgNO3 (10 mol %) in THF was found to be
an efficient catalyst for the activation of the electronically
deficient triple bond of 1 and its cyclization to 3,3-difluoro-
4,5-dihydrofuran 2. This methodology is a nice regiochemical
complement to our earlier synthesis of 2,2-difluorodihydrofurans
6 from the isomeric fluoroallenylalcohol 5 (eq 1).13
Synthesis of 3,3-Difluoro-2-phenyltetrahydrofuran (4a). After
the standard preparation for compounds 2a (0.5 mmol scale), which
was described previously, the organic solvent was evaporated
moderately. Pd black (0.1 g) and THF (1.5 mL) were added to the
flask, and hydrogenation was carried out under 30 atm of hydrogen
gas for 24 h at room temperature. After 24 h, Pd black was removed
by the celite filtration, then Pd black (0.1 g) and THF (1.5 mL)
were renewed and the reaction was maintained for another 15 h
under the same condition. After the reaction, Pd black was removed
by celite filtration and the solvent was evaporated. Compound 4a
was isolated by silica gel chromatography with hexane/EtOAc (15/
1
1) in 74% yield. H NMR (CDCl3) δ 2.37-2.46 (m, 2H), 4.00
Experimental Section
(dq, J ) 8.5, 1.0 Hz, 1H), 4.20 (dt, J ) 8.0, 1.0 Hz, 1H), 4.74 (dt,
J ) 12.5, 0.5 Hz, 1H), 7.26-7.31 (m, 5H); 19F NMR (CDCl3) δ
-103.94 (dq, J ) 230.1, 13.0 Hz, 1F), -104.57 (dq, J ) 230.1,
13.0 Hz, 1F); 13C NMR (CDCl3) δ 35.5 (t, J ) 24.5 Hz), 65.3,
83.2 (t, J ) 27.3 Hz), 126.8, 128.1 (t, J ) 253.3 Hz), 128.2, 128.5;
IR (neat) 3035, 2962, 2883, 1959, 1737, 1498, 1456, 1321, 1115
cm-1; MS m/z (%) 184 (61, M+), 165 (28), 135 (9), 105 (33). Anal.
Calcd: C, 65.21; H, 5.47. Found: C, 65.20; H, 5.69.
Synthesis of 3,3-Difluoro-2-phenyl-4,5-dihyroduran (2a) and
3-Fluoro-2-phenylfuran (3a). Into the suspension of AgNO3 (0.05
mmol, 10 mol %) in THF (3 mL) was added the THF solution
starting material (1a) (0.5 mmol, 1.0 equiv) dropwise. The whole
reaction mixture was heated at reflux for 6 h. The reaction was
quenched by 10% HClaq (10 mL) and extracted by diethyl ether (3
× 10 mL) and the combined organic layers were washed with brine
and dried over anhydrous Na2SO4. After moderate evaporation of
the solvent, the corresponding dihydrofuran (2a) was observed by
19F NMR (δ -84.63 (ddd, J ) 248.0, 23.1, 19.8 Hz, 1F), -87.16
(ddd, J ) 248.0, 13.2, 13.2 Hz, 1F)), and 19F NMR yield was
obtained by using R,R,R-trifluoromethylbenzene as the internal
reference. The residue was treated with silica gel and diethyl ether,
and then the silica gel was dried with high vacuum after removing
diethyl ether; finally compound 3a was isolated by silica gel
chromatography with hexane in 55%. 1H NMR (CDCl3) δ 6.44 (s,
1H), 7.26-7.28 (m, 2H), 7.12-7.45 (m, 2H), 7.71-7.72 (m, 2H);
Acknowledgment. The authors are grateful to the National
Science Foundation (CHE-0513483) for its financial support,
to Prof. Pawel Kozlowski and Jadwaga Kuta (University of
Louisville) for computational studies, and to Professors T.
Konno and T. Ishihara (Kyoto Institute of Technology) for their
help in obtaining HRMS data.
Supporting Information Available: Analytical and spectro-
scopic data for 3b-j, 3l,m, and 4b and 4d-i. This material is
available free of charge via the Internet at http://pubs.acs.org.
(13) Wang, Z.; Hammond, G. B. J. Org. Chem. 2000, 65, 6547-6552.
JO701616C
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