Synthesis of 2,4,5-trisubstituted 3-fluorofurans via sequential iodocyclization and cross-coupling of gem-difluorohomopropargyl alcohols

Article abstract of DOI:10.1021/jo800088y

(Chemical Equation Presented) The iodocyclization of gem- difluorohomoallenyl and gem-difluorohomopropargyl alcohols with I₂ and ICl, respectively, produced the corresponding fluorinated iodofuran analogues in good yields. The iodo substituent

Full text of DOI:10.1021/jo800088y

SCHEME 1. Synthetic Access to Fluorinated Furans from
Alcohols 2 and 4
Synthesis of 2,4,5-Trisubstituted 3-Fluorofurans
via Sequential Iodocyclization and
Cross-Coupling of gem-Difluorohomopropargyl
Alcohols
Satoru Arimitsu, Jesse M. Jacobsen, and
Gerald B. Hammond*
Department of Chemistry, UniVersity of LouisVille,
LouisVille, Kentucky 40292
gb.hammond@louisVille.edu
ReceiVed January 14, 2008
conditions (Scheme 1).6 However, these methodologies use a
proton (H+) electrophile, which does not permit installing a
synthetic handle to access multi-substituted fluorinated furans.
If instead we could use a halide electrophile, we would then be
able to install this reactive halide on the furan structure, which
could eventually be functionalized by further cross-coupling
reactions. We are now pleased to report the synthesis of
fluorinated iodofurans and their conversion into 2,4,5-trisub-
stituted 3-fluorofurans using a Suzuki coupling reaction.
The iodocyclization of gem-difluorohomoallenyl and gem-
difluorohomopropargyl alcohols with I2 and ICl, respectively,
produced the corresponding fluorinated iodofuran analogues
in good yields. The iodo substituent in fluorinated 4-io-
dofurans was utilized as a synthetic handle to prepare multi-
substituted 3-fluorofurans using a Suzuki cross-coupling
reaction. The yields of both iodocyclization of gem-difluo-
rohomopropargyl alcohol and subsequent Suzuki coupling
were dramatically enhanced by microwave irradiation.
As a point of entry to the ensuing discussions, the iodocy-
clization of gem-difluorohomoallenyl alcohol 2 produced 2,2-
difluoro-3-iodo-2,5-dihydrofuran 3 under mild conditions (1
equiv). The expectedsand observedsiodocyclization pattern7
was driven by the high electrophilicity of the gem-difluorovinyl
carbon.8 In marked contrast, the lesser reactivity of the triple
bond in gem-difluorohomopropargyl alcohol 4a hindered its
The furan structure is a ubiquitous unit in a variety of natural
products, active pharmaceuticals, agricultural compounds, fra-
grances, and synthetic precursors.1 A concise synthetic meth-
odology for multi-substituted furans remains an important task
in modern organic chemistry.2 A particularly underdeveloped
area of furan chemistry is the synthesis of its fluorine congeners,3
despite the fact that the presence of fluorine has often enhanced
the pharmacokinetic properties of a parent molecule and that
many current pharmaceuticals contain fluorine(s).4
Our group has reported the indium-mediated selective syn-
thesis of gem-difluorohomoallenyl alcohol 2 and gem-difluo-
rohomopropargyl alcohol 4 from difluoropropargyl bromide 1.5
Both alcohols have demonstrated their usefulness as building
blocks in the synthesis of fluorinated furan analogues under basic
(4) For general reviews, see: (a) Uneyama, K. Organofluorine Chemistry;
Blackwell: Oxford, 2006. (b) Chambers, R. D. Fluorine in Organic
Chemistry; Blackwell: Oxford, 2004 (c) Kirsch, P. Modern Fluoroorganic
Chemistry; Wiley-VCH: Weinheim, Germany, 2004. (d) Koksch, B.;
Sewald, N.; Jakubke, H.-D.; Burger, K. Biomedical Frontiers of Fluorine
Chemistry; Ojima, I., McCarthy, J. R., Welch, J. T., Eds.; American
Chemical Society: Washington, DC, 1996. For examples of 3,3-gem-
difluoromethylenated nucleoacids, see: (e) Zhou, W.; Gumina, G.; Chong,
Y.; Wang, J.; Schinazi, R. F.; Chu, C. K. J. Med. Chem. 2004, 47, 3399-
3408. (f) Zhang, X.; Xia, H.; Dong, X.; Jin, J.; Meng, W.-D.; Qing, F.-L.
J. Org. Chem. 2003, 68, 9026-9033. (g) Patel, V. F.; Hardin, J. N.; Mastro,
J. M.; Law, K. L.; Zimmermann, J. L.; Ehlhardt, W. J.; Woodland, J. M.;
Starling, J. J. Bioconjugate Chem. 1996, 7, 497-510. (h) Hertel, L. W.;
Kroin, J. S.; Misner, J. W.; Tustin, J. M. J. Org. Chem. 1987, 52, 2406-
2409.
(5) For a review of gem-difluoroallenes, see: (a) Hammond, G. B. J.
Fluorine Chem. 2006, 127, 476-488. For synthesis of gem-difluoro-
homopropargyl alcohols, see: (b) Arimitsu, S.; Jacobsen, J. M.; Hammond,
G. B. Tetrahedron Lett. 2007, 48, 1625-1627. (c) Arimitsu, S.; Hammond,
G. B. J. Org. Chem. 2006, 71, 8865-8868. (d) Kirihara, M.; Takuwa, T.;
Takizawa, S.; Momose, T.; Nemoto, H.; Tetrahedron 2000, 56, 8275-
8280. (e) Wang, Z.-G.; Hammond, G. B. J. Org. Chem. 2000, 65, 6547-
2255.
(1) (a) Lipshutz, B. H. Chem. ReV. 1986, 86, 795-819. (b) Dean, F. M.
In AdVances in Heterocyclic Chemistry; Katritzky A. R., Ed.; Academic
Press: New York, 1983; Vol. 31, pp 273-344. (c) Nakanishi, K., Goto,
T., Ito, S., Natori, S., Nozoe, S., Eds.; Natural Products Chemistry;
Kodansha: Tokyo, 1974; Vols. 1-3.
(2) (a) Babudri, F.; Cicco, S. R.; Farinola, G. M.; Lopez, L. C.; Naso,
F.; Pinto, V. Chem. Commun. 2007, 3756-3758. (b) Kirsch, S. F. Org.
Biomol. Chem. 2006, 4, 2076-2080. (c) Minetto, G.; Raveglia, L. F.; Sega,
A.; Taddei, M. Eur. J. Org. Chem. 2005, 2, 5277-5288. (d) Stauffer, F.;
Neier, R. Org. Lett. 2000, 2, 3535-3537 and references cited therein.
(3) For examples of substituted 3-fluorofurans, see: (a) Pomeisl, K.;
Cejka, J.; Kvicala, J.; Paleta, O. Eur. J. Org. Chem. 2007, 5917-5923. (b)
Arimitsu, S.; Hammond. G. B. J. Org. Chem. 2007, 72, 8559-8561. (c)
Xu, W.; Chen, Q.-Y. Org. Biomol. Chem. 2003, 1, 1151-1156. (d) Sham,
H. L.; Batebenner, D. A. J. Chem. Soc., Chem. Commun. 1991, 1134-
1135.
(6) See refs 3b and 5d.
(7) (a) Yoshida, M.; Hayashi, M.; Shishido, K. Org. Lett. 2007, 9, 1643-
1646. (b) Hyland, C. J. T.; Hegedus, L. S. J. Org. Chem. 2006, 71, 8658-
8660. (c) Schultz-Fademrecht, C.; Zimmermann, M.; Fro¨hlich, R.; Hoppe,
D. Synlett 2003, 13, 1969-1972.
(8) Ichikawa, J. Pure Appl. Chem. 2000, 72, 1685-1689.
10.1021/jo800088y CCC: $40.75 © 2008 American Chemical Society
Published on Web 03/08/2008
2886
J. Org. Chem. 2008, 73, 2886-2889

TABLE 1. Screening Conditions for the Iodocyclization of 4a
SCHEME 2. Reaction Mechanism for the Iodocyclization of
4
base
iodine solvebt
yields of
entry (1.2 equiv) sourcea (0.1 M) temp (°C) time
5a/6a (%)b
1
NaH
I2
THF
reflux
12 h complex
mixture
12 h 0/36 (6)
2
3
4
5
NaH
ICI
ICI
ICI
ICI
ICI
ICI
ICI
ICI
THF
THF
THF
THF
THF
DMF
reflux
reflux
reflux
reflux
91
t-BuOK
Na2CO3
K2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
12 h 0/46 (0)
12 h 54/0 (37)
12 h 9/0 (76)
5 min 63/8 (0) [66]c
5 min 50/trace (30)
5 min 0/36 (0)
5 min complex
mixturee
6d
7d
8d
9d
The published syntheses of 2,5-substituted-3-fluorofurans do
not permit functionalization at the 4-position of 3-fluorofurans.3
Thus, a readily apparent useful synthetic transformation of 5
or 6 could be the replacement of iodine with a suitable
substituent using a cross-coupling reaction. An obvious approach
would be the Suzuki coupling10 of arylboronic acids. Indeed,
phenylboronic acid reacted with 6a to furnish 7aa in excellent
yield in only 0.5 h (entry 1, Table 3). Microwave irradiation
proved critical for the efficiency of this reaction since the same
reaction at reflux not only failed to consume 6a after 12 h but
also led to the formation of byproducts. Electron-rich or electron-
deficient aryl boronic acids reacted with 6a in satisfactory yields
(entries 2-6, Table 3). Furthermore, 3-thienylboronic acid (entry
7, Table 3) and (E)-cinnamylboronic acid (entry 8, Table 3)
gave the corresponding sp2-sp2 coupling products in good and
moderate yields, respectively, with only a slight change in the
reaction time. Notably, the Suzuki coupling of 5 spontaneously
yielded only 7 (entries 11-13, Table 3), with no trace of the
corresponding 4,5-dihydrofuran.
91
CH3CN 91
CH2Cl2 91
10d
11d
Na2CO3
Na2CO3
ICI
ICI
toluene 91
ether
5 min trace/0 (64)
5 min 16/23 (13)
91
a 1.5 equiv was used. b Yield was determined by 19F NMR, and the values
in parentheses refer to the amount of recovered starting material 4a. c The
value in brackets was the isolated yield of 6a after silica gel chromatography.
d The reaction was carried out in a closed vial in a microwave reactor. e 6a
isolated in 12% yield.
TABLE 2. Microwave-Mediated Iodocyclization of
gem-Difluorohomopropargyl Alcohol 4
isolated yields
entry
R
R′
of 5 or 6 (%)
The two proposed mechanisms for the iodocyclization of 4
are depicted in Scheme 2. Initial deprotonation of 4 by a base
gives rise to an oxyanion, which can then attack either on the
CF2 carbon in a 3-exo-tet fashion (Path a, Scheme 2)11 or on
the triple bond in a 5-endo-dig fashion (Path b, Scheme 2).12,13
The conversion of acetylenic epoxide intermediates into furans
via their cumulene intermediates, in the presence of bases, has
been reported.14 However, for this transformation to occur, alkyl
substrates are required on R. Fortunately, we were able to
recrystallize 5f and obtain an X-ray analysis (Figure 1), which,
in turn, allowed us to use the 19F NMR spectral data of crude
5 (prior to aromatization) to confirm that, in all cases, 3,3-
difluoro-4-iodo-4,5-dihydrofuran 5 was produced, regardless of
the substrates R and R′. This experimental fact shored up support
for Path b as the most likely mechanism for our reaction. The
1
2
3
4
5
6
n-Hex
n-Hex
n-Hex
n-Hex
BnOCH2
Ph
Ph
66 (6a)
62 (6b)
76 (6c)
46 (5d)a
56 (5e)a
49 (5f)a
4-MeO-C6H4
4-CF3-C6H4
BnOCH2
Ph
Ph
a Silica gel was deactivated by Et3N.
iodocyclization, as demonstrated by the fact that strong bases,
such as NaH and t-BuOK, caused the decomposition of product
or starting material (entries 1-3, Table 1), and no reaction
occurred using K2CO3 and a reactive electrophile (ICl) at reflux
temperatures for 12 h (entry 5, Table 1). However, the
combination of iodomonochloride (ICl) and Na2CO3 gave the
desired iodocyclization product 5a selectively, in moderate yield
and with little decomposition (entry 4, Table 1).
The unreactive nature of 4a prompted us to investigate
whether microwave irradiation would hasten the desired io-
docyclization (entries 6-11, Table 1). Gratifyingly, 4a was
quickly consumed to yield 5a as a major product in satisfactory
yield after only 5 min of microwave irradiation. Following silica
gel chromatography, the aromatic product 6a was obtained in
66% yield (entry 6, Table 1).
(9) The use of normal silica gel for isolation resulted in the decomposition
of the benzyl ether group (entries 4 and 5, Table 2) and a difficult separation
from byproducts (entry 6, Table 2).
(10) For reviews of the Suzuki-Miyaura cross-coupling, see: (a) Bellina,
F.; Carpita, A.; Rossi, R. Synthesis 2004, 2419-2440. (b) Kotha, S.; Lahiri,
K.; Kaschinath, D. Tetrahedron 2002, 58, 9633-9695. (a) Miyaura, N.;
Suzuki, A. Chem. ReV. 1995, 95, 2457-2483.
(11) A similar base-mediated cyclization of gem-difluorohomopropargyl
alcohol was reported. This report claimed that 3-fluoro-2,5-substituted furans
were obtained via a 3-exo-tet cyclization. See ref 3d.
(12) El-Taeb, G. M. M.; Evans, A. B.; Jones, S.; Knight, D. W.
Tetrahedron Lett. 2001, 42, 5945-5948.
The scope of this reaction is shown in Table 2. Aryl substrates
with electron-donating or -withdrawing groups at the homopro-
pargyl position gave the corresponding 4-iodofuran 6 in good
isolated yields (entries 1-3, Table 2). Interestingly, use of silica
gel deactivated with triethylamine (Et3N) furnished 5 instead
of the aromatized derivative 6 (entries 4-6, Table 2).9
(13) A cyclic iodonium ion intermediate has been proposed. See:
Barluenga, J.; Rodr´ıguez, M. A.; Campos, P. J. J. Org. Chem. 1990, 55,
3104-3106 and references cited therein.
(14) (a) Marshall, J. A.; Dubay, W. J. J. Am. Chem. Soc. 1992, 114,
1450-1456. (b) Marshall, J. A.; DuBay, W. J. J. Org. Chem. 1991, 56,
1685-1687.
J. Org. Chem, Vol. 73, No. 7, 2008 2887

TABLE 3. Microwave-Mediated Suzuki Coupling of 5 or 6
isolated
yield of 7 (%)
entry
R
R′
R1
timea (h)
1
2
3
4
5
6
7
8
9
10
11
12
13
n-Hex
n-Hex
n-Hex
n-Hex
n-Hex
n-Hex
n-Hex
n-Hex
n-Hex
n-Hex
n-Hex
BnOCH2
Ph
Ph (6a)
Ph (6a)
Ph (6a)
Ph (6a)
Ph (6a)
Ph (6a)
Ph (6a)
Ph (6a)
4-MeO-C6H4 (6b)
4-CF3-C6H4 (6c)
BnOCH2 (5d)
Ph (5e)
Ph
0.5
0.5
1.5
1.0
0.5
0.5
1.0
1.5
2.0
1.0
1.5
1.0
1.5
98 (7aa)
78 (7ab)
72 (7ac)
63 (7ad)
66 (7ae)
63 (7af)
71 (7ag)
58 (7ah)
85 (7ba)
75 (7ca)
50 (7da)
51 (7ea)
77 (7fa)
3,4-(OCH2O)-C6H3
4-CHO-C6H4
4-CN-C6H4
4-F-C6H4
4-CF3-C6H4
3-thienyl
(E)-PhCHCH2
Ph
Ph
Ph
Ph
Ph
Ph (5f)
a Reaction progress was monitored by TLC or GC-MS.
3-Fluoro-5-n-hexyl-4-iodo-2-phenylfuran (6a). An oven-dried
microwave vial (10 mL size) fitted with a stir bar, under argon
atmosphere, was charged with sodium carbonate (0.6 mmol, 1.2
equiv) into which gem-difluorohomopropargyl alcohol 4a (0.5
mmol) in THF (2.0 mL) was added via syringe. The mixture was
stirred vigorously for 10 min before being cooled in an ice bath
for 5 min followed by slow addition of iodine monochloride (0.75
mmol, 1.5 equiv) in THF (3.0 mL). The vial was then placed in a
CEM Discover microwave synthesizer at 91 °C for 5 min (at 150
W, 250 psi max), and the temperature was monitored by the
microwave-attached computer during the reaction. After cooling
to room temperature, the reaction was quenched with aqueous
sodium bisulfite (12.0 mL, 3/1 ) water/saturated sodium bisulfite).
The mixture was extracted with ether, and the combined organic
extracts were washed with brine and dried over anhydrous MgSO4.
The organic solvent was carefully removed in vacuo treating with
ca. 1.0 g of silica gel to induce aromatization. The resulting powder
was placed on top of a silica gel column chromatograph and eluted
with hexane to furnish 6a (122 mg, 66%) as a pale yellow oil: 1H
NMR (CDCl3) δ 0.92-0.94 (m, 3H), 1.36-1.40 (m, 6H), 1.69-
1.74 (m, 2H), 2.72 (dt, J ) 2.0, 8.0 Hz, 2H), 7.27 (dt, J ) 1.5, 6.5
Hz, 1H), 7.43 (dt, J ) 2.0, 8.5 Hz, 2H), 7.67 (dd, J ) 1.5, 7.0 Hz,
2H); 19F NMR (CDCl3) δ -159.21 (s, 1F); 13C NMR (CDCl3) δ
14.1, 22.5, 27.8, 28.0, 28.6, 31.4, 57.6 (d, J ) 24.1 Hz), 123.2 (d,
J ) 4.3 Hz), 127.0, 128.6, 128.7, 135.1 (d, J ) 20.1 Hz), 149.7 (d,
J ) 253.8 Hz), 154.1 (d, J ) 4.8 Hz); IR (neat) 3057, 2927, 2857,
1943, 1872, 1634, 1495, 1417, 1147, 1017, 759 cm-1; MS m/z (%)
373 (100, M+ + H), 372 (14), 302 (44), 246 (3), 176 (6), 106 (9);
HRMS (EI) calcd for C16H18FIO (M+) 372.0386, found 372.0375.
3-Fluoro-5-n-hexyl-2,4-diphenylfuran (7aa). An oven-dried
microwave vial (10 mL size) fitted with a stir bar under argon
atmosphere was charged with Pd(PPh3)4 (0.035 mmol, 10 mol %)
and phenylboronic acid (1.4 mmol, 4.0 equiv), into which 3-fluoro-
4-iodofuran 6a (0.35 mmol) was added along with EtOH (0.5 M
relative to 6a), 0.35 mL of aqueous Na2CO3 (0.2 g/mL), and toluene
(0.05 M). The vial was then capped under argon and placed in a
CEM Discover microwave synthesizer at 115 °C for 30 min (at
150 W, 250 psi max), and the temperature was monitored by the
microwave-attached computer during the reaction. After cooling
to room temperature, the reaction mixture was quenched with
saturated NH4Cl followed by extraction with ether. The combined
organic layer was washed with brine and dried over anhydrous
MgSO4. After evaporation of the solvent, the residue was purified
on a silica gel column chromatograph eluted with hexane affording
product 7aa as a colorless oil (111 mg, 98% yield): 1H NMR
(CDCl3) δ 0.92 (t, J ) 7.0 Hz, 3H), 1.31-1.44 (m, 6H), 1.77
FIGURE 1. Single-crystal X-ray structure of 5f.
electronically deficient nature of the alkyne moiety in 4 had
been verified through DFT calculations.3b
In summary, whereas the iodocyclization of gem-difluoro-
homoallenyl alcohol 2 produced 2,2-difluoro-3-iodo-2,5-dihy-
drofuran 3 at low temperature, the iodocyclization of gem-
difluorohomopropargyl alcohol 4 required use of microwave
irradiation to yield 3,3-difluoro-4-iodo-4,5-dihydrofurans 5 or
3-fluoro-4-iodofurans 6 in satisfactory yields. This investigation
clearly demonstrated that the iodocyclization proceeds via a
5-endo-dig mode on the electronically deficient triple bond.
Finally, fluorinated 4-iodofuran analogues 5 and 6 were suc-
cessfully used in the synthesis of fully substituted 3-fluorofurans
7 by microwave-mediated Suzuki coupling.
Experimental Section
2,2-Difluoro-3-iodo-4-triisopropylsilyl-2,5-dihydrofuran (3).
To a solution of I2 (0.55 mmol, 1.1 equiv) and K2CO3 (1.1 mmol,
2.2 equiv) in THF (4.0 mL) was added a solution of difluoro-
homoallenyl alcohol 2 (0.5 mmol, 1.0 equiv) in THF (1.0 mL) at
0 °C. The resulting mixture was stirred for 0.5 h at 0 °C, then the
reaction mixture was quenched by H2O (20 mL) and extracted by
Et2O (10 mL × 3). The combined organic layer was washed by
5% aqueous solution of saturated sodium bisulfite (10 mL × 1)
and then dried over MgSO4. The desired product was isolated by
flash silica gel chromatography with hexane as an eluent, after
which 3 (116 mg, 60%) was obtained as a white crystal: 1H NMR
(CDCl3) δ 1.15 (s, 18H), 1.45 (m, 3H), 4.84 (t, J ) 11.3 Hz, 2H);
19F NMR (CDCl3) δ -61.18 (s); 13C NMR (CDCl3) δ 11.3, 18.6,
81.9, 92.2 (t, J ) 38.0 Hz), 132.2 (t, J ) 249.5 Hz), 151.7; IR
(CCl4) 2949, 2870, 1577, 1461, 1348, 1257, 1174 cm-1; mp )
33-34 °C; MS m/z (%) 371 (100), 195 (5), 158 (5). Anal. Calcd
for C13H23F2IOSi: C, 40.21; H, 5.97. Found: C, 40.49; H,
5.95.
2888 J. Org. Chem., Vol. 73, No. 7, 2008

(quintet, J ) 7.5 Hz, 2H), 2.79 (t, J ) 8.0 Hz, 2H), 7.28 (t, J )
7.0 Hz, 1H), 7.37-7.40 (m, 1H), 7.44-7.48 (m, 6H), 7.76 (d, J )
8.0 Hz, 2H); 19F NMR (CDCl3) δ -166.21 (s, 1F); 13C NMR
(CDCl3) δ 4.0 (d, J ) 11.6 Hz), 22.5, 27.2 (t, J ) 11.5 Hz), 28.2,
28.9, 31.5, 114.8 (d, J ) 15.3 Hz), 123.2 (d, J ) 16.3 Hz), 126.6
(d, J ) 16.4 Hz), 127.2 (d, J ) 22.1 Hz), 128.5, 128.7, 129.3 (d,
J ) 4.8 Hz), 130.2, 134.3 (d, J ) 20.3 Hz), 141.2, 147.8 (d, J )
256.0 Hz), 150.1 (d, J ) 4.8 Hz); IR (neat) 3058, 2954, 2927, 2856,
1945, 1872, 1802, 1749, 1645, 1499, 1421 cm-1; MS m/z (%) 322
(2, M+), 254 (71), 233 (3), 205 (2), 106 (6). Anal. Calcd for C22H23-
FO: C, 81.95; H, 7.19. Found: C, 81.91; H, 7.31.
Acknowledgment. The authors are grateful to the National
Science Foundation (CHE-0513483) for its financial support,
and to Professor T. Ishihara and Dr. T. Konno (Kyoto Institute
of Technology) for their help in obtaining HRMS data.
Supporting Information Available: Analytical and spectro-
scopic data for 6b,6c, 5d-5f, 7ab-7ah, and 7ba-7fa and CIF
information for 5f. This material is available free charge via the
Internet at http://pubs.acs.org.
JO800088Y
J. Org. Chem, Vol. 73, No. 7, 2008 2889