Preparation of brominated 2-alkoxythiophenes via oxidation and etherification of 2-thienyltrifluoroborate salts

Article abstract of DOI:10.1021/ol3022897

The synthesis of ring brominated long-chain 2-alkoxythiophenes is reported, involving mild (Oxone) oxidation of readily prepared 2-thienyltrifluoroborate salts followed by Mitsunobu etherification. Both procedures are operationally straightforward and use inexpensive reagents. Using this approach, several novel mono- and dibrominated octyloxythiophenes with previously elusive substitution patterns were prepared. One such compound was elaborated to a novel 5-alkoxythieno[3,2-b]thiophene-2-carboxylate ester, marking the first synthetic entry into this family of compounds.

Full text of DOI:10.1021/ol3022897

ORGANIC
LETTERS
2012
Vol. 14, No. 19
5058–5061
Preparation of Brominated
2‑Alkoxythiophenes via Oxidation and
Etherification of 2‑Thienyltrifluoroborate
Salts
Jonathan I. Tietz, Alexander J. Seed, and Paul Sampson*
Department of Chemistry and Biochemistry, Kent State University, Kent, Ohio 44242,
United States
psampson@kent.edu
Received August 16, 2012
ABSTRACT
The synthesis of ring brominated long-chain 2-alkoxythiophenes is reported, involving mild (Oxone) oxidation of readily prepared
2-thienyltrifluoroborate salts followed by Mitsunobu etherification. Both procedures are operationally straightforward and use inexpensive
reagents. Using this approach, several novel mono- and dibrominated octyloxythiophenes with previously elusive substitution patterns were
prepared. One such compound was elaborated to a novel 5-alkoxythieno[3,2-b]thiophene-2-carboxylate ester, marking the first synthetic entry
into this family of compounds.
Alkoxythiophene subunits have recently attracted atten-
tion in a variety of materials applications. The more
synthetically accessible 3-alkoxythiophenes have found
particular application in conducting polymers1 for photo-
voltaic and nonlinear optical applications. Although 2-
alkoxythiophenes have been less extensively explored, they
have found applications as liquid crystals,2 photochromic
materials,3 potential nonlinear optical (NLO) materials via
organometallic complexes,4 and bioactive targets.5
Traditional approaches for the alkoxylation of hetero-
aromatic systems include Ullmann-type copper-mediated
reactions6 and nucleophilic aromatic substitution.7 How-
ever, despite several examples of high-yielding alkoxylation
to afford 3-alkoxythiophenes1e,8 (reported yields range
from 40 to 90% but are typically above 80%), these
approaches are not amenable to functionalization at the
C-2 position of the thiophene ring. 2-Methoxylation9 and
2-ethoxylation9b,10 of halothiophenes can sometimes be
efficient, but yields varysubstantially (10À88%) depending
on the substrate and are typically modest. Increasing the
alkyl tail length results in reduced yields2c,11 even under
(1) (a) Sunitha, M. S.; Adhikari, A. V.; Vishnumurthy, K. A.;
Smijesh, N.; Philip, R. Chem. Lett. 2012, 41, 234–236. (b) Zhang, W.;
Tao, F.; Xi, L. Y.; Meng, K. G.; Wang, Z.; Li, Y.; Jiang, Q. J. Mater. Sci.
2012, 47, 323–331. (c) Yanmao, D.; Lu, J. M.; Xu, Q. F.; Yan, F.; Xia,
X. W.; Wang, L. H.; Hu, L. Synth. Met. 2010, 160, 409–412. (d) Wu,
I. C.; Lai, C. H.; Chen, D. Y.; Shih, C. W.; Wei, C. Y.; Ko, B. T.; Ting,
C.; Chou, P. T. J. Mater. Chem. 2008, 18, 4297–4303. (e) Shi, C. J.; Yao,
Y.; Yang, Y.; Pei, Q. B. J. Am. Chem. Soc. 2006, 128, 8980–8986.
(2) (a) Pantalone, K.; Seed, A. J. Liq. Cryst. 2002, 29, 945–950.
(b) Herbert, M. R.; Sonpatki, V. M.; Jakli, A.; Seed, A. J. Mol. Cryst.
Liq. Cryst. 2001, 365, 1137–1144. (c) Kiryanov, A. A.; Sampson, P.;
Seed, A. J. J. Mater. Chem. 2001, 11, 3068–3077.
(6) For a review: Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed.
2003, 42, 5400–5449.
ꢀ
(7) For a recent example: Grubb, A. M.; Zhang, C.; Jakli, A.; Sampson,
(3) Shibata, K.; Kobatake, S.; Irie, M. Chem. Lett. 2001, 618–619.
(4) Fonseca, A. M.; Raposo, M. M. M.; Sousa, A. M. R. C.; Kirsch,
G.; Beley, M. Eur. J. Inorg. Chem. 2005, 4361–4365.
(5) (a) Binder, D.; Pyerin, M.; Pusterer, F. Monatsh. Chem. 1999, 130,
645–651. (b) Harris, C. S.; Germain, H.; Pasquet, G. Tetrahedron Lett.
2008, 49, 5946–5949. (c) Parker, R. A.; Kariya, T.; Grisar, J. M.; Petrow,
V. J. Med. Chem. 1977, 20, 781–791. (d) Mohamadi, F.; Spees, M. M.;
Grindey, G. B. J. Med. Chem. 1992, 35, 3012–3016.
P.; Seed, A. J. Liq. Cryst. 2012, 39, 1175–1195.
(8) (a) Shafir, A.; Lichtor, P. A.; Buchwald, S. L. J. Am. Chem. Soc.
2007, 129, 3490–3491. (b) Niu, J. J.; Guo, P. R.; Kang, J. T.; Li, Z. G.;
Xu, J. W.; Hu, S. J. J. Org. Chem. 2009, 74, 5075–5078. (c) Goldoni, F.;
Iarossi, D.; Mucci, A.; Schenetti, L. J. Heterocycl. Chem. 1997, 34, 1801–
1804. (d) Iwatsuki, S.; Kubo, M.; Itoh, Y. Chem. Lett. 1993, 22, 1085–
1088. (e) Kunz, T.; Knochel, P. Chem.;Eur. J. 2011, 17, 866–872.
(f) Maiti, D. Chem. Commun. 2011, 47, 8340–8342.
r
10.1021/ol3022897
Published on Web 09/24/2012
2012 American Chemical Society

aggressive conditions. Efficient access to 2-alkoxythiophenes
is possible by reaction of γ-keto esters with Lawesson’s
reagent; however, this approach requires an aryl substituent
at the C-5 position of the resulting 2-alkoxythiophene.12
Other analogous sulfurization approaches suffer from low
yield/reproducibility or problematic mixtures of products.13
In contrast to phenolic systems, Williamson etherification of
hydroxythiophenes (which exist as thienones14 in the absence
of strong hydrogen-bonding groups) gives mixtures of pro-
ducts due to unwanted reaction at the C-3 and C-5 sites.15
Recently, several palladium-16 and copper-8a,e,17 catalyzed
coupling approaches to 3-alkoxythiophenes from halothio-
phenes and alcohols have been reported; however, none of
these methods have been extended to 2-alkoxythiophenes.
Thus, the preparation of 2-alkoxythiophenes remains a
significant synthetic challenge.18
Figure 1. Strategic approach to brominated 2-alkoxythiophene
targets from bromothiophene precursors.
We required a series of brominated 2-alkoxythiophenes
3cÀe as syntheticintermediates enroute toother materials.
However, no good literature methods exist for the pre-
paration of C-3 and C-4 brominated 2-alkoxythiophenes,
as the previously discussed approaches are generally in-
efficient and alkoxylation of dibromothiophenes tends to
proceed with poor regioselectivity.9b
Herein we report the development of a strategically
distinct approach to ring brominated 2-alkoxythiophenes
that involves the selective metalation of a range of bro-
mothiophene precursors en route to the corresponding
3-, 4-, or 5-bromo-2-thienyltrifluoroborates. Mild oxida-
tion to the corresponding 2(5H)-thienones followed by
Mitsunobu etherification then affords the brominated
2-alkoxythiophene target compounds (Figure 1).
Trifluoroborate salts have recently attracted attention
as easily handled boronic acid analogs that are stable
to a range of reaction conditions, including a variety of
oxidants19 (TPAP/NMO, Swern, Dess-Martin periodi-
nane, and IBX) which leave the trifluoroborate moiety
intact. Interestingly, as recently reported by Molander and
Cavalcanti,20 aryl trifluoroborates can be efficiently oxi-
dized to phenols with Oxone in acetone and water at room
temperature. The resulting compounds were highly pure
after only a silica plug filtration. Although the authors
reported the successful oxidation of phenyl, benzo[b]furan-
2-yl, benzo[b]thien-2-yl, and 3-thienyltrifluoroboratesalts,
2-thienyltrifluoroborates were not studied. However, we
reasoned that these intermediates would offer an attractive
approach to novel brominated 2(5H)-thienones 2bÀe,
since it is well-known that hydroxythiophenes instantly
tautomerize14 to 2(5H)-thienones.
A series of 2-thienyltrifluoroborate salts 1aÀe were
readily prepared from commercially available and inex-
pensive thiophene precursors via the corresponding boro-
nic acids;21 the syntheses of these materials are described in
the Supporting Information.
Oxidation of 1aÀe to the corresponding 2(5H)-thienones
2aÀe was achieved via a modified version of Molander’s
recent procedure20 (Table 1). In the operationally straight-
forward oxidation procedure, 2-thienyltrifluoroborate
salt 1 in acetone (0.2 M) was mixed with aqueous Oxone
(9) (a) Keegstra, M. A.; Peters, T. H. A.; Brandsma, L. Synth.
Commun. 1990, 20, 213–216. (b) Keegstra, M. A.; Peters, T. H. A.;
Brandsma, L. Tetrahedron 1992, 48, 3633–3652. (c) de Meijere, A.; Zhao,
L. G.; Belov, V. N.; Bossi, M.; Noltemeyer, M.; Hell, S. W. Chem.;Eur.
J. 2007, 13, 2503–2516. (d) Casarini, D.; Lunazzi, L.; Placucci, G.;
Venturini, A. J. Org. Chem. 1991, 56, 414–417. (e) Effenberger, F.;
Wurthner, F.; Steybe, F. J. Org. Chem. 1995, 60, 2082–2091. (f) Binder,
D.; Noe, C. R.; Holzer, W.; Rosenwirth, B. Arch. Pharm. (Weinheim,
Ger.) 1985, 318, 48–59. (g) Andersen, K. E.; Begtrup, M.; Chorghade,
M. S.; Lee, E. C.; Lau, J.; Lundt, B. F.; Petersen, H.; Sorensen, P. O.;
Thogersen, H. Tetrahedron 1994, 50, 8699–8710. (h) Higuchi, H.; Uraki,
Y.; Yokota, H.; Koyama, H.; Ojima, J.; Wada, T.; Sasabe, H. Bull.
Chem. Soc. Jpn. 1998, 71, 483–495. (i) Hallberg, A.; Frejd, T.; Gronowitz,
S. J. Chem. Soc., Perkin Trans. 1 1980, 1390–1392. (j) Higuchi, H.;
Koyama, H.; Yokota, H.; Ojima, J. Tetrahedron Lett. 1996, 37, 1617–
1620. (k) Stanetty, P.; Puschautz, E. Monatsh. Chem. 1989, 120, 65–72.
(l) Gol’dfarb, Y. L.; Kalik, M. A.; Zav’yalova, V. K. Chem. Heterocycl.
Compd. 1981, 17, 126–132.
(10) (a) Meudt, A.; Rausch, B. J. (Archimica G.m.b.H., Germany).
Preparation of alkoxythiophenes and related compounds. U.S. Patent
20080071084 A1, 2008. (b) Chen, G.; Wang, H. C.; Robinson, H.; Cai, J. W.;
Wan, Y. Q.; Ke, H. M. Biochem. Pharmacol. 2008, 75, 1717–1728. (c) Irie,
M. (Japan Science and Technology Corp.). Diheteroarylethene photo-
chromic material. WO Patent 2002070624 A1, 2003.
(11) Puschmann, I.; Erker, T. Monatsh. Chem. 1994, 125, 927–932.
(12) (a) Sonpatki, V. M.; Herbert, M. R.; Sandvoss, L. M.; Seed, A. J.
J. Org. Chem. 2001, 66, 7283–7286. (b) Kiryanov, A. A.; Sampson, P.;
Seed, A. J. J. Org. Chem. 2001, 66, 7925–7929.
(13) (a) Brunet, J.; Paquer, D.; Rioult, P. Phosphorus, Sulfur, Silicon
Relat. Elem. 1977, 3, 377–379. (b) Sagitdinov, I. A.; Schubert, H. J. Org.
Chem. USSR (Engl. Transl.) 1978, 14, 988–992.
(19) Molander, G. A.; Petrillo, D. E. J. Am. Chem. Soc. 2006, 128,
9634–9635.
(20) Molander, G. A.; Cavalcanti, L. N. J. Org. Chem. 2011, 76, 623–
630.
€
(14) Hornfeldt, A. B.; Gronowitz, S. Arkiv. Kem. 1963, 21, 239–257.
(15) Pedersen, E. B.; Lawesson, S.-O. Tetrahedron 1971, 27, 3861–
(21) The trifluoroborate salts 1aÀe were prepared from a series of
readily available thiophenes: thiophene (1a), 2-bromothiophene (1b),
2,4-dibromothiophene (1c), 3,4-dibromothiophene (1d), and 3-
bromothiophene (1e). Most procedures followed literature protocols,
although some improvements were made, including a simplified pre-
paration of 3,4-dibromothiophene. For representative procedures for
preparation of thienyl boronic acids and BF3K salts, see: (a) Collis,
G. E.; Burrell, A. K.; Scott, S. M.; Officer, D. L. J. Org. Chem. 2003, 68,
8974–8983. (b) Molander, G. A.; Canturk, B.; Kennedy, L. E. J. Org.
Chem. 2009, 74, 973–980. (c) Molander, G. A.; Fumagalli, T. J. Org.
Chem. 2006, 71, 5743–5747.
3868.
(16) Wu, X.; Fors, B. P.; Buchwald, S. L. Angew. Chem., Int. Ed.
2011, 50, 9943–9947.
(17) (a) Martins, A.; Lautens, M. J. Org. Chem. 2008, 73, 8705–8710.
(b) Wolter, M.; Nordmann, G.; Job, G. E.; Buchwald, S. L. Org. Lett.
2002, 4, 973–976. (c) Marsella, M. J.; Carroll, P. J.; Swager, T. M. J. Am.
Chem. Soc. 1995, 117, 9832–9841.
(18) (a) Gronowitz, S. Thiophene and its derivatives. In The Chem-
istry of Heterocyclic Compounds; Wiley: New York, 1985; pp 1À133.
€
(b) Hornfeldt, A. B. Sv. Kem. Tidskr. 1968, 80, 343–356.
Org. Lett., Vol. 14, No. 19, 2012
5059

Table 1. Oxone-Mediated Oxidationof 2-Thienyltrifluoroborate
Salts 1 to 2(5H)-Thienones 2a
Table 2. Synthesis of Substituted 2-Alkoxythiophenes by
Mitsunobu Etherificationa
time
yield
(%)b
time
yield
(%)b
entry
product
R1
R2
R3
(h)
entry
product
R1
R2
R3
(min)
1
2
3
4
5
3a
3b
3c
3d
3e
H
Br
H
H
H
H
H
1
24
1
83
1
2
3
4
5
6
7
2a
2b
2c
2c
2d
2d
2e
H
Br
H
H
H
H
H
H
H
5
5
71
c
H
H
À
H
H
79c
79
Br
Br
H
H
86
87
80
Br
Br
Br
Br
H
H
5
Br
Br
1
d
H
60
30
60
60
À
1
Br
Br
Br
63
77
76
a Conditions: (i) PPh3 (3 equiv), CH2Cl2, À10 °C, (ii) DIAD
(3 equiv), À10 °C, 10 min, (iii) 1-octanol (3 equiv), À10 °C, 30 min,
(iv) substrate 2 (1 equiv), À10 °C f rt, 1 h, unless otherwise stated.
b Isolated yield after column chromatography (petroleum ether).
c Only trace amounts of product detected by 1H NMR.
a Conditions: substrate (0.1 M), Oxone (0.2 M, 2 equiv), in acetone/
H2O (1:1), rt, ambient atmosphere. b Isolated yield after silica plug
filtration (petroleum ether). c Product decomposes upon storage.
d Significant (>10%) presence of a byproduct after silica plug filtration.
We modified Harris’ conditions for experimental conve-
nience and lowered expense. 2(5H)-Thienones 2 were trea-
ted with 3 equiv each of diisopropyl azodicarboxylate
(DIAD), PPh3, and 1-octanol in anhydrous dichlorome-
thane at ca. À10 °C under an argon atmosphere (Table 2).
After 1 h at room temperature, the reaction mixture was
concentrated and filtered through a short silica plug with
petroleum ether to remove the polar byproduct. The result-
ing crude products 3 could easily be further purified
by column chromatography to afford air-stable, colorless
liquids. Using this method, we prepared 3a (entry 1) and
3cÀe (entries 3À5) in excellent yields (80À87%). This
reaction was amenable to scale-up (∼2 g quantities of 3c
and 3d were prepared) with no change in yield.
(0.4 M in potassium monopersulfate) at room temperature
under an ambient atmosphere. Quenching with acid, work-
up, and elution through a silica plug with dichloromethane
furnished the desired 2(5H)-thienone 2 in high purity.
Although good yields (71À79%) were obtained for 2aÀc
after only 5 min of reaction (Table 1, entries 1À3), the
formation of 2d was slower, requiring 1 h to reach a
comparable yield (entries 5 and 6). Compound 2e was also
prepared using this extended reaction time (entry 7). Inter-
estingly, when the reaction leading to 2c was allowed to
proceed for 1 h (entry 4), a significant amount (ca. 10%)
of an unidentified byproduct formed, as seen by 1H NMR;
it was thus important to limit the reaction time to 5 min
(entry 3). However, this impurity was easily separable by
recrystallization of 2c. Similar byproduct formation was
not seen for 2dÀe. Compounds 1a and 1b were not exposed
to the 1 h reaction conditions due to concerns regarding the
stabilityof2aand 2bandbecausegood yieldswereachieved
after 5 min.
Interestingly, despite the efficiency of this chemistry
when using other substrates, 5-bromo-2(5H)-thienone 2b
could not be transformed in this way to desired product 3b
(Table 2, entry 2). After 24 h under these conditions, only
1
a trace of the desired product was seen by H NMR.
Additionally, a larger proportion of the protodebromi-
nated adduct 3awas noticed, indicative of a competing side
reaction with substrate 2b.
2(5H)-Thienones 2a (liquid)22 and 2b (solid, mp =
23 °C)23 are somewhat air-sensitive and decompose even
on storage in the freezer. In contrast, 2(5H)-thienones
2cÀe are high-melting (ca. 80À114 °C) air-stable solids
that crystallize easily.
Elaboration of 2(5H)-thienones 2aÀe tothe correspond-
ing 2-alkoxythiophenes 3aÀe required a selective O-alky-
lation procedure that avoided the known problems associ-
ated with the simple O-alkylation of 2(5H)-thienones.15
Our attention was drawn to a recent report by Harris and
co-workers,5b who achieved the Mitsunobu etherification
of the parent 2(5H)-thienone 2a using di-tert-butyl azodi-
carboxylate (DTAD) and polystyrene-supported PPh3
with a variety of alcohols.
Scheme 1. Elaboration of 2-Alkoxythiophene 3c to Novel
5-Alkoxythienothiophene 6
(22) Frisell, C.; Lawesson, S.-O. Org. Synth., Coll. Vol. 5, 1973, 642À645.
(23) Jakobsen, H. J. Tetrahedron 1967, 23, 3737–3742.
5060
Org. Lett., Vol. 14, No. 19, 2012

In order to preliminarily demonstrate the usefulness
of these 2-alkoxythiophenes as synthetic building blocks,
we have prepared the first long-chain alkoxythienothio-
phene from 2-alkoxythiophene 3c (Scheme 1). Previously,
only a handful of simple short-chain (OR = OMe, OEt,
Ot-Bu) 5-alkoxythieno[3,2-b]thiophenes have been reported.24
Importantly, the methods used were harsh as well as
inefficient and could not be extended to other alkyl
chains. Indeed, in our hands, an analogous nucleophilic
substitution approach to 6 from a 2-chlorothieno[3,2-b]-
thiophene-2-carboxylate ester gave no traces of the de-
sired product.
Formylation of 3c with LDA and N-formylpiperidine
afforded 4 in excellent yield (92%). Exploiting our recently
reported method for thienothiophene synthesis,25 we trea-
ted aldehyde 4 with nonyl mercaptoacetate 5 in the pre-
sence of base at 65 °C, affording thienothiophene 6 in good
yield (86%) via a tandem nucleophilic aromatic substitu-
tion and aldol condensation reaction (we saw no difference
in the two-step yield whether or not intermediate 4 was
purified).
In summary, we have developed the first efficient syn-
thetic approach to long-chain ring brominated 2-alkoxy-
thiophenes. This oxidation and etherification sequence,
starting from readily prepared potassium 2-thienyltrifluo-
roborate salts, is operationally straightforward and em-
ploys inexpensive reagents. Moreover, it allows access to
2-alkoxythiophenes bearing halogens as functional han-
dles in previously elusive substitution patterns. Efforts are
ongoing in our laboratory to expand the scope of this
transformation and to explore the use of these ring bromi-
nated 2-alkoxythiophenes as synthetic building blocks en
route to electron-rich organic materials.
Acknowledgment. Financial support from the Ohio
Board of Regents (Research Incentive Grant) and Kent
State University is gratefully acknowledged.
(24) (a) Blenkle, M.; Boldt, P.; Brauchle, C.; Grahn, W.; Ledoux, I.;
Nerenz, H.; Stadler, S.; Wichern, J.; Zyss, J. J. Chem. Soc., Perkin Trans.
2 1996, 1377–1384. (b) Mazaki, Y.; Takiguchi, N.; Kobayashi, K. Chem.
Lett. 1991, 1117–1120. (c) Testaferri, L.; Tiecco, M.; Zanirato, P. J. Org.
Chem. 1975, 40, 3392–3395.
(25) (a) Tietz, J. I.; Mastriana, J. R.; Sampson, P.; Seed, A. J. Liq.
Cryst. 2012, 39, 515–530. (b) Gipson, R. M.; Sampson, P.; Seed, A. J.
Liq. Cryst. 2010, 37, 101–108.
Supporting Information Available. Experimental pro-
1
cedures, characterization data, and H and 13C NMR
spectra for new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 19, 2012
5061