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Facile Synthesis of 3-(-Haloalkyl)thiophenes as Key Building Blocks for Functionalized Thiophenes and Polythiophenes.

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1989. 1413:C.Hongo, M . Sihazaki, S. Yamada, I. Chihata, J. Agric. Food
Chum. 24 (1976)903;S. Yamada. C. Hongo, I. Chibata. Agric. 5101.Chem.
41 (1977)2413.
[S] J. Peisach, H. J. Strecker, J. Biol. Chem. 237 (1962)2255;[2a]. Chap. 35,
p. 2195. and references cited therein.
[6] K. Drauz, A. Kleemann. J. Martens, P. Scherherich, F. Effenherger, J. Org.
Cham. 5 1 (1986)3494, and references cited therein; S. Lafquih Tizonani,
J:P. Lavergue, P. Viallefont, R. Jaquier, Tetrahedron 36 (1980)2961
[7] A. Yaron, D. Mlynar. Biochem. Biophys. Res. Commun. 32 (1968)658.
[8] W. Leuchtenherger, U. Plocker, Chem. Ing. Tech. 60 (1988) 16.
[9] S. Kang, Y. Minematsu, Y. Shimohigashi, M. Waki, N. Izumiya, Mem.
F m Sci. K?ushu Univ. Ser. C16 (1987)61.
[lo] Nomenclature Committee of the International Union of Biochemistry:
Enzvmr Nomenclature. Academic Press, New York 1984. p. 366.
[ I l l M Kikuchi. I. Koshiyama. D. Fukushima, Biochim. Biophys. Acra 744
tive Grignard reaction to afford 2a-e (GC monitoring),
whereas 3-@-methoxyphenoxy)propyl bromide (1, n =
3),['Od] like 1,3-dihalopropanes, undergoes elimination on
reaction with magnesium to yield cyclopropanes."
The nickel-catalyzed Grignard coupling of 3-bromothiophene (3) and the alkylmagnesium bromides 2a-e in the
presence of 0.1-1 mol% NiDPPPC1,f''l as catalyst in refluxing ether [Eq. (b)] leads to the previously unknown,
Rr
I
_
+
NIDPPPCI,
B r M g ( C H 2 ) nOeOCH3
(1983)180.
- MgBr,
3
Facile Synthesis of 3-(o-Haloalkyl)thiophenes as
Key Building Blocks for Functionalized Thiophenes
and Polythiophenes**
By Peter Bauerle.* Frank Wiirthner, and Stephan Heid
Dedicuted to Professor Franz Effenberger on the occasion
of his 60th birthday
3-Alkylthiophenes containing a terminal leaving group in
the alkyl chain are central intermediates for the synthesis of
functionalized 3-alkylthiophenes and poly(3-alkylthienylenes), which are currently under intensive
The coupling of monomeric thiophenes to form conjugated
polymers occurs at the 2- and S-positions,['I thereby allowing
covalent attachment of functional groups via alkyl chains in
the 3-position (or 4-position). Functionalized 3-alkylthiophenes were previously only accessible starting from 3methylthi~phene[~]
or 3-(2-hydro~yethyl)thiophene[~]
by a
tedious sequence of chain-lengthening steps. Moreover,
those with shorter alkyl chains are difficult to polymerize.[4a1
We have now developed a facile synthesis of 3-alkylthiophenes containing a terminal halogen substituent on an alkyl
chain of length n 2 4. These compounds may be used as key
building blocks for the preparation of functionalized 3alkylthiophenes and poly(3-aIkylthienylene~).[~~
Since the use of 3-lithiothiophene in alkylation reactions is
restricted,[61 the synthesis of 3-alkylthiophenes was approached via nickel-catalyzed Grignard couplings[71 of
alkylmagnesium bromides with 3-bromothiophene, which is
readily accessible by a new procedure.[81The direct extension
of this reaction to a,@-dihaloalkanes, however, does not lead
to the necessary mono-Grignard compounds.[g1On the other
hand, the a-(p-methoxyphenoxy)alkyl bromides 1, easily
prepared from a,o-dihaloalkanes and hydroquinone
monomethyl ether (HCM),[lo1react readily with magnesium
to give the corresponding Grignard compounds 2 [Eq. (a)].
Compounds 1 a-e (n = 4-6,8,10) undergo nearly quantita-
4
terminally protected 3-[o-(p-methoxy-phenoxy)alkyl]
thiophenes 4, which may be obtained, after a single recrystallization, in 63-81 YOyield as a colorless, analytically pure sol(Table 1).
Table 1. Results of the nickel-catalyzed Grignard coupling o f 3 with the alkylmagnesium bromides 2 a - e to give the terminally HCM-protected thiophenes
4 and their ether cleavage with hydrogen halides to give the 3-(w-bromoalkyl)thiophenes 5 or the 3-(w-iodoalkyl)thiophenes6.
n
[%]
a
b
c
d
e
4
5
6
8
10
5
4
Yield
M.p.
rC]
76 [a, h] 34-35
81 [h]
52
79
41
63
30-31
70
48-49
6
Yield
[%I
B.p. at
Yield
1 0 - ~ torr [Oh]
["Cl
B.p. at
iO-'torr
["Cl
51[c]
75
76
70
73[d]
60--65
80
90
105
120
70
80
100
60
64
68
59
70[e]
11s
135
[a] Three isomeric butenes identified as hyproducts by GC/MS(EI): m / z 56
( M a ) . [h] 1.5% of 1,(2n)-his(p-methoxyphenoxy)alkaneisolated as byproduct.
[c] 10% 4,5,6,7-tetrahydrohenzo[h]-thiophene
isolated as byproduct. [d] Addition of 5 mol% hexadecyltrimethylphosphonium bromide. [el Addition of
5 mol% methyItriphenylphosphonium iodide.
Of the numerous ether cleavage methods,['41 that with
hydrogen halide/acetic anhydride * I o q141 proved best suited
for the cleavage of the HCM protecting group in 4. Thiophenes 4 were thus converted directly and-with the exception of 4 a-free of byproducts into the 3-(w-bromoalkyl)thiophenes 5 and the 3-(w-iodoalkyl)thiophenes 6 [Eq. (c)].
(CH,)"Hal
B r ( C H , ) n O ~ O C H 3Mg/Et,O
A/6h
BrMg(CH2)nO+H3
1
-
(a)
4
2
[*I Dr. P. Bauerle, E Wiirthner, S. Heid
Institut fur Organische Chemie, Biochemie und Isotopenforschung der
UniversitHt
Pfaffenwaldring 55. D-7000 Stuttgart 80 (FRG)
[**I Thiophenes, Part 1. This work was supported by the Volkswagen-Stiftung
(A 2 I/61584),the Deutsche Forschungsgemeinschaft, and Hoechst AG
(donation of 3-bromothiophene). We thank Dr. A . Bandi (UniversitHt
Stuttgart) for the GC/MS(EI) analyses.
Angew. Chem. I n [ . Ed. Engl. 29 (1990) N o . 4
0 VCH
5, Hal = Br
6, Hal = I
The best yields were obtained using HBr/Ac,O at 100"(32025 h for 5 and HI/Ac,O at 80 OC/l5-25 h for 6. Addition of
phase-transfer catalysts helps keep within the given limits the
time required for ether cleavage of the longer-chain homologues, which become increasingly insoluble. After separation of the simultaneously formed hydroquinone followed
Verlagsgesellschaft mbH. 0-6940 Weinheim, 1990
0570-0833/90/0404-0419 $02.50/0
41 9
by chromatographic and distillative workup, halides 5 and 6
were obtained as analytically pure compounds in 51 -76 YO
yield" 51 (Table 1). The 3-(o-iodoalkyl)thiophenes 6 are also
accessible by Finkelstein reaction
from bromides 5, as
was shown for the conversion of bromide 5b to iodide 6b
(85 YOyield).
The methods described here allow a two-step synthesis
with the exception of 6a [4b1-~f the previously unknown
terminal bromine- and iodine-substituted 3-alkylthiophenes
5 and 6 , respectively, with chain lengths n 2 4, starting from
3-bromothiophene (3).
General Experimental Procedure
4 : Compound 1 (0.1 25 mol) in 40 mL of anhydrous ether was added under inert
atmosphere to magnesium turnings (3.16g, 0.13 mol) in 10 mL of ether. The
reaction mixture was then refluxed for 5-6 h. The Grignard solution of 2 was
subsequently transferred via cannula to a second apparatus and added dropwise at O'C to NiDPPPCI, (70 mg, 0.1 mol%) and 3 (17.2 g, 0.106 mol) over
1 h. The reaction mixture was refluxed for 12-15 h a n d afterwards hydrolyzed
with 40 mL of 1 N HCI and 150 mL of ice water followed by extraction with
several portions of ether. Washing to neutrality and drying of the combined
organic phases and removal of the solvent in vacuo afforded a yellowish-white
solid, which was recrystallized from n-hexane or methanol to give analytically
pure 4.
5: A mixture of HBr (48%; 20.2 g, 0.12 mol) and acetic anhydride (20.2 g,
0.198 mol) was added under inert atmosphere to 4 (0.02 mol) and the reaction
mixture was heated at 100°C for 20-25 h. After dilution with water, the mixture was extracted several times with ether and the combined organic phases
were washed to neutrality with saturated NaHCO, solution. Drying of the
organic phase and removal of the solvent afforded a yellow-brown oil, from
which hydroquinone was precipitated by addition of an n-hexaneiether mixture The solution was then filtered, transferred to a short silica gel column, and
eluted with hexane. Removal of the solvent gave 5, mostly analytically pure, as
a colorless oil, which may be further purified by kugelrohr distillation.
6 : A mixture of freshly distilled HI (57%; 26.9 g, 0.12 mol) and acetic anhydride (20.2 g, 0.198 mol) was added under inert atmosphere to 4 (0.02 mol) and
the reaction mixture was heated at 80 "C for 15-25 h. After dilution with water,
the mixture was extracted several times with ether and the combined organic
phases were decolorized by treatment with a thiosulfate solution. Further
workup was carried out as described for 5.
Received. October 25, 1989 [Z 3609 El
German version: Angeu. Chem. 102 (1990) 414
Publication delayed at authors' request
CAS Registry numbers:
la, 2033-83-2; Ib, 125878-81-1; lc, 20744-11-0; Id, 125878-82-2; le, 125878.833; 3, 872-31-1; 4a, 125878-84-4; 4b, 125878-85-5; 4c, 125878-86-6; 4d, 12587887-7; 4e, 125878-88-8; Sa, 125878-89-9; 5b, 125878-90-2; 5c, 125878-91-3; 5d,
125878-92-4, Se, 125878-93-5; 6a, 114896-68-3; 6b, 125878-94-6; 6c. 125878.957; 6d, 125878-96-8, 6e, 125878-97-9; 4,5,6,7-tetrahydrobenzo[b]thiophene,
13129.1 7-4.
[I] F. Gamier. Angew. Chem. Adv. Muter. 101 (1989) 529, Angew. Chem. Int.
Ed. Engl. Adv. Maler. 28 (1989) 513; Adv. Mater. 1989, 117.
[2] G . Tourillon in T. Skotheim (Ed.): Handbook of Conducting Pol.ymers,
Vol. 1 , Marcel Dekker, New York 1986, p. 293 ff.
[ 3 ] a) P. Cagniant, G. Merle, D. Cagniant, Bull. SOC.Chrm. Fr. 1970, 308; b)
C. F. Shu, M. S. Wrighton, ACS Symp. Ser. 378 (1988) 408.
[4] a) P. Audebert, G. Bidan, M. Lapkowski, D. Limousin in M. Kuzmany,
M. Mehring, S. Roth (Eds.): Electronic Properties ofconjugated Polymers,
(Springer Ser. Solid Stale Sci. 76, (1987) 366); b) Y Ikenoue, N. Uotani,
A. 0. Patil, F. Wudl, A. J. Heeger, Synth. Met 30 (1989) 305.
[5] P. Bduerle, K:U. Gaudl, Adv. Muter. 2 (1990) 185.
161 For example, a) W. Baarschers, Can. J. Chem. 54 (1976) 3056; b) S.
Gronowitz, T.Frejd, 0. Karlsson, K. Lawitz, P. Pedaja, K. Petterson,
Chem. Scr. 18 (1981) 192; c) J. A. Elvtdge, S. P. Jones, T. L. Peppard, J.
Chem. Sot. Perkins Trans. I 1982, 1089.
420
(1
VCH Verlagsgesellschuft mbH, 0-6940 Weinheim. 1990
[7] a) K. Tamao. S. Kodama, I. Nakajimd, M. Kumada, A. Minato, K.
Suzuki, Tetrahedron 28 (1982) 3347; b) C. Van Pham, H. B. Mark, Jr., H.
Zimmer, Synlh. Commun. 16 (1986) 689
[XI a) U. Dettmaier, K. Eichler, K. Kuhlein, E. I. Leupold, H. Litterer, Angew.
Chem. 99 (1987) 470; Angew. Chem. Int. Ed. Engl. 26 (1987) 468; b) S.
Kato, M. Ishizaki, Jpn. Kokai Tokkyo Koho JP 62 148 480 (1 957), Tokuyama Soda Co., Ltd.; Chem. Abstr. 108 (1988) 150299s.
[9] J. von Braun. W. Sobecki, Chem. Ber. 44 (1911) 1918.
[lo] a) K. Ziegler, H. Weber, Chem. Ber. 70 (1937) 1275; b) K. Ziegler, H.
Weber, H. G. Gellert, ibid. 75 (1942) 1715; c) A. W. Nineham, J1 Chem.
Sac. 1953,2601 ; d) J. N. Ashley, R. F. Collins, M. Davis, N. E. Sirett. ibid.
1958, 3303.
(111 The collected gas was characterized by GC/MS(EI): m/z 42 ( M e ) ;see also
N. Zelinsky, J. Gutt, Chem. Ber. 40 (1907) 3049.
[121 NiDPPPC1, = (1 .3-bis(diphenylphosphino)propanedichloronickel(1~):
G. R. van Hecke, W. de W. Horrocks, Jr., Inorg. Chrm. 5 (1966) 1968.
[13j All thiophenes 4 gave satisfactory C, H, S analyses and ' H NMR spectra
(300 MHz, CDCI,, TMS as standard): e.g., 4c,d: 6, = 7.213 (dd,
3J(5',4') = 4.96, 4J(5',2')= 2.91 Hz, 1 H ; H-5'), 6.918 (dd, 'J(4',5') =
5.00. 4J(4',2') = 1.31 Hz, 1 H ; H-4), 6.900 (dd, 4 J ( 2 , 5 ' ) = 2 98, 4 J ( 2 ' , 4 )
= 1.27Hz, 1 H;H-2'),6.815(~,4H;H,,),3.879(t,~5(1.2) = 6.49Hz,2H;
H-l), 3.714 (s, 3 H ; OCH,), 2.629 (I, 'J(6,5) = 7.48 Hz, 2 H ; H-6), 1.745
(m, 2 H ; H-2), 1.610 (m, 2 H ; H-5), 1.53-1.35 (m, 4 H ; H-3,4).
(141 a) R. L. Burwell, Chem. Rev. 54 (1954) 615; b) H. Meerwein in: HoubenWeyl-Miiller, Methoden der Organischen Chemie. 4. Aufl., Bd. 613. Thieme,
Stuttgart 1965. p. 143ff.; c) M. V. Bhatt, S . U. Kulkarni, Synthesis 1983,
249.
[15] All thiophenes 5 and 6 gave satisfactory C, H, halogen. S analyses and
' H NMR spectra (300 MHz, CDCI,, TMS as standard), e.g., 5d:
6, = 7.147 (dd, 'J(5',4') = 4.86, 4J(S,2')= 2.95 Hz, 1 H ; H-S'), 6.843 (dd,
' J ( 4 , S )= 4.86, 4J(4',2') = 1.21 Hz, 1 H; H-4'), 6 828 (dd, 4J(2',5') =
2.86, 4J(2',4') = 1.28 Hz, 1 H ; H-2'), 3.310 (t, 'J(l.2) = 6.82 Hz, 2 H ; Hl), 2.548 (t, 3J(6.5) = 7.62 Hz, 2 H ; H-6), 1.770 (m, 2 H ; H-2). 1.555 (m,
2 H ; H-5), 1.43-1.21 ( m , 4 H ; H-3,4). 6c: 6, = 7.220 (dd, 'J(S.4') = 4.86,
4J(5',2') = 2.99 Hz, 1 H ; H-S'), 6.917 (dd, ' J ( 4 ' , 5 ' ) = 4.85, 45(4,2')=
1.20 Hz, 1 H ; H-4'). ca. 6.90 (dd, 4 J ( 2 , 4 ) = 1.22 Hz, ' J ( 2 , S ) not determinable, 1 H ; H-2'), 3.161 (t, 'J(l,2) = 7.01 Hz, 2 H ; H-1), 2.619 (t.
'J(6,5) = 7.61 Hz, 2 H ; H-6), 1.82 (m. 2 H ; H-2), 1.65 (m, 2 H ; H-5) 1.481.27 (m. 4 H ; H-3,4).
CH Activation of Acetonitrile by Alkyl Compounds
of the Early Lanthanoids: Dimeric CyanomethylLanthanoid Complexes with CH,CN Bridges **
By Hero J. Heeres, Auke Meetsrna, and Jan H . Teuben*
Considerable progress has been made in the exciting field
of CH bond activation of saturated and unsaturated hydrocarbons by highly electrophilic do(f") organolanthanoids,
actinoids and early transition metal compounds.['] An outstanding example is the activation of the normally inert CH
bonds of methane by complexes of the type Cp:MMe
(Cp* = q5-pentamethylcyclopentadienyl;M = Lu, Sc and
Y).['l Recently, we have shown that Cp:LnCH(SiMe,),
compounds (Ln = La and Ce) are efficient catalysts for the
cyclodimerization of alkynes MeC = CR (R = Me, Et, nPr) to
substituted 3-alkylidenecy~lobutenes.~~~
The first step in the
reaction sequence is a propargylic metalation of one of the
relatively acidic methyl protons of MeC = CR. This prompted us to study the interactions between Cpf Ln-alkyl compounds and other substrates containing active C-H bonds.
Initially, we focused our attention on nitriles containing at
least one a-C-H bond. Metalated nitriles, well-known for
group 1 elements,[41are highly reactive species which are very
useful intermediates in organic synthesis.[51In this communication the novel and facile metalation of acetonitrile by pen[*] Prof. Dr. J. H. Teuben, Drs. H. J. Heeres, Drs. A. Meetsma
Groningen Centre for Catalysis and Synthesis, Department of Chemistry
University of Groningen
Nijenborgh 16, 9747 NL-AG Groningen (The Netherlands)
[**I This work was supported by Shell Research BV.
0570-0833/90/0404-0420S 02.5010
Angew. Chem. Int. Ed. Engl. 29 (1990) No. 4
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