The nucleophilic 5-endo-trig cyclization of gem-difluoroolefins with homoallylic functional groups: Syntheses of ring-fluorinated dihydroheteroaromatics

Article abstract of DOI:10.1039/b004978f

Gem-Difluoroolefins bearing homoallylic tosylamido, hydroxy, or mercapto groups undergo intramolecular nucleophilic substitution of the nitrogen, oxygen, or sulfur with loss of fluorine via a 5-endo-trig process, leading to 2-fluoro-2-pyrrolines, 5-fluoro

Full text of DOI:10.1039/b004978f

The nucleophilic 5-endo-trig cyclization of gem-difluoroolefins with homoallylic
functional groups: syntheses of ring-fluorinated dihydroheteroaromatics
Junji Ichikawa,*a Masaki Fujiwara,a Yukinori Wada,a Tatsuo Okauchib and Toru Minami*b
a Department of Chemistry, Graduate School of Science, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo
113-0033, Japan. E-mail: junji@chem.s.u-tokyo.ac.jp; Fax: +81-3-5841-4345; Phone: +81-3-5841-4345
b Department of Applied Chemistry, Kyushu Institute of Technology, Sensui-cho, Tobata, Kitakyushu 804-8550, Japan
Received (in Cambridge, UK) 21st June 2000, Accepted 15th August 2000
First published as an Advance Article on the web 18th September 2000
gem-Difluoroolefins bearing homoallylic tosylamido, hy-
droxy, or mercapto groups undergo intramolecular nucleo-
philic substitution of the nitrogen, oxygen, or sulfur with loss
of fluorine via a 5-endo-trig process, leading to 2-fluoro-
2-pyrrolines, 5-fluoro-2,3-dihydrofurans, or -thiophenes in
high yields.
homoallylic position, we tried the regioselective hydroboration
of 1,1-difluoro-1,3-dienes 7, which were readily prepared from
2,2,2-trifluoroethyl toluene-p-sulfonate and vinyl halides in a
one-pot operation according to our method.8 The electron-rich,
non-fluorinated double bond in 7 might be more reactive toward
borane reagents. Treatment of difluorodienes 7 with 9-bora-
bicyclo[3.3.1]nonane (9-BBN) under reflux in THF selectively
promoted hydroboration as expected to generate difluorohomo-
allylboranes, and successive treatment with alkaline aqueous
hydrogen peroxide gave gem-difluorohomoallyl alcohols 1a–c
in good yields (Scheme 2). The corresponding nitrogen- and
sulfur-containing substrates 2a–e, 3a,b were easily obtained
from 1 as shown in Scheme 2.
5-endo-trig cyclization has long been considered to be a
geometrically disfavored process in accord with Baldwin’s
rules.1 Efficient examples of the cyclization, however, have
been recently devised in radical-initiated2 and electrophile-
driven3 ring closures. In contrast with these two types of
5-endo-trig cyclizations, the corresponding nucleophile-driven
ring closure has still rarely been observed in synthetic
chemistry.4,5
The cyclization of homoallyl alcohols 1a,b was attempted by
treatment with 1.2 eq. of NaH in several solvents. While the use
DMPU or NMP gave no cyclized products, DMF, DMA, or
DMSO successfully promoted the 5-endo-trig cyclization to
afford 5-fluoro-2,3-dihydrofurans 4a,b in good yields (Table 1,
Entries 1,2).9† KH was less effective than NaH, and high-
dilution conditions ([1a] = 0.03 mol L21) raised the yield by
gem-Difluoroolefins possess remarkable reactivity toward
nucleophilic substitution for their fluorine atoms via addition–
elimination processes.6 As one of its applications, we have
recently disclosed that b,b-difluorostyrenes bearing ortho-
nitrogen, oxygen, or sulfur heteroatoms readily undergo
nucleophilic 5-endo-trig cyclization to provide ring-fluorinated
heteroaromatics: 2-fluorinated indoles, benzo[b]furans, and
benzo[b]thiophenes.5 Such unique reactivity of gem-difluoro-
olefins is exerted presumably due to (i) the highly polarized C–
10% compared to the case of [1a] = 0.2 mol L21
.
Moreover, we examined the 5-endo-trig cyclization of the
substrates with N-nucleophiles under similar conditions.
Whereas N-unsubstituted and N-butylhomoallylamines 2c,d did
not cyclize, the N-phenyl substrate 2e afforded 4-methyl-
1-phenyl-3-(3-phenylpropyl)-2-pyrrolidone 8 via hydrolysis of
C double bond (significant single bond character implied by 13
C
NMR: ca. 150 and 90 ppm for CF2NC), which would allow
initial 5-membered ring formation, and (ii) the successive
elimination of fluoride ion suppressing the reverse ring opening.
In this ring-forming reaction the substrates had a benzene ring
as an sp2-carbon linker between the nucleophilic functional
group and the difluoroolefin part.
In order to broaden the scope of this nucleophilic 5-endo-trig
cyclization and rule out the possibility of an 6p-electrocycliza-
tion mechanism, we investigated the reaction of gem-di-
fluoroolefins 1–3 bearing an N-, O-, or S-functional group
which was linked by two sp3 carbons to the olefinic carbon.
Herein we report a facile synthesis of selectively ring-
fluorinated pyrroline 5, dihydrofuran 4, and dihydrothiophene 6
(Scheme 1), which are difficult to access despite the potential
uses of ring-fluorinated heterocycles as components of agro-
chemicals, pharmaceuticals, and dyestuffs.7
gem-Difluoroolefin substrates were designed to bear a
nucleophilic nitrogen, oxygen, or sulfur atom at the homoallylic
position suitable for substitution in a 5-endo-trig fashion. To
introduce a functional group (HY) at the gem-difluoro-
Scheme 2 Preparation of gem-difluoroolefins 1–3. Reagents and condi-
tions: i, 9-BBN (1.1–1.4 eq.), THF, reflux, 6–7 h; ii, aq.H2O2, aq. NaOH,
0 °C, 2 h; iii, BocNHTs (1 eq.), PPh3 (1 eq.), EtO2CNNNCO2Et (1 eq.),
THF, rt, 2 h; iv, CF3CO2H (15 eq.), CH2Cl2, rt, 2 h; v, phthalimide (1 eq.),
PPh3 (1 eq.), EtO2CNNNCO2Et (1 eq.), THF, rt, 2 h; vi, NH2NH2•H2O (2
eq.), EtOH, reflux, 2 h; vii, TsCl (1 eq.), Py, rt, 8 h; viii, BunNH2 (26 eq.),
reflux, 6 h; ix, PhNH2 (26 eq.), reflux, 6 h; x, AcSNa (1 eq.), DMF, 70 °C,
3 h; xi, K2CO3 (1 eq.), MeOH, 0 °C, 1 h.
Scheme 1 Nucleophilic 5-endo-trig cyclization of gem-difluoroolefins
1–3.
DOI: 10.1039/b004978f
Chem. Commun., 2000, 1887–1888
This journal is © The Royal Society of Chemistry 2000
1887

Table 1 Synthesis of ring-fluorinated dihydroheteroaromatics 4–6a
Entry
YH
R1
R2
Substrate
Base (eq.)
Time
Product
Yield (%)b
1
2
3
4
5
6
OH
OH
PhNH
TsNH
SH
CH2CH(Me)Ph
Bun
(CH2)3Ph
CH2CH(Me)Ph
(CH2)3Ph
(CH2)3Ph
Me
CH2Ph
Me
Me
Me
1ac
1b
2e
2bc
3b
3a
NaH (1.2)
NaH (1.2)
NaH (1.1)
NaH (1.1)
NaH (1.1)
NaOMe (1.0)
7 h
11 h
24 h
4 d
4 h
8 h
4ac
4b
8
67
62
62
80
76
69
5c
6
SC(O)Me
Me
6
a The reaction was conducted in DMF at 90 °C. [Substrate] = 0.02–0.03 mol L21 b Isolated yield. c 1+1 Diastereomer mixture.
.
¶ The fluorine-free analogue, dimethyl 4-methyleneglutamate was reported
to cyclize to 5-methoxycarbonyl-3-methylene-2-pyrrolidone via 5-exo-trig
pathway without formation of the 5-endo-trig product.1b,14
∑ 10: dF (471 MHz, CDCl3–C6F6) 61.8 (1F, t, JFH = 4.8 Hz).
1 (a) J. E. Baldwin, J. Chem. Soc., Chem. Commun., 1976, 734; (b) J. E.
Baldwin, J. Cutting, W. Dupont, L. Kruse, L. Silberman and R. C.
Thomas, J. Chem. Soc., Chem. Commun., 1976, 736; (c) J. E. Baldwin,
R. C. Thomas, L. I. Kruse and L. Silberman, J. Org. Chem., 1977, 42,
3846.
2 For recent reports, see: A. J. Clark, C. P. Dell, J. M. Ellard, N. A. Hunt
and J. P. McDonaph, Tetrahedron Lett., 1999, 40, 8619; D. T. Davies,
N. Kapur and A. F. Parsons, Tetrahedron Lett., 1999, 40, 8615 and
references cited therein; H. Ishibashi, A. Toyao and Y. Takeda, Synlett,
1999, 1468 and references cited therein; S. Bogen, M. Gulea, L.
Fensterbank and M. Malacria, J. Org. Chem., 1999, 60, 4920 and
references cited therein; J. Cassayre and S. Z. Zard, Synlett, 1999, 501;
M. Ikeda, M. Hamada, T. Yamashita, K. Matsui, T. Sato and H.
Ishibashi, J. Chem. Soc., Perkin Trans. 1, 1999, 1949; A. Kittaka, T.
Asakura, T. Kuze, H. Tanaka, N. Yamada, K. T. Nakamura and T.
Miyasaka, J. Org. Chem., 1999, 64, 7081; Y. Nonami, J. Baran, J.
Sosnicki, H. Mayr, A. Masuyama and M. Nojima, J. Org. Chem., 1999,
64, 4060; C. Chatgilialoglu, T. Gimisis and G. P. Spada, Chem. Eur. J.,
1999, 5, 2866; J. Gao and J. Rusling, J. Org. Chem., 1998, 63, 218.
3 For recent reports, see: A. D. Jones, D. W. Knight, A. L. Redfern and J.
Gilmore, Tetrahedron Lett., 1999, 40, 3267 and references cited therein;
S. B. Bedford, K. E. Bell, F. Bennett, C. J. Hayes, D. W. Knight and
D. E. Shaw, J. Chem. Soc., Perkin Trans. 1, 1999, 2143 and references
cited therein; F. Bravo, M. Kassou and S. Castillón, Tetrahedron Lett.,
1999, 40, 1187.
4 D. Craig, N. J. Ikin, N. Mathews and A. M. Smith, Tetrahedron, 1999,
55, 13471 and references cited therein. For the 5-endo-trig process onto
a p-allylpalladium system, see: S. Thorimbert and M. Malacria,
Tetrahedron Lett., 1998, 39, 9659. For the ab initio calculation on the
cyclization of 4,4-difluorobut-3-en-1-ol, see: T. Yamazaki, S. Hiraoka,
J. Sakamoto and T. Kitazume, J. Phys. Chem. A, 1999, 103, 6820; T.
Yamazaki, S. Hiraoka, J. Sakamoto and T. Kitazume, J. Fluorine
Chem., 2000, 101, 309.
5 J. Ichikawa, Y. Wada, T. Okauchi and T. Minami, Chem. Commun.,
1997, 1537.
6 L. G. Sprague, K. B. Baucom, S. F. Sellers and R. A. DuBoisson, in
Chemistry of Organic Fluorine Compounds II, ed. M. Hudlicky and
A. E. Pavlath, ACS Monograph 187, American Chemical Society,
Washington, DC, 1995, p. 729.
7 M. J. Silvester, Adv. Heterocyclic Chem., 1994, 59, 1; L. G. Sprague,
K. B. Baucom, S. F. Sellers and R. A. DuBoisson, Aldrichim. Acta,
1991, 24, 31; Organofluorine Chemistry, Principles and Commercial
Applications, ed. R. E. Banks, B. E. Smart and J. C. Tatlow, Plenum
Press, New York, 1994.
8 J. Ichikawa, C. Ikeura and T. Minami, Synlett, 1992, 739.
9 For the synthesis of fluorofurans, see: A. K. Forrest and P. J. O’Hanlon,
Tetrahedron Lett., 1995, 36, 2117; K. Burger and B. Helmreich,
J. Chem. Soc., Chem. Commun., 1992, 348; H. L. Sham and D. A.
Betebenner, J. Chem. Soc., Chem. Commun., 1991, 1134.
10 For the synthesis of fluoropyrroles, see: M. S. Novikov, A. F.
Khlebnikov, E. S. Sidorina and R. R. Kostikov, J. Fluorine Chem.,
1998, 90, 117 and references cited therein.
11 For the synthesis of fluorothiophenes, see: D. F. Andrés, E. G. Laurent
and B. S. Marquet, Tetrahedron Lett., 1997, 38, 1049 and references
cited therein.
12 T. Kitazume and T. Ohnogi, Synthesis, 1988, 615; T. Fuchikami, Y.
Shibata and Y. Suzuki, Tetrahedron Lett., 1986, 27, 3173.
13 D. K. Hutchinson and P. L. Fuchs, J. Am. Chem. Soc., 1987, 109,
4930.
Scheme 3 Competitive cyclization: 5-endo-trig vs. 5-exo-trig Reagents and
conditions: i, NaH (1.1 eq.), DMF, 100 °C, 0.3 h.
the expected 2-fluoropyrroline (Entry 3). The N-4,4-difluoro-
but-3-enyltoluene-p-sulfonamide 2b underwent the desired ring
closure to give 2-fluorinated pyrroline 5 in 80% yield (Entry
4).10‡
As a further example of the cyclization, the intramolecular
substitution of sulfur nucleophiles (which Baldwin’s rules allow
for the normally disfavored 5-endo-trig process) was also
examined.1b The reaction of 3b under similar conditions to
those for 1 and 2 provided 5-fluorinated dihydrothiophene 6 in
76% yield (Entry 5).11 In addition, treatment of thioacetic S-acid
ester 3a with sodium methoxide allowed the cyclization via in
situ generated thiolate to give 6 (Entry 6).§
In order to demonstrate the favored nature of 5-endo-trig
cyclization in gem-difluoroolefins, we tried the competitive
reaction between 5-endo-trig and 5-exo-trig processes. The b,b-
difluoro-a,b-unsaturated ester 9 bearing a 2-toluene-p-sulfona-
midoethyl group was designed as a substrate which could
undergo the Michael reaction and the transacylation via 5-endo-
trig and 5-exo-trig processes, respectively. Compound 9 was
prepared by the SN2A reaction of methyl 2-(trifluoromethyl)pro-
penoate12 with benzyloxymethylcopper13 and successive depro-
tection of the benzyl group, followed by the introduction of an
NHTs group according to the same procedure for 2b. On
treatment of 9 with NaH in DMF, the 5-endo-trig cyclization
proceeded to lead exclusively to the 2-fluorinated pyrroline
derivative 10 as shown in Scheme 3.¶∑
In conclusion, normally ‘disfavored’ 5-endo-trig ring clo-
sures are successfully achieved in the intramolecular addition–
elimination reaction of gem-difluoroolefins bearing nucleo-
philic heteroatoms linked by two sp3 carbons to the vinylic
carbon as well as two sp2 carbons.5 Thus, gem-difluoro-
homoallylamine, alcohol, and thiol derivatives open a new way
to the syntheses of selectively ring-fluorinated heterocyclic
compounds.
We gratefully acknowledge the financial support for this
research by a grant from Central Glass Co., Ltd. to J. I. We also
thank F-Tech, Inc. for a generous gift of 2-(trifluoromethyl)pro-
penoic acid.
Notes and references
† 4b: dF (471 MHz, CDCl3–C6F6) 42.4 (1F, s).
‡ 5: dF (471 MHz, CDCl3–C6F6) 36.2 (0.5F, s), 36.6 (0.5F, s).
§ 6: dF (471 MHz, CDCl3–C6F6) 35.7 (1F, br s).
14 For examples where N-substituents played an important role, see: B.
Tarnchompoo, C. Thebtaranonth and Y. Thebtaranonth, Tetrahedron
Lett., 1987, 28, 6675; A. Padwa and B. H. Norman, J. Org. Chem., 1990,
55, 4801.
1888
Chem. Commun., 2000, 1887–1888