Platform for Ring-Fluorinated Benzoheterole Derivatives: Palladium-Catalyzed Regioselective 1,1-Difluoroallylation and Heck Cyclization

Article abstract of DOI:10.1021/acs.orglett.5b03390

The synthesis of difluoromethylene-containing heterocycles was achieved via the palladium-catalyzed 1,1-difluoroallylation of heteronucleophiles followed by intramolecular Heck reaction. The allylic substitution of 3-bromo-3,3-difluoropropene was regiosel

Full text of DOI:10.1021/acs.orglett.5b03390

Letter
pubs.acs.org/OrgLett
Platform for Ring-Fluorinated Benzoheterole Derivatives: Palladium-
Catalyzed Regioselective 1,1-Difluoroallylation and Heck Cyclization
Takeshi Fujita, Kazuki Sugiyama, Shohei Sanada, Tomohiro Ichitsuka, and Junji Ichikawa*
Division of Chemistry, Faculty of Pure and Applied Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8571, Japan
S
* Supporting Information
ABSTRACT: The synthesis of difluoromethylene-containing
heterocycles was achieved via the palladium-catalyzed 1,1-
difluoroallylation of heteronucleophiles followed by intra-
molecular Heck reaction. The allylic substitution of 3-bromo-
3,3-difluoropropene was regioselectively accomplished by
heteronucleophiles without rearrangement to give the
corresponding 1,1-difluoroallylated compounds whose Heck
cyclization proceeded in a 5-exo manner to afford ring-
difluorinated indolines and dihydrobenzofurans. Their defluorinative allylic substitution further provided 2-fluoroindoles and 2-
fluorobenzofurans.
llylic substitutions including nucleophilic reactions (SN2′
the obtained 3,3-difluoroallyl compounds 3 afforded 3-
difluoromethylated 2,3-dihydrobenzoheteroles. In contrast,
we herein disclose the complete switching of the regiose-
lectivity in the reactions of 1 with heteronucleophiles 2 using
a palladium catalyst (Scheme 1b). The α-selective substitution
of 1 with 2-bromophenols 2a and 2-bromoanilines 2b
selectively proceeded via the Tsuji−Trost reaction to afford
O- and N-(1,1-difluoroallyl) compounds 5.6 Furthermore,
their subsequent 5-exo Heck reaction7 provided ring-
difluorinated benzoheterole derivatives 6.8
First, we sought a suitable base for the α-selective Tsuji−
Trost reaction using 2-bromophenol (2aa) in the presence of
4 mol % of Pd(OAc)2 and 16 mol % of PPh3 (Table 1).
Weak bases (NaHCO3 and KHCO3) were found to be
ineffective in this reaction (entries 2 and 3). The use of
NaOMe promoted the selective formation of the α-
substitution product 5aa, albeit in low yield (entry 4). Both
the yield of 5aa and the 5aa/3aa ratio were drastically
improved by the use of t-BuOK or NaH without the loss of
the C−Br bond of 2aa (entries 5 and 6). When the amount
of Pd(OAc)2 was reduced to 1 mol % (entry 7), 5aa was
obtained in 97% isolated yield. Notably, the Pd catalysts
switched the regioselectivity in the allylic substitution of 1
with 2aa since γ-selective substitution proceeded with Cs2CO3
in the absence of Pd catalysts, as we have reported previously
(entry 1).5
A
and SN2 reaction) and palladium-catalyzed reactions (the
Tsuji−Trost reaction) have been applied in various synthetic
processes as one of the most important organic reactions.1
Despite the versatility of allylic substitution, it is often difficult
to control the regioselectivity of unsymmetrically substituted
allylic substrates. For example, gem-difluoroallylic electrophiles
have served as two-fluorine-containing three-carbon building
blocks; substitution on their carbon atoms α or γ to the
fluorine substituents affords 1,1- or 3,3-difluoroallylic com-
pounds, respectively.2−4 The regioselectivity in such reactions
has not been well controlled; however, it has been typically
determined by the choice of substrate. Even worse for product
selectivity, both of the difluoroallylated products are
susceptible to further C−F substitution by nucleophiles.
In recent times, we developed a base-mediated selective
SN2′ reaction of 3-bromo-3,3-difluoropropene (1) with
brominated heteronucleophiles 2 (Scheme 1a).5 In this
previous report, the subsequent 5-exo radical cyclization of
Scheme 1. Regioswitchable Allylic Substitution of 3-Bromo-
3,3-difluoropropene (1)
The α-selective Tsuji−Trost reaction of 2-bromophenols 2a
was then investigated with the optimal conditions obtained
above (Table 2). Phenols 2ab and 2ac with electron-donating
methyl and methoxy groups along with phenol 2ad with an
electron-withdrawing cyano group successfully underwent
regioselective allylation with 1 in the presence of the Pd
Received: November 26, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03390
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Organic Letters
Letter
Table 1. Screening of Bases for the α-Selective Tsuji−Trost
Reaction with Phenol 2aa
Table 3. Synthesis of Dihydrobenzofurans 6a
a
a
entry
x
base (y equiv)
time (min)
5aa (%)
3aa (%)
b
c
c
1
Cs2CO3 (1.0)
NaHCO3 (1.0)
KHCO3 (1.0)
NaOMe (1.1)
t-BuOK (1.0)
NaH (1.0)
30
60
60
30
30
15
30
16
79
2
3
4
5
6
7
4
4
4
4
4
1
2
2
2
2
2
3
4
3
27
92
96
c
NaH (1.0)
97
a
Yield was determined by 19F NMR measurements using PhCF3 as an
a
b
b
Isolated yield. 1,2,2,6,6-Pentamethylpiperidine was used instead of
internal standard. 1 (2.0 equiv), N-methyl-2-pyrrolidone (NMP), 90
°C. See ref 5. Isolated yield.
c
NaOAc.
Table 2. 1,1-Difluoroallylation of Phenols 2a
reaction of 2ba with 1 was conducted under the optimal
conditions for phenols 2a, both the 1,1-difluoroallylated
compound 5ba and 3,3-difluoroallylated compound 3ba
were obtained in an almost 1:1 ratio (entry 1). To improve
the yield and the regioselectivity, several bidentate phosphine
ligands were used with Pd2(dba)3·CHCl3 (entries 2−5).
Among them, 4,5-bis(diphenylphosphino)-9,9-dimethylxan-
thene (Xantphos), which was used with NaH, provided the
highest total yield of 5ba and 3ba (entry 5), albeit with no
selectivity. Other bases used with Xantphos were thus
examined for α-selective substitution (entries 6−9). Although
t-BuOK was comparable to NaH (entry 6), lithium bases
(LiH, LDA, and LHMDS) improved the 5ba/3ba ratios,
providing excellent total yields of 5ba and 3ba (entries 7−9).
Further screening of solvents and temperatures (entries 10−
15) revealed that LHMDS exhibited the best efficiency in
ether at 0 °C (entry 15).
Since the isolation of 5b from 3b proved troublesome, we
attempted the direct synthesis of N-sulfonyl-2,2-difluoro-3-
methyleneindolines 6b via the 1,1-difluoroallylation of N-
sulfonylanilines 2b followed by Heck cyclization using the
mixtures of 5b and 3b obtained immediately after aqueous
workup (Table 5). When a crude mixture of 5ba and 3ba
prepared with 1.1 equiv of 1 under the optimal conditions
above was treated with 1 mol % of Pd(OAc)2, 10 mol % of
NEt3, and 1.2 equiv of sodium benzoate, N-tosyl-2,2-difluoro-
3-methyleneindoline (6ba) was obtained in 84% isolated yield
from 2ba (entry 1). Similarly, N-tosylanilines 2bb and 2bc
bearing electron-donating groups (Me and OMe) and 2bd−bf
bearing halogen substituents (F, Cl, and Br) successfully
underwent the sequence of 1,1-difluoroallylation and Heck
cyclization to afford the corresponding indolines 6bb−bf in
high yields (entries 2−6). Notably, in each case, the selective
and almost quantitative formation of 5b in the 1,1-
difluoroallylation step was confirmed by 19F NMR measure-
ment. 1,1-Difluoroallylation of N-mesylanilines 2bg and 2bh
also proceeded at room temperature, leading to selective
formation of 5bg and 5bh, whose Heck cyclization gave N-
mesylindolines 6bg and 6bh in good yields (entries 7 and 8).
In addition, the 2,2-difluorinated 3-methylene-2,3-dihydro-
benzoheteroles obtained via the aforementioned sequence
were further transformed into 2-fluorobenzoheteroles (eqs
1−3).8a,10 2,2-Difluorinated dihydronaphthofuran 6af under-
a
b
Isolated yield. Yield was determined by 19F NMR measurement
using PhCF3 as an internal standard.
catalyst. The corresponding 1,1-difluoroallylated compounds
5ab−ad were obtained in 94, 93, and 95% yields, respectively
(entries 2−4). The 1,1-difluoroallylation of chlorine-substi-
tuted bromophenol 2ae proceeded without the loss of its C−
Cl and C−Br bonds, leading to the formation of 5ae in 96%
yield (entry 5). 1-Bromo-2-naphthol (2af) also participated in
the reaction to give 5af in 94% yield (entry 6).9
The obtained 1,1-difluoroallylated compounds 5a under-
went an intramolecular Heck reaction in a 5-exo manner to
afford 2,2-difluorinated 3-methylene-2,3-dihydrobenzofuran 6a
(Table 3). Upon treatment of 5aa with 1 mol % of Pd(OAc)2
and 5.0 equiv of NaOAc, dihydrobenzofuran 6aa was
synthesized in 94% yield. Irrespective of the substituents on
the aromatic rings, the 5-exo Heck reactions of 5ab−af
successfully proceeded to afford the corresponding difluori-
nated dihydrobenzofuran 6ab−af in high to excellent yields
(entries 2−6).
Next, we sought suitable conditions for the 1,1-
difluoroallylation of sulfonamides with 3-bromo-3,3-difluor-
opropene (1) using N-(2-bromophenyl)-4-methylbenzenesul-
fonamide (2ba) as a model substrate (Table 4). Although the
B
DOI: 10.1021/acs.orglett.5b03390
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Organic Letters
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Table 4. Screening of Conditions for the α-Selective Tsuji−Trost Reaction with Aniline 2ba
a
a
entry
ligand
PPh3
base (x equiv)
solvent
conditions
5ba (%)
3ba (%)
b
1
NaH (1.0)
NaH (1.0)
NaH (1.0)
NaH (1.0)
NaH (1.0)
t-BuOK (1.0)
LiH (1.0)
THF
THF
THF
THF
THF
THF
THF
THF
THF
DMF
hexane
ether
ether
ether
ether
40 °C, 4 h
40 °C, 2 h
40 °C, 2 h
40 °C, 2 h
40 °C, 2 h
40 °C, 1 h
40 °C, 3 h
40 °C, 0.5 h
40 °C, 0.5 h
40 °C, 1 h
40 °C, 4 h
40 °C, 4 h
rt, 0.5 h
36
39
3
c
2
dppe
ND
c
3
dppb
ND
3
4
dppf
25
49
47
62
55
63
54
13
50
86
91
92
28
48
49
36
31
37
46
5
5
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
6
7
8
LDA (1.2)
d
9
LHMDS (1.2)
LHMDS (1.2)
LHMDS (1.2)
LHMDS (1.2)
LHMDS (1.2)
LHMDS (1.2)
d
d
d
d
e
10
11
12
13
14
15
10
14
9
rt, 0.5 h
e
LHMDS (1.2)
0 °C, 1 h
8
a
b
c
Yield was determined by 19F NMR measurement using PhCF3 as an internal standard. Pd(OAc)2 (1 mol %), PPh3 (4 mol %). ND = not detected.
d
e
THF solution. Ether solution.
Table 5. Synthesis of Indolines 6b from Anilines 2b
b
5b + 3b
(%)
time
(h)
c
d
entry
2b
conditions
5b:3b
6b (%)
1
2
3
2ba
2bb
2bc
2bd
2be
2bf
0 °C, 1 h
0 °C, 2 h
0 °C, 2 h
0 °C, 2 h
0 °C, 0.5 h
0 °C, 0.5 h
rt, 0.5 h
99
93:7
92:8
92:8
93:7
94:6
95:5
91:9
93:7
1
6ba, 84
6bb, 82
6bc, 88
6bd, 78
6be, 78
6bf, 82
6bg, 60
6bh, 60
quant
quant
quant
98
2
2
e
4
0.5
0.5
0.5
1
5
6
7
8
quant
94
2bg
2bh
rt, 0.5 h
97
1
a
b
Ether solution. Yield was determined by 19F NMR measurement
c
using PhCF3 as an internal standard. Ratio was determined by 19F
NMR measurement. Isolated yield. NEt3 (4 mol %).
d
e
6af with 4-octyne via β-fluorine elimination also proceeded in
the presence of Et3SiH to afford the 3-allylated 2-
fluoronaphthofuran 9 in 89% yield (eq 3).11 Similarly,
indoline 6ba underwent nickel-catalyzed coupling with 3-
hexyne to give the corresponding 2-fluoroindole 10 in 87%
yield (eq 4).
went SN2′ substitution with benzylmethylamine to afford 3-
(aminomethyl)-2-fluoronaphthofuran 7 in 99% yield, requiring
neither catalysts nor additives (eq 1).3 In the case of indoline
derivative 6ba, the SN2′ reaction was completed more quickly
to give the corresponding N-tosylated 2-fluoroindole 8 in 95%
yield (eq 2). The nickel-catalyzed defluorinative coupling of
In summary, we have disclosed that (i) 1,1-difluoroallylation
of phenols and N-sulfonylanilines with 3-bromo-3,3-difluor-
C
DOI: 10.1021/acs.orglett.5b03390
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Organic Letters
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N. Org. Lett. 2007, 9, 3465−3468. (e) Pigeon, X.; Bergeron, M.;
opropene (1) was accomplished by a palladium catalyst and
(ii) its practical use provided a facile synthetic platform for
ring-fluorinated benzoheterole derivatives. In light of our
previously reported synthesis of difluoromethylated dihydro-
benzoheteroles via the base-mediated 3,3-difluoroallylation
with 1,5 the current method serves as a complementary
approach to fluorine-containing benzoheterole derivatives,
which are promising for pharmaceutical and agrochemical
uses.12
́ ́
Barabe, F.; Dube, P.; Frost, H. N.; Paquin, J.-F. Angew. Chem., Int.
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Lett. 2014, 16, 1398−1401.
(6) Most recently, Zhang et al. reported the palladium-catalyzed
regioselective 1,1-difluoroallylation of aromatic carbons by using
arylboronic acids. See: (a) Min, Q.-Q.; Yin, Z.; Feng, Z.; Guo, W.-H.;
Zhang, X. J. Am. Chem. Soc. 2014, 136, 1230−1233. (b) Zhang, B.;
Zhang, X. Chem. Commun. 2016, DOI: 10.1039/C5CC08394J.
(7) For recent reports on heterocycle construction via the 5-exo
Heck cyclization, see: (a) Lubkoll, J.; Millemaggi, A.; Perry, A.;
Taylor, R. J. K. Tetrahedron 2010, 66, 6606−6612. (b) Newman, S.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b03390.
2014, 70, 3665−3674. (e) Kroger, D.; Schluter, T.; Fischer, M.;
̈
̈
Geibel, I.; Martens, J. ACS Comb. Sci. 2015, 17, 202−207.
(8) For synthesis of 2,2-difluorinated dihydrobenzoheteroles, see:
(a) Bailey, J.; Plevey, R. G.; Tatlow, J. C. Tetrahedron Lett. 1975, 16,
869−870. (b) Maksimov, A. M.; Platonov, V. E. Heteroat. Chem.
1992, 3, 373−384.
Experimental details, characterization data, and NMR
spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
■
(9) Use of 2-bromobenzenethiol instead of 2-bromophenols
afforded the corresponding S-3,3-difluoroallylated product exclusively,
even in the presence of the Pd catalyst.
*E-mail: junji@chem.tsukuba.ac.jp.
Notes
(10) For synthesis of 2-fluorobenzofurans and 2-fluoroindoles, see:
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1992, 1992, 831−832. (c) Hodson, H. F.; Madge, D. J.; Slawin, A.
N. Z.; Widdowson, D. A.; Williams, D. J. Tetrahedron 1994, 50,
1899−1906. (d) Ichikawa, J.; Wada, Y.; Okauchi, T.; Minami, T.
Chem. Commun. 1997, 1537−1538. (e) Martín-Santamaría, S.;
Carroll, M. A.; Carroll, C. M.; Carter, C. D.; Pike, V. W.; Rzepa,
H. S.; Widdowson, D. A. Chem. Commun. 2000, 649−650.
(f) Ichikawa, J.; Wada, Y.; Fujiwara, M.; Sakoda, K. Synthesis 2002,
2002, 1917−1936. (g) Ichikawa, J.; Nadano, R.; Mori, T.; Wada, Y.
Org. Synth. 2011, 83, 111−120. (h) Truong, T.; Klimovica, K.;
Daugulis, O. J. Am. Chem. Soc. 2013, 135, 9342−9345. (i) Shao, Q.;
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by a Grant-in-Aid for Scientific
Research (B) (No. 25288016) and a Grant-in-Aid for Young
Scientists (B) (No. 26870079) from JSPS. We acknowledge
Tosoh F-Tech, Inc., for the generous gift of 3-bromo-3,3-
difluoropropene.
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