Two-step synthesis of difluoromethyl-substituted 2,3-dihydrobenzoheteroles

Article abstract of DOI:10.1021/ol5001582

3-Difluoromethylated 2,3-dihydrobenzoheteroles, 2,3-dihydrobenzofurans, 2,3-dihydrobenzothiophenes, and indolines were readily synthesized from ortho-heterosubstituted bromobenzenes, 2-bromophenols, 2-bromobenzenethiols, and 2-bromoanilines, respectively,

Full text of DOI:10.1021/ol5001582

Letter
pubs.acs.org/OrgLett
Two-Step Synthesis of Difluoromethyl-Substituted
2,3‑Dihydrobenzoheteroles
Takeshi Fujita, Shohei Sanada, Yosuke Chiba, Kazuki Sugiyama, and Junji Ichikawa*
Division of Chemistry, Faculty of Pure and Applied Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8571, Japan
S
* Supporting Information
ABSTRACT: 3-Difluoromethylated 2,3-dihydrobenzo-
heteroles, 2,3-dihydrobenzofurans, 2,3-dihydrobenzothio-
phenes, and indolines were readily synthesized from ortho-
heterosubstituted bromobenzenes, 2-bromophenols, 2-bromo-
benzenethiols, and 2-bromoanilines, respectively, in two steps:
(1) γ-selective allylic substitution of 3-bromo-3,3-difluoropropene with heteronucleophiles and (2) intramolecular radical
cyclization of the resulting 3,3-difluoroallylic compounds.
he difluoromethyl (CHF2) group occupies a significant
position among fluorinated functional groups, exhibiting
Scheme 1. Synthetic Routes to Difluoromethylated
Benzoheterole Derivatives
T
unique properties derived from the steric and electronic
characteristics of fluorine.1 In particular, the CHF2 group has
been regarded as a bioisostere of the hydroxy group,2 and
indeed difluoromethylated compounds are increasingly found
in bioactive substances, particularly agrochemicals.3 Further-
more, due to the electron-withdrawing effect of fluorine, the
difluoromethyl group serves as a proton donor for hydrogen
bonding, albeit with a hydrophobic nature.4
Despite the interesting potential of the CHF2 group,
conventional approaches to ring-difluoromethylated com-
pounds have significant limitations; they require tedious
reactions and toxic reagents such as diethylaminosulfur
trifluoride (DAST).5−8 Thus, building block approaches to
difluoromethylated compounds that include effective trans-
formation of a fluorine-containing functional group into a
CHF2 group have attracted increasing attention.1c,9,10 Quite
recently, a few methods for direct difluoromethylation have also
been reported.11
In our previous study on the building block approach, we
developed an intramolecular SN2′ reaction of 2-trifluoromethyl-
1-alkenes bearing nucleophilic moieties for the regioselective
synthesis of difluoromethylated heterocycles, such as indoles
(Scheme 1A).9 Herein, we describe a two-step synthesis of 3-
difluoromethylated 2,3-dihydrobenzoheteroles 3 (Scheme 1B).
The reaction proceeds via (i) the SN2′ allylic substitution of 3-
bromo-3,3-difluoropropene with readily available 2-bromo-
phenols 1a, 2-bromobenzenethiols 1b, and 2-bromoanilines
1c under basic conditions12 and (ii) the subsequent intra-
molecular radical cyclization of the intermediary 3,3-difluoro-
allylic compounds 2.13 It is noteworthy that both the
installation of the CHF2 substituent and construction of the
dihydrobenzoheterole framework are simultaneously achieved
in this process. Thus, this methodology ensures regio-defined
introduction of a CHF2 group on the heterocyclic ring.
First, we sought a base that was suitable for the SN2′
allylation with 3-bromo-3,3-difluoropropene using 2-bromo-
phenol (1aa) as a model substrate (Table 1). While an amine
and an organolithium reagent were practically ineffective
(entries 1 and 2), alkali metal hydrides enhanced the formation
of the allylation products 2aa and 4aa (entries 3 and 4). In
comparison with sodium hydride, potassium hydride highly
improved the 2aa/4aa ratio. A similar trend was observed using
carbonate salts (entries 5−7). In terms of both efficiency and
selectivity, cesium carbonate was found to be the best among
the bases examined (entry 7). The efficiency and selectivity of
the formation of 2aa in the reaction with cesium carbonate in
N,N-dimethylformamide (DMF) was improved when 3-bromo-
3,3-difluoropropene was increased to 2 equiv, affording a 56%
yield of 2aa with a 2:1 ratio of 2aa/4aa (entry 8).14 Moreover,
this reaction was sensitive to the solvent used (entries 9−13).
Thus, N-methyl-2-pyrrolidone provided better results than
DMF (entries 12 and 7, respectively), and ultimately 2aa was
obtained in 79% yield with an approximately 5:1 ratio of 2aa/
4aa in the reaction using 2 equiv of 3-bromo-3,3-difluoropro-
pene (entry 13).14,15
We believe that the size of the countercation may affect the
selectivity because the 2aa/4aa ratio was generally improved as
Received: January 17, 2014
Published: February 19, 2014
© 2014 American Chemical Society
1398
dx.doi.org/10.1021/ol5001582 | Org. Lett. 2014, 16, 1398−1401

Organic Letters
Letter
selective reaction to afford the corresponding 3,3-difluoroallyl
compounds 2ab−2ae in good yields, whereas electron-
withdrawing groups (e.g., CN) induced the selective formation
of the undesired 1,1-difluoroallyl products 4a.16 Intriguingly,
the reaction of 2-bromothiophenol (1ba) smoothly proceeded
at room temperature to afford a high yield (94%) of the 3,3-
difluoroallylated product 2ba with exclusive selectivity, even
when only 1 equiv of 3-bromo-3,3-difluoropropene was used.17
This perfect selectivity may be the result of the ionic size effect
of both sulfur and cesium.
In contrast to phenols 1a, the SN2′-selective allylation of 2-
bromoanilines 1c with 3-bromo-3,3-difluoropropene was
effectively promoted using butyllithium as the base, which
resulted in the exclusive formation of 3,3-difluoroallyl products
2c in good to high yields (Scheme 3). In addition, 2-
Table 1. Screening of Conditions for the SN2′-Selective
Reaction with Phenol 1aa
2aa
4aa
a
a
entry
x
base
solvent
conditions
(%)
(%)
1
1.0
1.0
1.0
1.0
1.0
1.0
1.0
2.0
1.0
1.0
1.0
1.0
2.0
DMAP
n-BuLi
NaH
DMF
THF
DMF
DMF
DMF
DMF
DMF
DMF
EtOH
90 °C, 1.5 h
−78 to 80 °C, 4 h
100 °C, 1.5 h
100 °C, 4 h
100 °C, 2 h
100 °C, 2 h
100 °C, 17 h
100 °C, 4 h
90 °C, 2 h
6
16
1
2
1
3
29
41
16
37
42
56
trace
55
49
62
79
48
13
27
37
28
28
trace
23
21
21
16
4
KH
5
Na2CO3
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
6
7
Scheme 3. 3,3-Difluoroallylation of Anilines 1c via SN2′-
8
Selective Reaction
9
10
11
12
13
MeCN 90 °C, 2 h
DMSO 100 °C, 3 h
NMP
100 °C, 3 h
90 °C, 0.5 h
NMP
a
Isolated yield.
the diameter of the countercation increased (Table 1, entries 3
and 4; entries 5−7). In the case of cesium carbonate, the
intermediary cesium phenoxide formed in equilibrium could
attack the carbon atom α or γ to the fluorine substituents of 3-
bromo-3,3-difluoropropene. Under the optimal conditions,
cesium phenoxide appears to predominantly attack the less
hindered γ-carbon atom, avoiding the steric hindrance between
the cesium core and the fluorine substituents on the α-carbon
atom.
a
−78 to 80 °C, 8 h.
With the optimal conditions in hand, the substrate scope was
then investigated (Scheme 2). Several functionalized (Me-,
MeO-, and Cl-bearing) 2-bromophenols 1ab−1ad and 1-
bromo-2-naphthol (1ae) successfully underwent the SN2′-
bromoanilines bearing not only a methyl or fluorine substituent
but also an electron-withdrawing substituent (CF3) successfully
participated in the SN2′ reaction. The exclusive formation of 2c
may be attributed to the steric hindrance caused by the N−H
and N−Ar bonds on the nitrogen atom of the intermediary
lithium amides, which leads to exclusive attack of lithium amide
on the carbon atom γ to the fluorine substituents in 3-bromo-
3,3-difluoropropene.
Scheme 2. 3,3-Difluoroallylation of Phenols 1a and
Benzenethiols 1b via SN2′-Selective Reaction
Next, the intramolecular radical cyclization was investigated
with tributyltin hydride using 2aa as a model substrate (Table
2). The choice of radical initiator and solvent was found to be
critical for efficient cyclization. Triethylborane with oxygen
(entry 1) and 2,2′-azobis(4-methoxy-2,4-dimethylvaleronitrile)
(V70, entry 2) were inappropriate as initiators for this reaction.
In contrast, 2,2′-azobis(isobutyronitrile) in hexane effectively
promoted the radical cyclization in the 5-exo fashion to give the
desired 3-difluoromethyl-2,3-dihydrobenzofuran (3aa) in 92%
isolated yield (entry 7) without the formation of the 6-endo
cyclization product.
The synthesis of 3-difluoromethylated 2,3-dihydrobenzo-
heteroles 3 was investigated under the conditions described
above (Scheme 4). Regardless of the heteroatoms and
substituents attached to the aromatic rings, the 3,3-difluoroallyl
compounds 2 successfully underwent intramolecular radical
cyclization to afford 3-difluoromethyl-2,3-dihydrobenzofurans
3a, 3-difluoromethyl-2,3-dihydrobenzothiophenes 3b, and 3-
difluoromethylindolines 3c in good to high yields (61%−96%).
a
b
3-Bromo-3,3-difluoropropene (5.0 equiv), DMF, 100 °C, 2 h. 3-
c
Bromo-3,3-difluoropropene (1.0 equiv), DMF, rt, 3 h. N.D. = Not
detected.
1399
dx.doi.org/10.1021/ol5001582 | Org. Lett. 2014, 16, 1398−1401

Organic Letters
Letter
Table 2. Effect of Reaction Conditions on the Radical
Cyclization of 3,3-Difluoroallyl Compound 2aa
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and 1H, 13C, and 19F NMR spectra of
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
S
a
AUTHOR INFORMATION
Corresponding Author
entry
initiator (mol %)
solvent
conditions
3aa (%)
■
1
2
3
4
5
6
7
Et3B(200) + O2 (1 atm)
V70 (20)
toluene
benzene
benzene
toluene
MeCN
DCE
−78 °C, 9 h
rt, 8 h
35
2
*E-mail: junji@chem.tsukuba.ac.jp.
Notes
AIBN (50)
80 °C, 24 h
100 °C, 8 h
80 °C, 12 h
80 °C, 12 h
20
8
AIBN (20)
The authors declare no competing financial interest.
AIBN (10)
trace
30
AIBN (10)
ACKNOWLEDGMENTS
b
■
AIBN (10)
hexane
80 °C, 4 h
92
We thank Mr. M. Shinjo (University of Tsukuba) for help in
preparing substrates. We also acknowledge Tosoh F-Tech, Inc.
for the generous gift of 3-bromo-3,3-difluoropropene.
a
b
19F NMR yield using PhCF3 as an internal standard. Isolated yield.
Scheme 4. Synthesis of 3-Difluoromethylated
Dihydrobenzoheteroles 3 via Radical Cyclization of 3,3-
Difluoroallyl Compounds 2
REFERENCES
■
(1) (a) Uneyama, K. Organofluorine Chemistry; Blackwell Publishing:
Oxford, 2006; pp 1−100. (b) Gladysz, J. A.; Jurisch, M. Top. Curr.
Chem. 2012, 308, 1−24. (c) Ichikawa, J. J. Synth. Org. Chem., Jpn. 2010,
68, 1175−1184.
(2) (a) Houlton, J. S.; Motherwell, W. B.; Ross, B. C.; Tozer, M. J.;
Williams, D. J.; Slawin, A. M. Z. Tetrahedron 1993, 49, 8087−8106.
(b) Lloyd, A. E.; Coe, P. L.; Walker, R. T. J. Fluorine Chem. 1993, 62,
145−160. (c) Xu, Y.; Qian, L.; Pontsler, A. V.; McIntyre, T. M.;
Prestwich, G. D. Tetrahedron 2004, 60, 43−49. (d) Chowdhury, M. A.;
Abdellatif, K. R. A.; Dong, Y.; Das, D.; Suresh, M. R.; Knaus, E. E. J.
Med. Chem. 2009, 52, 1525−1529. (e) Meanwell, N. A. J. Med. Chem.
2011, 54, 2529−2591.
(3) (a) Hong, S.; Smith, A. E. J. Agric. Food Chem. 1996, 44, 3393−
3398. (b) Ehrenfreund, J.; Tobler, H.; Walter, H. WO2004035589A1,
2004. (c) Tobler, H.; Walter, H.; Ehrenfreund, J. Corsi, C.
WO2007048556A1, 2007. (d) Ziv, D.; Mishael, Y. G. J. Agric. Food
Chem. 2008, 56, 9159−9165.
(4) Erickson, J. A.; McLoughlin, J. I. J. Org. Chem. 1995, 60, 1626−
1631.
(5) For syntheses of difluoromethyl compounds using DAST, see:
(a) Middleton, W. J. J. Org. Chem. 1975, 40, 574−578. (b) Singh, R.
P.; Shreeve, J. M. Synthesis 2002, 17, 2561−2578 and references cited
therein.
(6) For reviews on syntheses of difluoromethyl compounds, see:
(a) Hu, J.; Zhang, W.; Wang, F. Chem. Commun. 2009, 7465−7478.
(b) Hu, J. J. Fluorine Chem. 2009, 130, 1130−1139. (c) Liang, T.;
Neumann, C. N.; Ritter, T. Angew. Chem., Int. Ed. 2013, 52, 8214−
8264.
(7) For reports on ring difluoromethylation on carbon atoms, see:
(a) Bujok, R.; Makosza, M. Synlett 2002, 1285−1286. (b) Sasson, R.;
Hagooly, A.; Rozen, S. Org. Lett. 2003, 5, 769−771. (c) Hugenberg,
a
Bu3SnH (1.0 equiv).
V.; Frohlich, R.; Haufe, G. Org. Biomol. Chem. 2010, 8, 5682−5691.
̈
(d) Hagooly, Y.; Rozen, S. Org. Lett. 2012, 14, 1114−1117. (e) Mizuta,
S.; Stenhagen, I. S. R.; O’Duill, M.; Wolstenhulme, J.; Kirjavainen, A.
K.; Forsback, S. J.; Tredwell, M.; Sandford, G.; Moore, P. R.; Huiban,
M.; Luthra, S. K.; Passchier, J.; Solin, O.; Gouverneur, V. Org. Lett.
2013, 15, 2648−2651.
(8) For reports on ring difluoromethylation on heteroatoms, see:
(a) Prakash, G. K. S.; Weber, C. W.; Chacko, S.; Olah, G. A. Org. Lett.
2007, 9, 1863−1866. (b) Zhang, W.; Wang, F.; Hu, J. Org. Lett. 2009,
11, 2109−2112. (c) Prakash, G. K. S.; Zhang, Z.; Wang, F.; Ni, C.;
Olah, G. A. J. Fluorine Chem. 2011, 132, 792−798.
(9) For our reports on building block approaches to ring-
difluoromethylated compounds, see: (a) Mori, T.; Ichikawa, J. Chem.
Lett. 2004, 33, 1206−1207. (b) Mori, T.; Iwai, Y.; Ichikawa, J. Chem.
Lett. 2005, 34, 778−779. (c) Nadano, R.; Iwai, Y.; Mori, T.; Ichikawa,
J. J. Org. Chem. 2006, 71, 8748−8754. (d) Ichikawa, J.; Iwai, Y.;
Nadano, R.; Mori, T.; Ikeda, M. Chem.Asian J. 2008, 3, 393−406.
In summary, we disclosed a facile approach to the synthesis
of difluoromethyl-substituted dihydrobenzoheteroles starting
from readily available bromoarenes and 3-bromo-3,3-difluoro-
propene. This sequence provides a powerful protocol for the
regioselective introduction of CHF2 substituents, which has
attracted increasing attention.18
The 2,3-dihydrobenzoheterole frameworks thus formed have
been recognized as enormously important structures in
pharmaceutical science; e.g., this structure can be found in a
diuretic19 and a putative entactogen drug.20 Because difluoro-
methylated dihydrobenzoheteroles are hybrids of two pharma-
ceutically important components, the CHF2 group and the
dihydrobenzoheterole framework, they are expected to serve as
new bioactive compounds.
1400
dx.doi.org/10.1021/ol5001582 | Org. Lett. 2014, 16, 1398−1401

Organic Letters
Letter
(10) For reports on the building block approach by other groups, see:
(a) Gonzalez, J.; Foti, C. J.; Elsheimer, S. J. Org. Chem. 1991, 56,
4322−4325. (b) Marcotte, S.; Gerard, B.; Pannecoucke, X.; Feasson,
́
Chem. Soc. 2012, 134, 20521−20532. (h) Baker, M. S.; Yadav, V.; Sen,
A.; Phillips, S. T. Angew. Chem., Int. Ed. 2013, 52, 10295−10299.
(19) Patel, A.; MacMahon, S.; Chalmers, J.; Neal, B.; Woodward, M.;
Billot, L.; Harrap, S.; Poulter, N.; Marre, M.; Cooper, M.; et al. Lancet
2007, 370, 829−840.
(20) Monte, A. P.; Marona-Lewicka, D.; Cozzi, N. V.; Nichols, D. E.
J. Med. Chem. 1993, 36, 3700−3706.
C.; Quirion, J.-C. Synthesis 2001, 929−933. (c) Mae, M.; Matsuura,
M.; Amii, H.; Uneyama, K. Tetrahedron Lett. 2002, 43, 2069−2072.
(d) Qiu, X.-l.; Qing, F.-l. J. Org. Chem. 2002, 67, 7162−7164. (e) Cox,
L. R.; DeBoos, G. A.; Fullbrook, J. J.; Percy, J. M.; Spencer, N. S.;
Tolley, M. Org. Lett. 2003, 5, 337−339. (f) Takachi, M.; Chatani, N.
Org. Lett. 2010, 12, 5132−5134. (g) Chen, Z.; Zhu, J.; Xie, H.; Li, S.;
Wu, Y.; Gong, Y. Org. Biomol. Chem. 2011, 9, 5682−5691.
(h) Fujikawa, K.; Fujioka, Y.; Kobayashi, A.; Amii, H. Org. Lett.
2011, 13, 5560−5563. (i) Shen, X.; Zhang, W.; Ni, C.; Gu, Y.; Hu, J. J.
Am. Chem. Soc. 2012, 134, 16999−17002.
(11) For recent reports on direct ring difluoromethylation on carbon
atoms, see: (e) Fujiwara, Y.; Dixon, J. A.; Rodriguez, R. A.; Baxter, R.
D.; Dixon, D. D.; Collins, M. R.; Blackmond, D. G.; Baran, P. S. J. Am.
Chem. Soc. 2012, 134, 1494−1497. (g) Fier, P. S.; Hartwig, J. F. J. Am.
Chem. Soc. 2012, 134, 5524−5527. (h) Iida, T.; Hashimoto, R.;
Aikawa, K.; Ito, S.; Mikami, K. Angew. Chem., Int. Ed. 2012, 51, 9535−
9538. (i) Prakash, G. K. S.; Ganesh, S. K.; Jones, J.-P.; Kulkarni, A.;
Masood, K.; Swabeck, J. K.; Olah, G. A. Angew. Chem., Int. Ed. 2012,
51, 12090−12094. (j) Fujiwara, Y.; Dixon, J. A.; O’Hara, F.; Funder, E.
́
D.; Dixon, D. D.; Rodriguez, R. A.; Baxter, R. D.; Herle, B.; Sach, N.;
Collins, M. R.; Ishihara, Y.; Baran, P. S. Nature 2012, 492, 95−99.
(12) For selective SN2′ allylation of difluoroallylic compounds, see:
Tellier, F.; Baudry, M.; Sauvet
5992.
̂
re, R. Tetrahedron Lett. 1997, 38, 5989−
(13) For intramolecular radical cyclization of 1,1-difluoro-1-alkenes,
see: (a) Morikawa, T.; Nishiwaki, T.; Iitaka, Y.; Kobayashi, Y.
Tetrahedron Lett. 1987, 28, 671−674. (b) Morikawa, T.; Uchida, J.;
Hasegawa, Y.; Taguchi, T. Chem. Pharm. Bull. 1991, 39, 2462−2464.
(c) Itoh, T.; Sakabe, K.; Kudo, K.; Ohara, H.; Takagi, Y.; Kihara, H.;
Zagatti, P.; Renou, M. J. Org. Chem. 1999, 64, 252−265.
(14) Unreacted 1aa assisted the 1,3-allylic rearrangement of 2aa to
4aa. To suppress this undesired process, the reaction time should be
shortened by the addition of an excess of 3-bromo-3,3-difluoro-
propene.
(15) When the reaction of 2-bromophenol 1aa was quenched at an
early stage (1 min), a 16% yield of the desired product 2aa and a 4%
yield of the side product 4aa were obtained. The 2aa/4aa ratio of this
reaction (80/20) was similar to that of the reaction quenched after 30
min (83/17). This result suggests that the side product 4aa can be
formed directly via the reaction of bromophenol 1aa with 3-bromo-
3,3-difluoropropene.
(16) Reactions of 3-bromo-4-hydroxybenzonitrile with 3-bromo-3,3-
difluoropropene afforded a 79% yield of the corresponding 1,1-
difluoroallyl product with exclusive selectivity.
(17) Alternatively, thioethers 2b were also prepared via the reaction
with 1,1-difluoroallene. Treatment of 1ba with 5 equiv of 1,1-
difluoropropa-1,2-diene in the presence of 0.5 equiv of KOH (THF,
60 °C, 12 h) exclusively afforded 2ba in 79% yield. In contrast, the
reaction of bromophenols 1a with 1,1-difluoropropa-1,2-diene
selectively provided undesirably allylated products 4a.
(18) For properties of difluoromethyl-substituted compounds, see:
(a) Chang, C.-W. T.; Chen, X. H.; Liu, H.-W. J. Am. Chem. Soc. 1998,
120, 9698−9699. (b) Lu, C.-P.; Ren, C.-T.; Lai, Y.-N.; Wu, S.-H.;
Wang, W.-M.; Chen, J.-Y.; Lo, L.-C. Angew. Chem., Int. Ed. 2005, 44,
6888−6892. (c) Xu, H.-L.; Li, Z.-R.; Wu, D.; Wang, B.-Q.; Li, Y.; Gu,
F. L.; Aoki, Y. J. Am. Chem. Soc. 2007, 129, 2967−2970. (d) Kwan, D.
H.; Chen, H.-M.; Ratananikom, K.; Hancock, S. M.; Watanabe, Y.;
Kongsaeree, P. T.; Samuels, A. L.; Withers, S. G. Angew. Chem., Int. Ed.
2011, 50, 300−303. (e) Baker, M. S.; Phillips, S. T. J. Am. Chem. Soc.
2011, 133, 5170−5173. (f) Cheng, T.-C.; Roffler, S. R.; Tzou, S.-C.;
Chuang, K.-H.; Su, Y.-C.; Chuang, C.-H.; Kao, C.-H.; Chen, C.-S.;
Harn, I.-H.; Liu, K.-Y.; Cheng, T.-L.; Leu, Y.-L. J. Am. Chem. Soc. 2012,
́
134, 3103−3110. (g) Chauvigne-Hines, L. M.; Anderson, L. N.;
Weaver, H. M.; Brown, J. N.; Koech, P. K.; Nicora, C. D.; Hofstad, B.
A.; Smith, R. D.; Wilkins, M. J.; Callister, S. J.; Wright, A. T. J. Am.
1401
dx.doi.org/10.1021/ol5001582 | Org. Lett. 2014, 16, 1398−1401