Nucleophilic 5-endo-trig cyclization of 3,3-difluoroallylic ketone enolates: Synthesis of 5-fluorinated 2-alkylidene-2,3-dihydrofurans

Article abstract of DOI:10.1055/s-0032-1317709

3,3-Difluoroallylic ketones readily undergo nucleophilic 5-endo-trig cyclization through their metal enolates to afford 5-fluorinated 2-alkylidene-2,3-dihydrofurans. O-Cyclization exclusively occurred via intramolecular substitution of the vinylic fluorin

Full text of DOI:10.1055/s-0032-1317709

LETTER
▌57
lNettuer cleophilic 5-endo-trig Cyclization of 3,3-Difluoroallylic Ketone Enolates:
Synthesis of 5-Fluorinated 2-Alkylidene-2,3-dihydrofurans
5-endo-trig Cyclization of 3,3-Difluoroallylic Ketone Enolates
Takeshi Fujita,a Kotaro Sakoda,b Masahiro Ikeda,a Masahiro Hattori,a Junji Ichikawa*a
a
Division of Chemistry, Faculty of Pure and Applied Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8571, Japan
Fax +81(29)8534237; E-mail: junji@chem.tsukuba.ac.jp
b
Department of Chemistry, Graduate School of Science, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received: 11.10.2012; Accepted after revision: 08.11.2012
6-endo-trig cyclization with sp3 and sp2 nucleophiles
Abstract: 3,3-Difluoroallylic ketones readily undergo nucleophilic
F
5-endo-trig cyclization through their metal enolates to afford 5-fluor-
inated 2-alkylidene-2,3-dihydrofurans. O-Cyclization exclusively
occurred via intramolecular substitution of the vinylic fluorines.
F
Y
Y
Y
Z
F
F2C
Z
Z
– F–
(1)
R
R
R
Key words: cyclization, fluorine, alkenes, furans, 5-endo-trig,
ketone enolates, vinylic substitution
Y
Z
TsN CH2
N
CR'
O
CH2
S
CH2 CR'
N
:
,
,
,
,
5-endo-trig cyclization with sp3 and sp2 nucleophiles
gem-Difluoroalkenes (1,1-difluoro-1-alkenes) have
unique reactivities toward nucleophiles, which are based
on their electron-deficient and highly polarized nature.
They facilitate extraordinary substitution reactions, which
hardly proceed in normal alkenes.1 Difluoroalkenes read-
ily undergo vinylic nucleophilic substitution (SNV) via ad-
dition to electrophilic difluoromethylene carbons and
subsequent fluoride elimination. We have already report-
ed syntheses of ring-fluorinated heterocycles by conduct-
ing the SNV reaction of difluoroalkenes in an intra-
molecular fashion.2 As well as sp3 heteroatom and carbon
nucleophiles,3 sp2 nucleophiles4 have also participated in
the 6-endo-trig cyclization to afford six-membered het-
erocycles (Scheme 1, eq 1). Furthermore, the high reactiv-
ity of 1,1-difluoro-1-alkenes has even allowed normally
‘disfavored’ 5-endo-trig cyclization,5–9 which provides
scaffolds for 2-fluoro-4,5-dihydroheteroles and 2-fluoro-
benzoheteroles (Scheme 1, eq 2).10 Addressing the next
challenge to the ‘disfavored’ process, we herein demon-
strate the 5-endo-trig cyclization with the metal enolates
of 3,3-difluoroallylic ketones, which are sp2 atom-based
ambident nucleophiles and rotationally restricted around
the anionic centers (Scheme 1, eq 3). This process effi-
ciently provides 2-alkylidene-2,3-dihydrofurans11 by (i)
constructing the heterocyclic ring and (ii) introducing a
fluorine substituent and an alkylidene group onto the pre-
scribed ring carbon.
F
F
F2C
Y–
F
Y
Y
– F–
(2)
R
R
R
Y: NTs, O, S
5-endo-trig cyclization with rotationally restricted sp2 nucleophiles
F
F
F2C
O
F
– F–
O
O
R3
R3
R1 R2 R4
R3
(3)
R1 R2
R4
R1
R2
R4
Scheme 1Intramolecular cyclization of gem-difluoroalkenes
lylic ketones 2 were obtained in moderate to high yield
(27–86%) via difluoromethylenation of ketoaldehydes 1
by a triaminophosphonium difluoromethylide, generated
in situ from dibromodifluoromethane and tris(dimethyl-
amino)phosphine (Scheme 2).13 Success of the exclusive-
ly selective difluoromethylenation of 1 was due to the
much higher reactivity of formyl groups compared to
ketone carbonyl groups.
First, we sought bases suitable for the enolate formation
and the subsequent 5-endo-trig cyclization by using diflu-
oroallylic ketone 2a as a model substrate (Table 1). Lithi-
um diisopropylamide (LDA) afforded the O-cyclization
product 5a as a single isomer, albeit in low yield, while the
C-cyclization product 6a was not detected at all (Table 1,
entry 1).14 Two-fold increase in the amount of LDA (2
equiv) turned out to be effective for the cyclization (Table
1, entry 2). Also, potassium hydride (1 equiv) exclusively
gave 5a and drastically improved its yield up to 79% (Ta-
ble 1, entry 3). As in the case of LDA, use of doubled
amounts of potassium hydride (2 equiv) was highly effec-
tive, leading to a 91% yield of the desired dihydrofuran 5a
(Table 1, entry 4). Thus, the nucleophilic 5-endo-trig cy-
The starting 3,3-difluoroallylic ketones are readily acces-
sible through the following chemoselective difluorometh-
ylenation protocol. 1,3-Ketoaldehydes 1, the precursors of
3,3-difluoroallylic ketones 2, were synthesized by the ac-
ylation of either morpholine enamines 3 or metal N-tert-
butyl enamides prepared by deprotonation of imines 4,
followed by hydrolysis (Scheme 2).12 Finally, difluoroal-
SYNLETT 2013, 24, 0057–0060
Advanced online publication: 10.12.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1317709; Art ID: ST-2012-U0877-L
© Georg Thieme Verlag Stuttgart · New York

58
T. Fujita et al.
LETTER
O
Table 2 5-endo-trig Cyclization of 3,3-Difluoroallylic Ketones 2
1)
(1.0 equiv)
O
Cl
R3
F
F2C
O
O
O
O
KH (2.0 equiv)
THF, reflux
Et2O, 0 °C to reflux, 5 h
R3
R4
N
R3
R3
R1
R1 R2
2) sat. aq NaHCO3
Et2O–H2O (2:3), 0 °C, 1 h
R1 R2
R4
R1 R2
R2
1
2
5
3
Entry
Time (h)
2
Product
Yield of 5 (%)
5a 91
CF2Br2 (2.0 equiv)
(Me2N)3P (4.0 equiv)
MS 4 Å
t-Bu
F
1) LDA (1.1 equiv)
Et2O, –78 to 0 °C, 2 h
N
O
1
n-C8H17
THF, –78 °C to r.t,
5–12 h
R1
O
2)
(1.0 equiv)
R2
Cl
R3
F
4
Et2O, r.t., 12 h
O
F2C
O
2
3
4
5
2
2
2
2
5b 97
5c 83
5d 75
5e 98
Ph
3) (COOH)2⋅2H2O (1.0 equiv)
R3
CH2Cl2–H2O (5:3), r.t., 1 h
R1 R2
F
O
2
Cy
Scheme 2 Synthesis of 3,3-difluoroallylic ketones 2
F
O
clization successfully proceeded even with rotationally
restricted sp2 nucleophiles in 2a. This is likely due to the
large polarization of the CF2=C moiety.10a
t-Bu
F
Table 1 Screening of Bases Suitable for 5-endo-trig Cyclization of
O
Ph
2a
F
F
n-C8H17
F2C
O
base
O
OMe
n-C8H17
+
n-C8H17
THF
reflux
O
F
O
6
7
2
5f 97
5g 91
2a
5a
6a
Entry
Base (equiv)
Time
Yield of 5a Yield of 6a
F
(%)
(%)
O
a
21
1
2
3
4
LDA (1.0)
LDA (2.0)
KH (1.0)
KH (2.0)
5 h
4 h
2 h
2 h
29
42
79
91
–
a
–
F
a
–
O
a
–
8
9
5
2
3
5h 91
5i 94
5j 97
a Not detected.
F
The optimized conditions obtained above for 2a were suc-
cessfully applied to the cyclizations of a variety of difluo-
roallylic ketones 2 (Table 2).15,16 Ketones 2b–g, which are
dimethylated at the allylic position, gave corresponding
fluorine-containing dihydrofurans 5b–g in good to excel-
lent yield. Difluoroallylic benzylic ketones 2e and 2f gave
2-benzylidene dihydrofurans 5e and 5f, respectively. Re-
actions of difluoroallylic ketones 2h–j, which possess a
cyclohexane ring at the allylic position, constructed a spi-
rocyclic structure in 5h–j. The reactions of α,α,α′,α′-tetra-
substituted ketones 2g and 2j were sluggish under the
same conditions. However, the longer reaction time or the
O
t-Bu
F
O
10a
a Pyridine was used as the solvent instead of THF.
Synlett 2013, 24, 57–60
© Georg Thieme Verlag Stuttgart · New York

LETTER
5-endo-trig Cyclization of 3,3-Difluoroallylic Ketone Enolates
Dupont, W.; Kruse, L.; Silberman, L.; Thomas, R. C. J.
59
use of pyridine as the solvent instead of THF improved the
yields of 5g or 5j, respectively. Intriguingly, dihydrofuran
derivatives 5a–f and 5i were obtained as single isomers
about the exo double bond, judging from 1H NMR and 13C
NMR studies. The configurations of 5a–f and 5i were as-
signed as Z-isomers by a NOESY experiment of 5b.17
This Z-selectivity in the formation of dihydrofurans 5a–f
and 5i is interpreted as follows: the Z-enolates seem to be
generated predominantly by deprotonation of difluoro-
allylic ketones 2 because of steric repulsion between sub-
stituents at both of the α positions of the carbonyl groups
in 2. The subsequent cyclization presumably proceeds
through the Z-enolates with retention of stereochemistry.
Chem. Soc., Chem. Commun. 1976, 736. (c) Baldwin, J. E.;
Thomas, R. C.; Kruse, L.; Silberman, L. J. Org. Chem. 1977,
42, 3846.
(6) Ichikawa, J.; Iwai, Y.; Nadano, R.; Mori, T.; Ikeda, M.
Chem. Asian J. 2008, 3, 393; and references cited therein.
(7) For recent reports on nucleophile-driven 5-endo-trig
cyclization, see: (a) Anderson, J. C.; Davies, E. A.
Tetrahedron 2010, 66, 6300. (b) Motto, J. M.; Castillo, Á.;
Greer, A.; Montemayer, L. K.; Sheepwash, E. E.; Schwan,
A. L. Tetrahedron 2011, 67, 1002.
(8) For recent reports on electrophile-driven 5-endo-trig
cyclization, see: (a) Stojanović, M.; Marković, R. Synlett
2009, 1997. (b) Kalamkar, N. B.; Kasture, V. M.; Dhavale,
D. D. Tetrahedron Lett. 2010, 51, 6745. (c) Saczewski, J.;
Gdaniec, M.; Bednarski, P. J.; Makowska, A. Tetrahedron
2011, 67, 3612.
(9) For recent reports on radical-initiated 5-endo-trig
cyclization, see: (a) Pattarozzi, M.; Ghelfi, F.; Roncaglia, F.;
Pagnoni, U. M.; Parsons, A. F. Synlett 2009, 2172. (b) Yu,
J.-D.; Ding, W.; Lian, G.-Y.; Song, K.-S.; Zhang, D.-W.;
Gao, X.; Yang, D. J. Org. Chem. 2010, 75, 3232.
(10) For 5-endo-trig cyclization of substrates with difluoroalkene
moieties, see: (a) Ichikawa, J.; Wada, Y.; Fujiwara, M.;
Sakoda, K. Synthesis 2002, 1917. (b) Ichikawa, J.; Nadano,
R.; Mori, T.; Wada, Y. Org. Synth. 2006, 83, 111.
(c) Ichikawa, J. Org. Synth. 2011, 88, 162. (d) Ichikawa, J.;
Wada, Y.; Okauchi, T.; Minami, T. Chem. Commun. 1997,
1537. (e) Ichikawa, J.; Fujiwara, M.; Wada, Y.; Okauchi, T.;
Minami, T. Chem. Commun. 2000, 1887. (f) Tanabe, H.;
Ichikawa, J. Chem. Lett. 2010, 39, 248. (g) Fuchibe, K.;
Takahashi, M.; Ichikawa, J. Angew. Chem. Int. Ed. 2012, 51,
12059.
(11) For selected examples of conventional synthetic
methodologies for 2-alkylidene-2,3-dihydrofurans, see:
(a) Tiecco, M.; Testaferri, L.; Tingoli, M.; Marini, F. J. Org.
Chem. 1993, 58, 1349; and references cited therein .
(b) Lattanzi, A.; Sagulo, F.; Scettri, A. Tetrahedron:
Asymmetry 1999, 10, 2023. (c) Fang, Y.; Li, C. Chem.
Commun. 2005, 3574. (d) Chen, Y.-F.; Wang, H.-F.; Wang,
Y.; Luo, Y.-C.; Zhu, H.-L.; Xu, P.-F. Adv. Synth. Catal.
2010, 352, 1163. (e) Montel, S.; Bouyssi, D.; Balme, G. Adv.
Synth. Catal. 2010, 352, 2315.
Difluoroallylic ketones 2, as shown in Table 2, underwent
5-endo-trig O-cyclization via their enolate forms. The re-
action afforded the corresponding 2-alkylidene-5-fluoro-
2,3-dihydrofurans 5 without the formation of C-cycliza-
tion products, 3-fluorocyclopent-3-en-1-ones 6. Although
5-endo-trig cyclization is assigned as disfavored in Bald-
win’s rules,5 the reactivity of 1,1-difluoro-1-alkenes
allows the substrates to undergo such an extraordinary cy-
clization.
In summary, we have demonstrated that 3,3-difluoroallyl-
ic ketone enolates exclusively underwent intramolecular
O-alkenylation to afford fluorinated dihydrofurans 5 bear-
ing a Z-exo-alkylidene unit. The cyclization proceeded in
a 5-endo-trig fashion, which is disfavored according to
Baldwin’s rules. In this process, a fluorine substituent was
introduced selectively onto the 5-position of the 2,3-dihy-
drofuran scaffold. Furthermore, since fluorinated 2-alkyl-
idene-2,3-dihydrofurans are unprecedented and highly
functionalized, it is expected that these compounds would
serve as parts of bioactive molecules and versatile inter-
mediates.18
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
r
t
(12) For the synthesis of 1,3-ketoaldehydes from enamines, see:
Kuhlmey, S.-R.; Adolph, H.; Rieth, K.; Opitz, G. Liebigs
Ann. Chem. 1979, 617.
(13) For difluoromethylenation of aldehydes with
dibromodifluoromethane and
References and Notes
(1) For recent reviews, see: (a) Uneyama, K. Organofluorine
Chemistry; Chap. 2.3; Blackwell Publishing: Oxford, 2006.
(b) Amii, H.; Uneyama, K. Chem. Rev. 2009, 109, 2119.
(2) (a) Ichikawa, J. In Fluorine-Containing Synthons, ACS
Symposium Series 911; Chap. 14; Soloshonok, V. A., Ed.;
Oxford University Press/ACS: Washington DC, 2005.
(b) Ichikawa, J. Chim. Oggi 2007, 25 (4), 54.
(3) (a) Wada, Y.; Ichikawa, J.; Katsume, T.; Nohiro, T.;
Okauchi, T.; Minami, T. Bull. Chem. Soc. Jpn. 2001, 74,
971. (b) Wada, Y.; Mori, T.; Ichikawa, J. Chem. Lett. 2003,
32, 1000. (c) Mori, T.; Ichikawa, J. Chem. Lett. 2004, 33,
590. (d) Ichikawa, J.; Sakoda, K.; Moriyama, H.; Wada, Y.
Synthesis 2006, 1590.
tris(trimethylamino)phosphine, see: (a) Naae, D. G.; Burton,
D. J. Synth. Commun. 1973, 3, 197. (b) Vinson, W. A.;
Prickett, K. S.; Spahic, B.; deMontellano, P. R. O. J. Org.
Chem. 1983, 48, 4661.
(14) Baldwin noted that when endocyclic alkylation of ketone
enolates constructs five-membered rings, O-cyclization
would be preferable because of an in-plane approach to
enolates. The chemoselectivity in our case could be partially
explained by a similar reasoning, albeit with the sp2-CF2
electrophile instead of sp3-C electrophiles. See: Baldwin, J.
E.; Kruse, L. I. J. Chem. Soc., Chem. Commun. 1977, 233.
(15) (Z)-5-Fluoro-3,3-dimethyl-2-(2-phenylethylidene)-2,3-
dihydrofuran (5b)
(4) (a) Ichikawa, J.; Wada, Y.; Miyazaki, H.; Mori, T.; Kuroki,
H. Org. Lett. 2003, 5, 1455. (b) Ichikawa, J.; Mori, T.;
Miyazaki, H.; Wada, Y. Synlett 2004, 1219. (c) Ichikawa, J.;
Wada, Y.; Kuroki, H.; Mihara, J.; Nadano, R. Org. Biomol.
Chem. 2007, 5, 3956.
To a suspension of KH (oil free, 46 mg, 1.2 mmol) in THF
(11 mL) was added 6,6-difluoro-4,4-dimethyl-1-phenylhex-
5-en-3-one (2b, 138 mg, 0.58 mmol), and the mixture was
heated to reflux for 2 h. After cooling to r.t., the reaction was
quenched with phosphate buffer (pH 7). Organic materials
were extracted with Et2O three times. The combined extracts
(5) For Baldwin’s rules, see: (a) Baldwin, J. E. J. Chem. Soc.,
Chem. Commun. 1976, 734. (b) Baldwin, J. E.; Cutting, J.;
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 57–60

60
T. Fujita et al.
LETTER
were washed with brine and dried over MgSO4. After
removal of the solvent under reduced pressure, the residue
was purified by TLC on silica gel (EtOAc–hexane, 1:5) to
give 5b (122 mg, 97%) as a colorless oil. 1H NMR (500
MHz, CDCl3): δ = 1.26 (d, JHF = 1.1 Hz, 6 H), 3.45 (d, J =
7.5 Hz, 2 H), 4.20 (d, JHF = 5.4 Hz, 1 H), 4.73 (td, J = 7.5 Hz,
JHF = 3.4 Hz, 1 H), 7.18–7.22 (m, 3 H), 7.27–7.30 (m, 2 H).
13C NMR (126 MHz, CDCl3): δ = 30.1 (d, JCF = 2 Hz), 30.9,
44.2 (d, JCF = 2 Hz), 79.7 (d, JCF = 8 Hz), 99.4, 125.9, 128.2,
128.4, 141.0, 157.5 (d, JCF = 276 Hz), 160.6 (d, JCF = 3 Hz).
19F NMR (470 MHz, CDCl3): δ = 46.2 (s). IR (neat): 3028,
2970, 2931, 1801, 1726, 1703, 1454, 1279, 1219, 1126,
1088, 993, 976, 748, 698 cm–1. Anal. Calcd for C14H15FO: C,
77.04; H, 6.93. Found: C, 76.80; H, 7.16%.
(17) In the NOESY experiment of dihydrofuran 5b, substantial
correlation between the methyl protons and the vinylic
proton Ha was observed. No NOE correlation was detected
between the methyl protons and the allylic protons Hb
(Figure 1).
F
Hb
Hb
O
Ha
Me
Me
(Z)-5b
(16) 3,3-Disubstituted5-fluoro-2-alkylidene-2,3-dihydrofurans5
Figure 1 NOE correlation between protons in dihydrofuran 5b
are air- and heat-stable.
(18) For a review on bioactivities of fluorinated compounds, see:
Müller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881.
Synlett 2013, 24, 57–60
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