A mild and practical copper catalyzed amination of halothiophenes

Article abstract of DOI:10.1016/j.tet.2004.11.017

We have found that N,N-dimethylethanolamine (deanol) is a useful solvent and ligand for copper catalyzed amination of a variety of unactivated and activated 2- or 3-halothiophenes. Primary amines, acyclic secondary amines, cyclic secondary amines and acyclic secondary amines with 2-hydroxyethyl functionality react with halothiophenes in moderate to excellent yields. The mildly basic conditions utilized are compatible with many functional groups. The amination of halobithiophenes has also been examined. The aminothiophenes produced by this method are important intermediates in a variety of electronic and optoelectronic materials. We have found that N,N-dimethylethanolamine (deanol) is a useful solvent and ligand for copper catalyzed amination of a variety of unactivated and activated 2- or 3-halothiophenes. Primary amines, acyclic secondary amines, cyclic secondary amines and acyclic secondary amines with 2-hydroxyethyl functionality react with halothiophenes providing the corresponding aminated thiophenes in moderate to excellent yields. The mildly basic conditions utilized are compatible with many functional groups. The amination of halobithiophenes has also been examined. The aminothiophenes produced by this method are important intermediates in a variety of electronic and optoelectronic materials.

Full text of DOI:10.1016/j.tet.2004.11.017

Tetrahedron 61 (2005) 903–918
A mild and practical copper catalyzed amination
of halothiophenes*
*
Zhikuan Lu and Robert J. Twieg
Department of Chemistry, Kent State University, Kent, OH 44242-0001, USA
Received 23 April 2004; revised 4 November 2004; accepted 5 November 2004
Available online 8 December 2004
Abstract—We have found that N,N-dimethylethanolamine (deanol) is a useful solvent and ligand for copper catalyzed amination of a variety
of unactivated and activated 2- or 3-halothiophenes. Primary amines, acyclic secondary amines, cyclic secondary amines and acyclic
secondary amines with 2-hydroxyethyl functionality react with halothiophenes in moderate to excellent yields. The mildly basic conditions
utilized are compatible with many functional groups. The amination of halobithiophenes has also been examined. The aminothiophenes
produced by this method are important intermediates in a variety of electronic and optoelectronic materials.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
Some of these preparative methods are generally limited by
either the availability of starting materials or by the
compatibility of sensitive functional groups in the sub-
strates. Multi-step synthesis may often be required to obtain
even the starting materials required for thiophene ring
building. Since the parent aminothiophenes are themselves
generally unavailable and unstable, an alkylation approach
to make N-substituted aminothiophenes is impractical.11,21
2-Methylaminothiophene and 2-isopropylaminothiophene
were made by electrophilic amination of cuprates with
N-alkyl-O-(trimethylsilyl) hydroxylamines but this method
is not compatible with other base sensitive functionality.16
Nucleophilic aromatic substitution (SNAr) is an established
and straightforward method, but it is limited to the
thiophenes with the appropriate type, number and location
of electron deficient-substituents. For example, Prim
demonstrated that some weakly activated bromothiophenes
such as 5-bromothiophene-2-carboxaldehyde react
efficiently with a variety of secondary aliphatic amines in
aqueous media by SNAr reaction and no transition metal
catalyst was required.14 However, 4-bromothiophene-2-
carboxaldehyde did not give any amination product with
cycloaliphatic amines under the same conditions. Amino-
thiophenes bearing a secondary amine group have been
prepared from 2-mercaptothiophene and the corresponding
aliphatic secondary amines.15 This method is still used to
prepare this family of compounds although it ‘requires
several unattractive steps with respect to yields and
substituent variations’.22 The oxidative intramolecular
coupling may be described as a special case of copper
mediated amination process, but it often requires sensitive
organometallic reagents that are not compatible with some
The thiophene ring is often substituted for benzene in many
materials and systems so as to deliver some enhanced
function, as in the case of pharmaceuticals1–3 and
optoelectronic materials.4,5 More specifically, and in spite
of an often relatively difficult synthesis, aminothiophenes
have been widely compared to anilines due to their
exceptional electronic properties.6 However, little in the
way of general or straightforward synthetic methodology
exists for amine-substituted thiophenes, especially those
that are electron-neutral or electron-rich. The methods
available for the synthesis of aminothiophenes include these
categories: (1) creation of the thiophene ring by conversion
of acyclic starting materials;7–10 (2) reactions of halothio-
phenes with metal amide, reduction of nitrothiophenes and
rearrangement reactions that are limited to the parent
aminothiophenes without alkyl substitution;11,12 (3) alkyl-
ation of one aminothiophene to create another;13 (4)
nucleophilic aromatic substitution of halogenated substrates
bearing one or more electron withdrawing and activating
substituents;14 (5) substitution reactions of mercaptothio-
phenes;15 (6) electrophilic substitution of thienyl cuprates
with N-alkylhydroxylamines;16 (7) oxidative intramolecular
coupling of amidocuprates17 and, finally, (8) transition
metal mediated amination reactions of halothiophenes.18–20
* Presented in part at the 227th ACS National Meeting, Anaheim, CA,
United States, March 28, April 1, 2004.
Keywords: Amination; Copper; Catalysis.
* Corresponding author. Tel.: C1 330 672 2791; fax: C1 330 672 3816;
e-mail: rtwieg@lci.kent.edu
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.11.017

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Z. Lu, R. J. Twieg / Tetrahedron 61 (2005) 903–918
functional groups, although in certain cases it has clear-cut
advantages for the application to bulky alkylamines and
arylamines.23,24
here provides an alternative and sometimes complementary
or superior approach to palladium-mediated aminations.
Transition metal mediated substitution reactions have been
extensively explored in recent years and have been
successfully applied to the amination of a range of
halothiophenes.25,26 Watanabe reported the amination of
unactivated bromothiophenes with diarylamines under
strongly basic conditions with t-BuONa and a Pd(OAc)2/
P-t-Bu3 catalyst. No aliphatic amines were examined in this
report.18 Rasmussen expanded the use of the same catalyst
system to reactions of 3-bromothiophene with primary and
secondary aliphatic amines.27 When primary amines were
used under these reaction conditions a mixture of 3-(N,N-
dialkyl) and 3-(N-alkyl)-aminothiophenes was obtained in
moderate yield. Luker described an amination reaction with
a palladium/BINAP catalyst and Cs2CO3 base for halothio-
phenes with a halogen activated by an electron-deficient
group. This method failed when applied to non-conjugated
activated halothiophenes such as the 2,4 isomer and electron
neutral or rich substrates.28 In a recent systematic report
Hartwig showed that unfunctionalized bromothiophenes
and other five membered haloheterocycles reacted smoothly
with N-methylaniline in the presence of Pd(dba)2/PtBu3.20
However, the reactions of hexylamine, dibutylamine,
piperidine, or morpholine with most 2-halothiophenes
afforded ‘little or no amination products’. Secondary amines
such as morpholine and 4-phenylpiperazine reacted with
3-bromothiophene in moderate to good yields but the
reactions of primary amines with 3-bromothiophene under
these conditions were less successful. For example,
n-hexylamine reacted with 3-bromothiophene in only
20–30% yield.
2. Results and discussion
In our initial communication, we reported a mild copper-
catalyzed amination reaction of aromatic iodides with
unhindered primary amines and cyclic secondary amines
by using N,N-dimethylethanolamine (deanol) as ligand and
solvent. While aryl bromides were generally not good
amination substrates we found that 2-bromothiophenes to be
exceptionally reactive. This observation prompted us to
explore further additional copper-mediated reactions of
bromothiophenes and amines. We have since investigated
the coupling of a larger variety of amines with 2-bromo-
thiophene and we have also found that 3-bromothiophene is
a good substrate for this reaction, even with primary amines.
This latter finding is in contrast to the case of some
palladium-catalyzed reactions of primary amines that have
been reported to poison reactions with 2-bromothiophenes
and are also not very successful for 3-bromothiophenes.20
We have also found that reaction of acyclic secondary
amines with bromothiophenes are only moderately success-
ful but acyclic secondary amines with b-hydroxyl function-
ality are exceptionally reactive towards bromothiophenes
and give very good amination yields.
The amination reaction conditions described here were
modified somewhat since our initial report.34 Copper metal
was originally used as the catalyst for 2-iodothiophenes and
copper metal alone has proven very successful for iodide
substrates. However, in the case of bromothiophenes a
mixture of copper metal and CuI (1:1 to 3:1) is employed as
an induction period is observed when copper metal alone is
used. The reaction temperatures and reaction times have
been chosen depending on the reaction progress monitored
by GC and TLC.
The copper-catalyzed Ullmann condensation is a very
attractive approach because of economic considerations
for large-scale industrial applications.29 In some cases,
stoichiometric amounts of copper and a polar aprotic solvent
such as HMPT were required for this method.30,31 Padwa
recently reported copper-catalyzed amidations of bromine
substituted furans and thiophenes in the presence of N,N0-
dimethylethylenediamine as ligand.19,32 Buchwald dis-
closed an example of copper catalyzed amination of
3-bromobenzothiophene with primary amines.33 In contrast,
copper catalyzed amination of the readily available electron
neutral 2-halo or 3-halo thiophenes still remains unexplored.
We have recently described a mild copper catalyzed
amination reaction with N,N-dimethylethanolamine
(deanol) as solvent and found that 2-iodo and 2-bromo-
thiophene could be successfully coupled with a variety of
primary amines and cyclic secondary amines.34 Sub-
sequently, deanol was examined as a ligand for copper-
catalyzed amidation of vinyl halides, but no accelerating
effect was observed in this case.35 The palladium catalyzed
amination of electron rich thiophenes with aliphatic amine
are not successful. It has been observed that copper and
palladium catalyzed amination processes often provide
complementary results.36 We now disclose the details of the
copper-catalyzed amination reactions of 2-halothiophenes
in deanol and extend the scope of this method to the
amination of 3-bromothiophene and halobithiophenes with
a more diverse selection of amines. The method described
The amination reactions of 2-iodothiophene with a range
of amines are found in Table 1. The reactions of
2-iodothiophene with both primary amines and cyclic
secondary amines proceed smoothly. Compared to iodo-
benzene, 2-iodothiophene is more reactive and shorter
reaction times and lower temperatures are required. The
coupling products between primary amine 2-iodothiophene
are somewhat unstable. Since N-monoalkylaminothio-
phenes are fairly unstable to oxidation and acidic conditions
due to tautomerization,11,37,38 we have employed Kugelrohr
distillation to purify these products. Nevertheless, once
purified they rapidly turn red upon exposure to air and/or
light. The reason for some of the relatively low yields here is
probably due at least in part to this poor stability and the
related mechanical losses during workup and purification.
We have found that 2-pyrrolidinothiophene is unstable on
silica gel unless the column is pretreated with 5%
triethylamine in hexane to neutralize the most active acidic
sites. However, 2-pyrrolidinothiophene is easily purified by
vacuum distillation. Thiophene derivatives with six-
membered ring amines are generally more stable than
analogues containing five-membered ring amines and
primary amines.

Z. Lu, R. J. Twieg / Tetrahedron 61 (2005) 903–918
Table 1. Copper metal catalyzed amination of 2-iodothiophene
905
Entry
1
Amine
Product
Temperature/time (8C/h)
Yield (%)a
91
60/10
2
3
H2Nn-Bu
60/11
70/10
62
87
4
75/24
62
a Isolated yield, with 10 mmol 2-iodothiophene and 1.5 equiv of amine.
Since 2-bromothiophene is more accessible than 2-iodo-
thiophene, and encouraged by our early results reacting this
bromide with pyrrolidine, we have extended this amination
reaction to other amines (Table 2). Cyclic six-member ring
amines also afforded very good yields of amination products
(Table 2, entries 2 and 3). Cyclic amines with hydroxyl
functionality were also examined. The reactivity of (S)-(C)-
pyrrolidinemethanol and 4-hydroxypiperidine are quite
similar to the amines without additional hydroxyl function-
ality (Table 2, entries 4 and 5). However, the reaction
between 2-bromothiophene and primary amines is not very
satisfactory. For example, when n-butylamine is coupled
with 2-bromothiophene, the reaction mixture turned black
quickly and the reaction did not proceed to completion.
Longer reaction times, higher catalyst loading and higher
reaction temperatures also resulted in incomplete
conversion of 2-bromothiophene. The reasons for the
difficulty in conversion of 2-bromothiophene are not
straightforward to elucidate. Hartwig observed an
immediate poisoning effect of hexylamine in the palladium-
catalyzed coupling of 2-bromothiophene with N-methyl-
aniline while the poisoning effect was not observed for the
reaction of bromobenzene with N-methylaniline.20 It
appears unlikely here that the primary amine alone would
poison the catalyst because primary amines are coupled to
3-bromothiophenes very successfully (Table 3, entries 1–3).
In another experiment, the reaction started with 10 mmol of
2-bromothiophene and a 1:1 ratio of pyrrolidine (1.2 equiv)
and n-butylamine (1.2 equiv) under the typical reaction
conditions. Incomplete conversion of 2-bromothiophene
was observed (w15% remained) and additional reaction
time and catalyst did not help. Interestingly, the ratio of the
two amination products was 1:1, the same mole ratio as the
starting amines, indicating similar reactivity for the two
amines. We assumed that the unstable 2-(n-butyl-
amino)thiophene product might interact with the active
catalytic species and inhibit the catalytic process. In order to
test this hypotheses, 30% mol of 2-(n-butylamino)thiophene
was added to the reaction of 2-bromothiophene and
pyrrolidine before the reaction started. The 2-(n-butyl-
amino)thiophene additive almost completely stopped this
reaction as less than 5% conversion of 2-pyrrolidinothio-
phene was observed after 48 h at 80 8C. Here again,
additional catalyst and reaction time did not further improve
the conversion. These experiments suggest that it is the
amination product of 2-bromothiophene or possibly some
degradation product of that amine product, rather than the
primary amine itself, that inhibits this copper-catalyzed
amination reaction. Due to the instability of 2-(n-butyl-
amino)thiophene, for characterization purposes we chose to
convert it to a more stable amide by reacting with acetic
anhydride in pyridine. The stable N-butyl-N-2-thienyl-
acetamide can be separated easily by flash chromatography
on silica gel (Table 2, entry 6).
In the case of halobenzenes, a limitation of this copper-
catalyzed deanol method was already observed in its
inapplicability to coupling with ordinary acyclic secondary
amines.34 For example, only 2% of N,N-diethylaniline was
isolated from the reaction of iodobenzene with diethylamine
with deanol/copper catalyst. It has been reported that the
palladium-catalyzed amination of 2-bromothiophene with
most secondary aliphatic amines is very challenging. For
example, no amination product was obtained from the
reaction of dibutylamine with 2-bromothiophene.20 How-
ever, we have found moderate success for the reaction
between an acyclic secondary amine with 2-bromothio-
phene (Table 2, entries 7 and 8). 2-N,N-Diethylaminothio-
phene was isolated in 39% yield and 2-N,N-
dipropylaminothiophene was isolated in 35% yield from
the respective amines and 2-bromothiophene with a high
loading of both catalyst (30–40%) and amine (4 equiv). No
advantage was observed for the use of 2-iodothiophene
instead of 2-bromothiophene in these reactions as a higher
amount of deanol ether byproduct was obtained (w20%
yield) using iodothiophene. The main reason for the low
yields here was that a slow poisoning effect quite similar to
the reaction of primary amine with 2-bromothiophene was
also observed in the reaction of diethylamine and dipropyl-
amine with 2-bromothiophene. However, the stability of
2-N,N-dialkylaminothiophenes appear to be higher than
2-N-monoalkylaminothiophenes and so a high catalyst and
amine loading could push the reaction to high conversion.
As yet another complication, the stability of 2-N,N-
dialkylaminothiophenes on silica gel is far less than

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Z. Lu, R. J. Twieg / Tetrahedron 61 (2005) 903–918
Table 2. Copper metal–cuprous iodide catalyzed amination of 2-bromothiophenes
Entry
Thiophene
Amine
Product
Temperature/time
(8C/h)
Yield (%)
1
2
80/50
80/50
81a
73a
3
4
80/72
80/50
65a
71a,b
5
6
80/50
64a
23c
H2Nn-Bu
Two steps
7
8
9
80/48
80/48
80/72
39d
35d
31a
10
11
80/24
80/24
81e
81e
12
80/48
15e
13
14
80/24
65/48
71a
77a
a Deanol was used as solvent, 10 or 20 mmol of bromothiophene and 1.5 equiv of amine.
b 10 mmol of amine and 15 mmol of 2-bromothiophene.
c Copper-catalyzed amination followed by acylation using acetic anhydride and pyridine.
d 40% mol of Cu and 4.0 equiv of amine.
e 2-Alkylaminoethanol was used as solvent.
2-pyrrolidinothiophene and so they were purified using a
neutral alumina column.
materials and polymers by nucleophilic aromatic substi-
tution reaction.39 With our standard method, in which
deanol was used as solvent and 2-(N-ethylamino)ethanol
was used as reactant, a low yield (31%, Table 2, entry 9) was
obtained in coupling with 2-bromothiophene. However,
when deanol was omitted and the amino alcohol was used as
the solvent, the reactions of 2-(N-methylamino)ethanol and
In contrast to the ordinary acyclic secondary amines, acyclic
secondary amines with 2-hydroxyethyl functionality pos-
sess extraordinary reactivity (Table 2, entries 9–12). Such
amines are frequently introduced into opto-electronic

Z. Lu, R. J. Twieg / Tetrahedron 61 (2005) 903–918
Table 3. Copper-catalyzed amination of 3-bromothiophenes
907
Entry
Thiophene
Amine
Product
Temperature/time
(8C/h)
Yield (%)
1
2
3
H2Nn-Bu
80/36
80/40
80/45
85a
86a
83a
H2NnC7H15
4
5
80/45
80/40
83a
73a
6
80/70
23a
7
8
9
85/60
80/24
80/45
15b
90c
45c
10
65–75/70
53a
a Deanol as solvent, 10 or 20 mmol of bromothiophene and 1.5 equiv of amine.
b 35% of Cu and CuI (4:1) and 4 equiv of diethylamine.
c Alkylaminoalcohol as solvent.
2-(N-ethylamino)ethanol with 2-bromothiophene both
afforded an 81% yield of the respective amination product.
No reaction was observed between 2-bromothiophene and
the aromatic amines aniline, diphenylamine and carbazole
under the typical reaction conditions. In contrast, the
reaction between 2-anilinoethanol and 2-bromothiophene
afforded the amination product in 15% yield when
2-anilinoethanol was used a solvent at 90 8C for 48 h.
Attempts to enhance this yield with higher temperature (up
to 120 8C), longer reaction time and higher catalyst loading
were all unsuccessful. In spite of the low yield, this
additional case substantiates the enhanced reactivity of
b-aminoethanols in copper-catalyzed aminations.
amination yield as the reaction of 2-bromothiophene, but the
product with methyl substitution is more stable (Table 2,
entry 13).40 The 5-proton may play a role in the instability of
2-piperidinothiophene and the methyl group may inhibit
reaction at this site in the tautomer of 2-piperidino-5-
methylthiophene. This copper-mediated method in deanol
also works well with thiophenes bearing conjugated
electron-withdrawing groups. 5-Bromo-2-thiophenecarbox-
aldehyde was successfully reacted with piperidine at 65 8C
and the corresponding 2-piperidinothiophene-5-carbox-
aldehyde was isolated in 77% yield (Table 2, entry 14).
The lower yield here compared to that obtained from the
corresponding aromatic nucleophilic substitution reaction
may be due to competitive C–Br reduction.14 The reaction
temperature employed here is lower compared to conditions
reported for the uncatalyzed aromatic nucleophilic substi-
tution reaction (110 8C).41 A similar reaction under the same
We have also examined the amination of some other
functionalized bromothiophenes. Coupling of 2-bromo-5-
methylthiophene with piperidine afforded almost the same

908
Z. Lu, R. J. Twieg / Tetrahedron 61 (2005) 903–918
Scheme 1. Amination of 2,5-dibromothiophene (1) with piperidine.
conditions but without copper catalyst was also examined.
Only 19% yield of amination product was separated and the
major byproduct was 2-thiophenecarboxaldehyde
accompanied by some decarbonylation product 2-bromo-
thiophene. This dehalogenation is often observed during
transition metal-catalyzed coupling or reduction.42,43 We
are still uncertain how the decarbonylation reaction
happened here, nevertheless the experiments prove that
copper played a catalytic role.
a labile 2-bromo-5-piperidinothiophene (2) that would react
with the catalytic copper species and precipitate out from
the solution. However, and to our surprise, when more
piperidine (6 equiv) and copper catalyst (20% mol, Cu/CuI
is 3:1) were used, all the 2,5-bromothiophene (1) was
consumed, the half reduced product 2-piperidinothiophene
(3) was isolated in 26% yield and 2,5-dipiperidinothiophene
(4) was now isolated in 46% yield.
Since intermediate 2 is present as a low concentration
species in all cases (with 1.2–6.0 equiv of piperidine and at
low or high catalyst loading), we assume that the
intermediate 2 is more reactive than other bromothiophenes
towards this copper-catalyzed amination reaction to form
products of reduction or amination. Scheme 2 describes a
competition between the desired catalytic reaction and the
‘Cu’ poisoning reaction. If the concentration of piperidine
and catalyst loading were both low, the amination reaction
of intermediate 2 would be slow. In this case, the reaction of
intermediate 2 with the active copper catalyst species
becomes a significant one and therefore the copper catalytic
species would precipitate out from the solution. This
process would slow down and eventually stop the catalytic
amination reaction; if the piperidine concentration and the
catalyst load are increased, intermediate 2 would react with
piperidine faster than reacting with copper species towards
the poisoning direction, and therefore the whole catalytic
reaction moves to the amination product and all the starting
material could be converted. However, the poisoning
reaction could not be excluded even in the later case
because a small amount of brown precipitate was also
observed.
We have also explored the amination of 2,5-dibromothio-
phene with the intended goal to prepare 2-bromo-5-
dialkylaminothiophenes (Scheme 1). However, we found
that the reaction of 1 with 1.2–3.0 equiv piperidine stopped
within 24 h and most of 1 was recovered. Analysis of the
reaction mixture by GC–MS indicates that the concentration
of the component assigned as 2-bromo-5-piperidinothio-
phene was low at all times during the whole reaction
process. Significant dehalogenation was also evident in this
reaction. For instance, after 48 h reaction between 2,5-
dibromothiophene and piperidine (3.0 equiv) at 80 8C, the
major products were isolated 2-piperidinothiophene (31%)
and 2,5-dipiperidinothiophene (20%) along with a smaller
amount of 2-bromothiophene. Although the 2-bromo-5-
piperidinothiophene was detected by GC–MS all attempts to
isolate a pure sample by silica gel chromatography failed.
This result is similar to the reaction of 2-bromothiophene
with primary amines wherein the reaction gradually came to
a halt prior to completion. The use of less amine (1.2 or
1.5 equiv) resulted in earlier termination of the reaction and
more (O50%) of 2,5-dibromothiophene remaining. After
aqueous work-up and extraction with diethyl ether, a
significant amount of black precipitate was observed in
the aqueous layer. This result may be due to the formation of
The amination of bromobithiophenes was also briefly
Scheme 2. Competition between the catalytic reaction and the ‘Cu’ poisoning reaction.
Scheme 3. Amination of 5-bromo-2,2-bithiophene (5) and 5,5-dibromo-2,2-bithiophene (6).

Z. Lu, R. J. Twieg / Tetrahedron 61 (2005) 903–918
909
explored as is illustrated in Scheme 3. Reaction of 5-bromo-
2,20-bithiophene (5) with piperidine appeared slightly more
facile than the reaction of 2-bromothiophene with piper-
idine, although the yield of 5-piperidino-2,20-bithiophene
(7) (63%) was less than the reaction giving 2-piper-
idinothiophene (3, Table 2, entry 2, 73%). It appears that
5-bromo-2,20-bithiophene (5) has a higher tendency to be
reduced than 2-bromothiophene as about 20% of 2,20-
bithiophene (9) was isolated from this reaction. Although
poisoning effects were noticeable for the amination of 2,5-
dibromothiophene, no obvious 0poisoning was observed in
the case of 5,50-dibromo-2,2 -bithiophene (6). To our
surprise, the ma0jor product (54%) from the reaction of
5,50-dibromo-2,2 -bithiophene (6) with piperidine was the
half reduced amination product 5-piperidino-2,20-bithio-
phene (7). The 5,50-dipiperidino-2,20-bithiophene (8) was
isolated in a substantially lower yield (14%) and the doubly
reduced product, 2,20-bithiophene (9) was also isolated in
9% yield.
afforded good yields (Table 3, entries 4–6) and the lack of
reactivity of 3-bromothiophenes towards acyclic secondary
amines is quite similar to that of 2-bromothiophene. The
ordinary acyclic secondary amines are again not reactive
under these conditions, but amines with 2-hydroxyethyl
functionality also possess significantly enhanced
reactivity for 3-bromothiophene. For instance, when the
2-(N-methylamino)ethanol and 2-(N-ethylamino)ethanol
were used as solvent, both successfully coupled with
3-bromothiophene and afforded 90 and 45% yields of the
respective amination products (Table 3, entries 8 and 9).
It is particularly interesting to apply this process to the
amination of 4-bromo-2-thiophenecarboxaldehyde since
this substrate failed to give any amination product by the
nucleophilic aromatic substitution method.14 We have
found that the present method does provide a moderate
yield of amination product when 4-bromo-2-thiophene-
carboxaldehyde reacts with piperidine at 65–75 8C (Table 3,
entry 10). The product of reductive debromination (2-thio-
phenecarboxaldehyde) was isolated as the major byproduct
and the decarbonylation product (2-piperidinothiophene)
was also observed as another byproduct. It is worth noting
that if the reaction was run at higher reaction temperature
(O85 8C), the amination product yield was not improved,
probably due to the instability of the aminothiophene-
carboxaldehyde or the starting aldehyde.
Based on these very preliminary results the copper-deanol
method appears to be quite useful for the amination of
dihalothiophenes and halooligothiophenes. However,
studies with these substrates do point out the role that
reduction plays in the diminution of yield of the desired
amination products. The use of more amine in these
reactions may be beneficial in minimizing the amount of
reduction.
A usually minor but ubiquitous competing side reaction of
the copper-catalyzed amination reaction of aryl halides in
deanol is aryl ether formation involving the alcohol group of
deanol. In our earlier study with aryl halide substrates the
aryl ether byproducts were isolated.34 In the case of the
thiophenes studied here no systematic effort was made to
isolate and characterize these deanol ether byproducts
except those from 2-bromothiophene and 3-bromothiophene
(see supporting information). The thiophene ethers from
deanol are significantly more polar than the desired amine
derivatives and were not isolated by chromatography. The
yield of these ether byproducts is estimated at 2–10%
depending on the reactivity of the specific halothiophenes
and amines. Larger amounts of aryl ethers were isolated
when acyclic secondary amines were used as reactants. The
more reactive iodothiophene gave less ether byproduct.
Another side reaction is the reduction of the halo group in
halothiophene. Bithiophenes and thiophenes with electron-
withdrawing substitution seem to afford more reduced
product. We found that this method could not be extended to
a useful synthesis of ether-substituted thiophenes. For
example, treatment of 2-iodothiophene with 3 equiv of
1-propanol and 15% mol Cu and CuI (2:1) catalyst for 24 h
at 80 8C (standard amination conditions), produced mainly
the deanol ether of 2-iodothiophene (w40% isolated) and
only a trace of 2-propoxythiophene was detected.
In order to expand and elucidate the scope of this mild
amination reaction for other electron-neutral and electron-
rich thiophenes, we have also performed reactions of
3-bromothiophene with a range of aliphatic amines. In
contrast to the unsuccessful or complicated product
distributions reported for palladium-catalyzed amination
reactions of primary amines with 3-bromothiophene,20,27
we found that the copper-mediated deanol method is a mild
and effective process even for primary amines.
Table 3 shows the copper-catalyzed amination results of
3-bromothiophenes. All the primary amines examined
afforded very good yields of monoarylation products in
contrast to palladium-catalyzed aminations that also gave
diarylation byproducts as well as monoarylation product.27
The successful amination of 3-bromothiophene with
primary amines may be related to the better stability of
3-(N-alkylamino)thiophenes compared with 2-(N-alkyl-
amino)thiophenes. Unlike 2-(N-alkylamino)thiophene, a
longer reaction time is less prone to decompose 3-(N-
alkylamino)thiophenes in the reaction system and no
poisoning effect was observed for 3-(N-alkylamino)thio-
phenes. Amines with longer alkyl chains required a
longer reaction time (entry 3, Table 3). In addition, the
3-aminothiophenes are fairly stable to air for short periods
and the products can be easily purified by flash chromato-
graphy on silica gel, however, they are not stable for long
term storage even at low temperature. The 3-bromothio-
phene is less reactive to acyclic secondary amines than
2-bromothiophene but the product is more stable and can be
isolated by silica gel chromatography. For instance, after
60 h reaction at high catalyst and amine loading, only 15%
of 3-N,N-diethylaminothiophene was isolated. Similar to
2-bromothiophene, most cyclic secondary amines also
All the workups and purifications described here were
carried out in the air and noticeable color changes of many
of these aminothiophenes were observed. Even refrigeration
will not prevent the degradation of neat samples of these
aminothiophenes, particularly the mono-alkylated amino-
thiophenes, and so immediate subsequent follow-up
reaction or use is suggested.

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Z. Lu, R. J. Twieg / Tetrahedron 61 (2005) 903–918
amination in deanol, in combination with other existing
methods, provides a means from wide range of aromatic
halide to aromatic amine transformation.
3. Experimental
3.1. General methods
Unless otherwise noted, all chemicals were used as received
from commercial suppliers. Copper metal (w45 mm
powder) and CuI were purchased from ACROS. 5-Bromo-
2,20-bithiophene and 5,50-dibromo-2,20-bithiophene were
prepared according to literature procedures.53 1H
(300 MHz) and 13C (75 MHz) NMR spectra were obtained
as solutions in CDCl3, and chemical shifts are reported in
parts per million (ppm) downfield from internal standard
Me4Si (TMS) for 1H and 13C coupling constants are
reported in hertz (Hz). Spectral splitting patterns are
designated as: s, singlet; d, doublet; t, triplet; q, quartet;
m, multiplet; comp, complex multiplet; and br, broad. The
infrared spectra were recorded neat on Bruker Vector 33 and
are reported in wave numbers (cmK1). Melting points were
measured on Olympus BH-2 polarized light microscope
equipped with a Mettler FP5 temperature controller and
FP52 hot stage. Low-resolution mass spectra were obtained
on a Thermo Finnigan Polaris Q Ion Trap GC(Trace GC
ultra)/MS with Electron Ionization or Chemical Ionization.
High-resolution mass spectra were obtained for selected
compounds on a Micromass Q-TOF II Mass Spectrometer at
the Mass Spectrometry and Proteomics Facility, Ohio State
University. Candidate samples for HRMS were chosen on
the basis of stability and as representative of the type of
amines prepared. The purity of all the isolated compounds
was higher than 95% which was examined by TLC, GC and
1H NMR. Copies of 1H and 13C NMR of all new compounds
and some of the known compounds are available in
supporting materials.
Figure 1. Proposed mechanism for copper-catalyzed amination in deanol.
The proposed mechanism is shown in Figure 1 and uses
aromatic halides and a primary amine as an example. The
reaction proceeds via a pathway involving copper (III)
intermediate(s) similar to the recently developed copper
catalyzed coupling reactions of pentavalent bismuth,
trimethylsiloxanes, aryboronic acids and arylstannanes.44–47
In the past, copper (III) intermediates were sometimes
described as elusive high-energy species that were unlikely
intermediates even though Cu(III) intermediate has often
been proposed for copper mediated coupling reactions.48,49
However, recently more and more copper (III) compounds
have been prepared and characterized with X-ray crystal-
lography and spectroscopic methods.50,51 Reductive
elimination of a copper (III) peralkyl intermediate has
been proposed for the 1,4-addition in organocuprate
reactions.52 In some cases, oxygen was used to convert a
copper (II) intermediate to a copper (III) intermediate to
facilitate reductive elimination.45 The catalytic cycle starts
with a Cu(I) deanol complex. The mechanism includes
mainly three steps: (a) oxidative addition of ArX occurs first
to generate two aromatic and deanol coordinated Cu(III)
species; (b) ligand exchange between X and amine; and (c)
reductive elimination which lead to the final amination
product. Reductive elimination of coordinated deanol and
aryl group leads to aryl deanol byproduct.
In most cases, aminothiophenes are sensitive to air, light and
acid but they are sufficiently stable for manipulation neat or
in solution. However, immediate use rather than protracted
storage (even at low temperature) is advised. For example,
severe decomposition was observed for 3-(N-benzyl-
amino)thiophene (Table 3, entry 2) and 3-N-(heptyl-
amino)thiophene (Table 3, entry 1) after two months of
storage in the freezer (K16 8C). Chromatography columns
employed for purification of sensitive compounds by gravity
or flash methods were prepared from a slurry of silica gel in
hexane/triethylamine (97:3).
3.1.1. 2-Pyrrolidinothiophene.54 (Table 1, entry 1) 2-
Iodothiophene (2.1 g, 10 mmol), pyrrolidine (1.1 g,
15 mmol), Cu metal (w45 mm powder, 64 mg, 1 mmol),
K3PO4$H2O (4.6 g, 20 mmol) and deanol (10 ml) were
added to a flask fitted with a magnetic stirbar, a condenser
and sealed with a septum. The reaction mixture was stirred
at 60 8C for 11 h under nitrogen positive pressure. After the
reaction cooled to room temperature, 10 ml of water was
added and the mixture was extracted with diethyl ether (3!
100 ml). The combined organic layers were then washed
with brine and dried over anhydrous MgSO4. Solvent was
removed by rotary evaporation and the residue was purified
In conclusion, we have demonstrated that copper-catalyzed
amination in N,N-dimethylethanolamine is a mild and
practical method to prepare amine derivatives from a
variety of 2 and 3-halothiophenes, 2,5-dihalothiophenes and
halobithiophenes. To our knowledge, this is the first report
of copper catalyzed reaction of unactivated halothiophenes
with aliphatic amines under such mild conditions. Primary,
secondary acyclic, and cyclic amines, and acyclic secondary
amines with hydroxyethyl functionality, provided moderate
to excellent yields of the corresponding aminated thio-
phenes. The application of this new copper mediated

Z. Lu, R. J. Twieg / Tetrahedron 61 (2005) 903–918
911
by Kugelrohr distillation (75 8C, 0.05 mmHg). The product
was obtained as a yellow liquid that turns blue on exposure
with a magnetic stirbar, a condenser and sealed with a
septum. The reaction mixture was stirred at 75 8C for 24 h
under nitrogen positive pressure. After the reaction cooled
to room temperature, 10 ml of water was added and the
mixture was extracted with diethyl ether (3!100 ml). The
combined organic layers were washed with brine and dried
over anhydrous MgSO4. Solvent was removed in vacuo, and
the residue was purified by flash chromatography on silica
gel eluted with hexane and then hexane/EtOAc (4:1). The
1
to air and is unstable on silica gel. (1.40 g, 91% yield). H
NMR (300 MHz, CDCl3) d 6.83 (dd, JZ5.4, 3.9 Hz, 1H),
6.42 (dd, JZ5.4, 1.2 Hz, 1H), 5.79 (dd, JZ5.4, 1.2 Hz, 1H),
3.32–3.28 (m, 4H), 2.07–2.02 (m, 4H). 13C NMR (75 MHz,
CDCl3) d 155.97, 126.94, 108.35, 100.08, 51.25, 25.90.
GC–MS (CI) 154.1 (MCH, 47), 52.9 (100), 153.1 (62),
152.1 (56), 55 (37), 91 (34), 120.1 (30).
1
product was obtained as a liquid, 1.04 g, 62% yield. H
NMR (300 MHz, CDCl3) d 6.80 (dd, JZ5.5, 3.9 Hz, 1H),
6.64 (dd, JZ5.5, 1.4 Hz, 1H), 6.16 (dd, JZ3.9, 1.4 Hz, 1H),
3.86–3.83 (m, 4H), 3.14–3.11 (m, 4H). 13C NMR (75 MHz,
CDCl3) d 159.5, 126.24, 112.87, 105.76, 66.56, 52.08. GC–
MS (CI) 170.01 (MCH, 100), 169.1 (67), 171.7 (15), 168.1
(13).
3.1.2. N-Butylthiophen-2-amine (Table 1, entry 2). 2-
Iodothiophene (2.1 g, 10 mmol), n-butylamine (1.1 g,
15 mmol), Cu metal (w45 mm powder, 64 mg, 1 mmol),
K3PO4$H2O (4.6 g, 20 mmol) and deanol (10 ml) were
added to a flask fitted with a magnetic stirbar, a condenser
and sealed with a septum. Air was removed from the
reaction system and replaced with nitrogen. The reaction
mixture was stirred at 60 8C for 11 h under nitrogen positive
pressure. After the reaction cooled to room temperature,
10 ml of water was added and the black mixture was quickly
extracted with diethyl ether (3!100 ml). The combined
organic layers were then washed with brine and dried over
anhydrous MgSO4 for 3 min. Solvent was removed in
vacuo, and the residue was purified by Kugelrohr distillation
(75 8C, 0.05 mmHg). The product was obtained as a light
yellow liquid, but quickly turned red on exposure to air
(0.96 g, 62% yield). 1H NMR (300 MHz, CDCl3) d 6.73 (dd,
JZ3.57, 5.50 Hz, 1H), 6.46 (dd, JZ1.38, 5.50 Hz, 1H),
6.02 (dd, JZ1.38, 3.57 Hz, 1H), 3.78 (s, br, 1H), 3.13 (t, JZ
7.0 Hz, 2H), 1.67–1.60 (m, 2H), 1.47–1.42 (m, 2H), 0.97 (t,
JZ7.3 Hz, 3H). 13C NMR (75 MHz, CDCl3) d 155.70,
126.39, 110.19, 103.80, 48.14, 31.85, 20.39, 14.04. GC–MS
(CI) 156.1 (MCH, 100), 112.1 (65), 155.1 (58), 100.1 (54),
67.1 (15), 157.1 (13).
3.1.5. 2-Pyrrolidinothiophene.54 (Table 2, entry 1) From
2-bromothiophene (160 mmol). 2-Bromothiophene (26.2 g,
160 mmol), pyrrolidine (17.2 g, 240 mmol), Cu metal
(w45 mm powder, 1.0 g, 16 mmol), K3PO4$H2O (73 g,
320 mmol) and deanol (160 ml) were added to a flask fitted
with a magnetic stirbar, a condenser and sealed with a
septum. The reaction mixture was stirred at 80 8C for 50 h
under nitrogen positive pressure. After the reaction cooled
to room temperature, 100 ml of water was added and the
mixture was extracted with diethyl ether (3!300 ml). The
combined organic layers were then washed with brine and
dried over anhydrous MgSO4. Solvent was removed by
rotary evaporation and the residue was purified by
distillation under vacuum (67–69 8C, 0.05 mmHg). The
product was obtained as a colorless liquid, 20.1 g, 81%
yield.
3.1.6. 2-Piperidinothiophene.15 (Table 2, entry 2) From
2-bromothiophene (20 mmol). 2-Bromothiophene (3.3 g,
20 mmol), piperidine (2.6 g, 30 mmol), Cu metal
(w45 mm powder, 64 mg, 1 mmol), CuI (190 mg,
1 mmol), K3PO4$H2O (9.2 g, 40 mmol) and deanol
(20 ml) were added to a flask with a magnetic stirbar, fitted
with a condenser and sealed with a septum. The reaction
mixture was stirred at 80 8C for 48 h under nitrogen positive
pressure. After the reaction cooled to room temperature
20 ml of water was added and the mixture was extracted
with diethyl ether (3!100 ml). The combined organic
layers were then washed with brine and dried over
anhydrous MgSO4. Solvent was removed in vacuo, and
the residue was purified by flash chromatography on silica
gel eluted with hexane and then hexane/EtOAc (10:1). The
product was obtained as a liquid (2.43 g, 73% yield).
3.1.3. 2-Piperidinothiophene.15 (Table 1, entry 3) From
2-iodothiophene (10 mmol). 2-Iodothiophene (2.1 g,
10 mmol), piperidine (1.3 g, 15 mmol), Cu metal
(w45 mm powder, 64 mg, 1 mmol), K3PO4$H2O (4.6 g,
20 mmol) and deanol (10 ml) were added to a flask fitted
with a magnetic stirbar, a condenser and sealed with a
septum. The reaction mixture was stirred at 70 8C for 10 h
under nitrogen positive pressure. After the reaction cooled
to room temperature, 10 ml of water was added and the
mixture was extracted with diethyl ether (100 ml, 3!). The
combined organic layers were then washed with brine and
dried over anhydrous MgSO4. Solvent was removed in
vacuo, and the residue was purified by flash chromatography
on silica gel eluted with hexane and then hexane/EtOAc
(10:1). The product was obtained as a liquid (1.45 g, 87%
1
yield). H NMR (300 MHz, CDCl3) d 6.79 (dd, JZ3.85,
5.50 Hz, 1H), 6.58 (dd, JZ1.38, 5.50 Hz, 1H), 6.11 (dd, JZ
1.38, 3.85 Hz, 1H), 3.13 (t, JZ5.6 Hz, 4H), 1.77–1.69 (m,
4H), 1.61–1.52 (m, 2H). 13C NMR (75 MHz, CDCl3) d
160.51, 126.24, 111.86, 105.02, 53.10, 25.59, 23.99. GC–
MS (CI) 167.1 (MCH, 87), 168.1 (100), 166.1 (46), 134.1
(24), 169.1 (13), 84.1 (11).
A larger scale reaction with 100 mmol of 2-bromothiophene
was also run. After 50 h the reaction was worked up by
extraction with diethylether and this ether solution was dried
over anhydrous MgSO4. Solvent was removed and the
product was further purified by vacuum fractional distilla-
tion with a Vigreux column. Bp 71–73 8C, 0.15 mmHg.
12.7 g, 76% yield.
3.1.4. 2-(Morpholino)thiophene.15 (Table 1, entry 4)
From 2-iodothiophene (10 mmol). 2-Iodothiophene (2.1 g,
10 mmol), morpholine (1.75 g, 20 mmol), Cu metal
(w45 mm powder, 64 mg, 1 mmol), K3PO4$H2O (4.6 g,
20 mmol) and deanol (10 ml) were added to a flask fitted
3.1.7. 2-(Morpholino)thiophene.15 (Table 2, entry 3)
From 2-bromothiophene (10 mmol). 2-Bromothiophene
(3.3 g, 20 mmol), morpholine (3.5 g, 40 mmol), Cu metal
(w45 mm powder) (64 mg, 1 mmol), CuI (190 mg,

912
Z. Lu, R. J. Twieg / Tetrahedron 61 (2005) 903–918
1 mmol), K3PO4$H2O (9.2 g, 40 mmol) and deanol (20 ml)
were added to a flask with a magnetic stirbar, a condenser
and sealed with a septum. The reaction mixture was stirred
at 80 8C for 72 h under nitrogen positive pressure. After the
reaction cooled to room temperature, 20 ml of water was
added and the mixture was extracted with diethyl ether (3!
100 ml). The combined organic layers were then washed
with brine and dried over anhydrous MgSO4. Solvent was
removed in vacuo, and the residue was purified by flash
chromatography on silica gel eluted with hexane and then
hexane/EtOAc (4:1). The product was obtained as a liquid
(2.18 g, 65% yield).
1.78–1.69 (m, 2H). 13C NMR (75 MHz, CDCl3) d 159.38,
126.35, 112.50, 105.98, 67.40, 49.94, 33.82. GC–MS (EI)
183.1 (MC, 100), 164.0 (43), 110.0 (37), 182.1 (19), 138.1
(19), 111.0 (15), 184.2 (14), 112.1 (14), 165.1 (10). IR (neat,
cmK1) 3344, 3106, 3069, 2943, 2819, 1528, 1450, 1380,
1336, 1258, 1222, 1197, 1142, 1112, 1069, 1055, 1011, 978,
878, 838, 774, 662.
3.1.10. n-Butyl-N-2-thienylacetamide (Table 2, entry 6).
2-Bromothiophene (3.3 g, 20 mmol), n-butylamine (3.0 g,
40 mmol), Cu metal (w45 mm powder, 64 mg, 1 mmol),
CuI (190 mg, 1 mmol), K3PO4$H2O (9.2 g, 40 mmol) and
deanol (20 ml) were added to a flask with a magnetic stirbar,
fitted with a condenser and sealed with a septum. Air was
removed from the reaction system and replaced with
nitrogen. The reaction mixture was stirred at 75 8C under
nitrogen positive pressure until almost all the 2-bromothio-
phene was consumed (usually about 24 h). After the
reaction cooled to room temperature, 20 ml of water was
added and the black mixture was quickly extracted with
diethyl ether (3!100 ml). The combined organic layers
were then washed with brine and dried over anhydrous
MgSO4. Solvent was removed by rotary evaporation and the
residue was Kugelrohr distilled (75 8C, 0.05 mmHg). The
distillate was quickly added to a premixed mixture of
pyridine (31 mmol) and acetic anhydride (30 mmol) and
stirred at room temperature for 3 h. EtOAc (200 ml) was
added and washed with water (40 ml, 3!). The organic
layer was dried over anhydrous MgSO4 and solvent was
removed. The residue was further purified by flash
chromatography on silica gel, eluted with hexane/ethyl
acetate (3:1). The product was obtained as liquid (0.90 g,
3.1.8. (S)-2-(2-Hydroxymethylpyrrolidino)thiophene
(Table 2, entry 4). 2-Bromothiophene (2.45 g, 15 mmol),
(S)-(C)-pyrrolidinemethanol (1.01 g, 10 mmol), Cu metal
(w45 mm powder, 64 mg, 1 mmol), CuI (190 mg, 1 mmol),
K3PO4$H2O (9.2 g, 40 mmol) and deanol (10 ml) were
added to a flask with a magnetic stirbar, fitted with a
condenser and sealed with a septum. The flask was cooled to
K78 8C, air was evacuated and nitrogen was backfilled. The
reaction mixture was stirred at 80 8C for 48 h under nitrogen
positive pressure. After the reaction cooled to room
temperature 20 ml of water was added and the mixture
was extracted with diethyl ether (3!100 ml). The com-
bined organic layers were then washed with brine and dried
over anhydrous MgSO4. Solvent was removed in vacuo, and
the residue was purified by column chromatography on
silica gel pretreated with 4% of triethylamine. The product
was eluted with hexane/EtOAc (4:1) and was obtained as an
oil (1.3 g, 71% % yield). 1H NMR (300 MHz, CDCl3) d 6.80
(dd, JZ3.8, 5.5 Hz, 1H), 6.45 (dd, JZ1.38, 5.50 Hz, 1H),
5.94 (dd, JZ1.38, 3.85 Hz, 1H), 3.79–3.72 (m, 1H), 3.65–
3.58 (m, 2H), 3.53–3.47 (m, 1H), 3.20–3.11 (m, 1H), 2.21 (t,
br. JZ5.6 Hz, 1H), 2.08–1.97 (m, 4H). 13C NMR (75 MHz,
CDCl3) d 156.30, 126.74, 109.50, 102.08, 64.93, 63.80,
53.75, 29.20, 24.86. MS (EI) 183.1 (MC, 32), 152.1 (100),
110.2 (33), 153.1 (18). HRMS (EI) calcd for C9H14NOS:
1
23%). H NMR (300 MHz, CDCl3) d 7.18 (dd, JZ1.38,
5.50 Hz, 1H), 6.91 (dd, JZ3.57, 5.50 Hz, 1H), 6.77 (dd, JZ
1.38, 3.57 Hz, 1H), 3.63 (t, JZ7.56 Hz, 2H), 1.94 (s, 3H),
1.57–1.47 (m, 2H), 1.36–1.23 (m, 2H), 0.88 (t, JZ7.3 Hz,
3H). 13C NMR (75 MHz, CDCl3) d 171.33, 146.01, 125.90,
125.36, 124.68, 49.86, 29.97, 22.57, 20.02, 13.92. GC–MS
(CI) 198.1 (MCH, 100), 156.1 (96), 197.0 (15), 100.1 (14),
155.1 (12), 157.1 (12), 112.1 (12), 199.1 (10), 196.1 (9).
HRMS (EI) calcd for C10H15NOSNa: 220.0772 (MCNa),
found: 220.0768.
184.0796 (MCHC), found: 184.0795. IR (neat, cmK1
)
3356, 3107, 3067, 2948, 2874, 2833, 1531, 1468, 1367,
1351, 1311, 1280, 1250, 1230, 1180, 1148, 1078, 1033,
1002, 982, 836, 754, 651.
3.1.9. 2-(4-Hydroxypiperidino)thiophene (Table 2, entry
5). 2-Bromothiophene (1.65 g, 10 mmol), 4-hydroxypiper-
idine (1.35 g, 13 mmol) Cu (32 mg, 0.5 mmol), CuI
(100 mg, 0.5 mmol), and deanol (10 ml) were added to a
flask with a magnetic stirbar, fitted with a condenser and
sealed with a septum. The flask was cooled to K78 8C, air
was evacuated and nitrogen was introduced. The reaction
mixture was stirred at 80 8C for 72 h under nitrogen positive
pressure. After the reaction cooled to room temperature
20 ml of water was added and the mixture was extracted
with diethyl ether (3!100 ml). The combined organic
layers were then washed with brine and dried over
anhydrous MgSO4. Solvent was removed in vacuo, and
the residue was purified by column chromatography on
silica gel pretreated with 3% of triethylamine and eluted
with hexane/EtOAc (3:1). The product was obtained as an
3.1.11. 2-N,N-Diethylaminothiophene.15 (Table 2, entry
7) 2-Bromothiophene (1.63 g, 10 mmol), diethyamine
(2.95 g, 40 mmol), Cu (190 mg, 3 mmol), CuI (100 mg,
0.5 mmol), and K3PO4$H2O (4.6 g, 20 mmol) and deanol
(10 ml) were added to a flask fitted with a magnetic stirbar, a
condenser and sealed with a septum. Air was removed and
replaced with nitrogen. The reaction mixture was stirred at
80 8C under nitrogen positive pressure for 48 h. After the
reaction cooled to room temperature, 150 ml of water was
added and the mixture was extracted with diethyl ether (3!
150 ml). The combined organic layers were then washed
with brine. Solvent was removed in vacuum, and the residue
was added to a short silica gel (pretreated with triethyl-
amine) column and eluted with hexane. A crude product
containing about 6% of 2-bromothiophene was obtained by
removing the solvent. The crude product was further
purified by column chromatography on neutral alumina
and the product was obtained as a liquid, 0.60 g, 39% yield.
1H NMR (300 MHz, CDCl3) d 6.77 (dd, JZ3.8, 5.5 Hz,
1H), 6.46 (dd, JZ1.4, 5.5 Hz, 1H), 5.91 (dd, JZ1.4, 3.8 Hz,
1
oil (1.18 g, 64.5% yield). H NMR (300 MHz, CDCl3) d
6.77 (dd, JZ3.85, 5.50 Hz, 1H), 6.59 (dd, JZ1.38, 5.50 Hz,
1H), 6.12 (dd, JZ1.38, 3.85 Hz, 1H), 3.88–3.79 (m, 1H),
3.49–3.42 (m, 2H), 2.98–2.90 (m, 2H), 2.04–1.95 (m, 2H),

Z. Lu, R. J. Twieg / Tetrahedron 61 (2005) 903–918
913
1H), 3.28 (q, JZ7.1 Hz, 4H), 1.18 (t, JZ7.1 Hz, 6H). 13C
NMR (75 MHz, CDCl3) d 157.58, 126.65, 109.48, 102.70,
47.53, 12.33. GC–MS (EI) 155.1 (MC, 57), 140.0 (100),
112.0 (85), 85.0 (34), 98.0 (29), 54.0 (27), 110.1 (21), 78.0
(19), 97.0 (17). IR (neat, cmK1) 3108, 3070, 2971, 2932,
2870, 1534, 1483, 1462, 1444, 1375, 1359, 1302, 1243,
1198, 1180, 1127, 1077, 1053, 834, 785, 753, 650, 564.
under nitrogen positive pressure. After the reaction cooled
to room temperature, 20 ml of water was added and the
mixture was extracted with diethyl ether (3!150 ml). The
combined organic layers were then washed with brine and
dried over anhydrous MgSO4. Solvent was removed in
vacuo, and the residue was purified by flash chromatography
on silica gel eluted with hexane/EtOAc (1:1). The product
was obtained as a liquid that easily changed to blue color,
2.54 g, 81% yield. 1H NMR (300 MHz, CDCl3) d 6.77 (dd,
JZ5.5, 3.8 Hz, 1H), 6.50 (dd, JZ5.5, 1.4 Hz, 1H), 5.98 (dd,
JZ3.8, 1.4 Hz, 1H), 3.78 (t, JZ5.6 Hz, 2H), 3.35 (t, JZ
5.6 Hz, 2H), 2.95 (s, 3H), 2.42 (s, br, 1H). 13C NMR
(75 MHz, CDCl3) d 159.05, 126.75, 110.74, 103.65, 59.85,
58.75, 41.64. MS (EI) 157.0 (25), 126.0 (100), 85.0 (14),
110 (11), 898.1 (9). IR (neat, cmK1) 3355, 3109, 3068,
2944, 2875, 2805, 1536, 1483, 1437, 1418, 1356, 1265,
1112, 1073, 1045, 836, 756, 655.
3.1.12. 2-N,N-Dipropylaminothiophene (Table 2, entry
8). 2-Bromothiophene (1.63 g, 10 mmol), dipropylamine
(4.0 g, 40 mmol), Cu (190 mg, 3 mmol), CuI (100 mg,
0.5 mmol), and K3PO4$H2O (4.6 g, 20 mmol) and deanol
(10 ml) were added to a flask fitted with a magnetic stirbar, a
condenser and sealed with a septum. Air was removed and
replaced with nitrogen. The reaction mixture was stirred at
80 8C under nitrogen positive pressure for 48 h. After the
reaction cooled to room temperature, 100 ml of water was
added and the mixture was extracted with diethyl ether (3!
150 ml). The combined organic layers were then washed
with brine. Solvent was removed in vacuum, and the residue
was added to a short silica gel (pretreated with triethyl-
amine) column and eluted with hexane. A crude product
containing about 8% of 2-bromothiophene was obtained by
removing the solvent. The crude product was further
purified by column chromatography on neutral alumina
and the product was obtained as a liquid, 0.65 g, 35% yield.
1H NMR (300 MHz, CDCl3) d 6.76 (dd, JZ3.8, 5.5 Hz,
1H), 6.41 (dd, JZ1.4, 5.5 Hz, 1H), 5.85 (dd, JZ1.4, 3.8 Hz,
1H), 3.20–3.15 (m, 4H), 1.71–1.58 (m, 4H), 0.94 (t, JZ
7.4 Hz, 6H). 13C NMR (75 MHz, CDCl3) d 158.26, 126.67,
108.67, 101.66, 56.06, 20.47, 11.67. GC–MS (EI) 183.1
(MC, 85), 126.2 (100), 154.1 (87), 112.2 (57), 184.1 (32),
85.3 (16), 78.2 (15), 127.1 (10). HRMS (EI) calcd for
C10H18NS: 184.1160 (MCHC), found: 184.1163. IR (neat,
cmK1) 3109, 3070, 2960, 2933, 2872, 1535, 1482, 1466,
1452, 1379, 1368, 1346, 1304, 1271, 1221, 1179, 1133,
1102, 1077, 1053, 960, 946, 882, 837, 749, 688, 649, 580,
571, 562.
3.1.15. 2-[Ethyl(2-thienyl)amino]ethanol (Table 2, entry
9 and 11). 2-Bromothiophene (3.3 g, 20 mmol), 2-(ethyl-
amino) ethanol 20 ml (also solvent), Cu metal (w45 mm
powder, 64 mg, 1 mmol), CuI (190 mg, 1 mmol), and
K3PO4$H2O (9.2 g, 40 mmol) were added to a flask fitted
with a magnetic stirbar, a condenser and sealed with a
septum. The reaction mixture was stirred at 80 8C for 24 h
under nitrogen positive pressure. After the reaction cooled
to room temperature, 20 ml of water was added and the
mixture was extracted with diethyl ether (3!150 ml). The
combined organic layers were then washed with brine and
dried over anhydrous MgSO4. Solvent was removed in
vacuum, and the residue was purified by flash chromato-
graphy on silica gel eluted with hexane/EtOAc (1:1). The
product was obtained as a liquid, very easily changed to blue
1
color, 2.77 g, 81% yield. H NMR (300 MHz, CDCl3) d
6.76 (dd, JZ5.5, 3.6 Hz, 1H), 6.52 (dd, JZ5.5, 1.4 Hz, 1H),
6.02 (dd, JZ3.6, 1.4 Hz, 1H), 3.74 (t, JZ5.6 Hz, 2H), 3.34–
3.28 (m, 4H), 1.16 (t, JZ7.2 Hz, 3H). 13C NMR (75 MHz,
CDCl3) d 157.40, 126.56, 111.24, 105.18, 59.83, 55.98,
49.82, 12.01. GC–MS (EI) 171.1 (24), 140.0 (100), 112.1
(52), 98 (16), 85 (21), 78 (16). IR (neat, cmK1) 3362, 3108,
3068, 2969, 2931, 2871, 1532, 1482, 1460, 1443, 1373,
1361, 1298, 1244, 1073, 1047, 835, 755, 652.
3.1.13. 2-[Ethyl(2-thienyl)amino]ethanol (deanol was
used as a solvent) (Table 2, entry 9). 2-Bromothiophene
(3.3 g, 20 mmol), 2-(ethylamino)ethanol (3.6 g, 40 mmol),
Cu metal (w45 mm powder, 64 mg, 1 mmol), CuI (190 mg,
1 mmol), K3PO4$H2O (9.2 g, 40 mmol) and deanol (20 ml)
were added to a flask fitted with a magnetic stirbar, a
condenser and sealed with a septum. The reaction mixture
was stirred at 80 8C for 72 h under nitrogen positive
pressure. After the reaction cooled to room temperature,
20 ml of water was added and the mixture was extracted
with diethyl ether (3!100 ml). The combined organic
layers were then washed with brine and dried over
anhydrous MgSO4. Solvent was removed in vacuo and the
residue was purified by flash chromatography on silica gel
eluted with hexane/EtOAc (4:1). The product was obtained
as a liquid, 1.06 g, 31% yield.
3.1.16. 2-[Phenyl(2-thienyl)amino]ethanol (Table 2,
entry 12). 2-Bromothiophene (3.3 g, 20 mmol), 2-anilino-
ethanol as solvent 20 ml (also solvent), Cu metal (w45 mm
powder, 64 mg, 1 mmol), CuI (190 mg, 1 mmol), and
K3PO4$H2O (9.2 g, 40 mmol) were added to a flask with a
magnetic stirbar, a condenser and sealed with a septum. The
reaction mixture was stirred at 85 8C for 48 h under nitrogen
positive pressure. After the reaction cooled to room
temperature, 20 ml of water was added and the mixture
was extracted with diethyl ether (3!100 ml). The com-
bined organic layers were then washed with water and brine.
Diethylether was removed in vacuo, and the anilinoethanol
was removed by Kugelrohr distillation. The residue was
purified by column chromatography on silica gel eluted with
hexane and ethyl acetate (9:1 to 3:1). The product was
obtained as a liquid, 0.65 g, 15% yield. 1H NMR (300 MHz,
CDCl3) d 7.28–7.22 (m, 2H), 7.03–6.89 (m, 5H), 6.72–6.70
(dd, JZ3.0, 1.2 Hz, 1H), 3.86 (s, 4H), 2.19 (s, br, 1H). 13C
NMR (75 MHz, CDCl3) d 152.15, 149.11, 129.32, 126.13,
120.84, 120.69, 120.48, 117.04, 60.05, 56.30. GC–MS (EI)
3.1.14. 2-(N-Methyl-NK2-hydroxyethylamino)thio-
phene (Table 2, entry 10). 2-Bromothiophene (3.3 g,
20 mmol), 2-(methylamino)ethanol 15 ml (also solvent),
Cu metal (K45 mm powder, 64 mg, 1 mmol), CuI (190 mg,
1 mmol), and K3PO4$H2O (9.2 g, 40 mmol) were added to a
flask with a magnetic stirbar, a condenser and sealed with a
septum. The reaction mixture was stirred at 80 8C for 24 h

914
Z. Lu, R. J. Twieg / Tetrahedron 61 (2005) 903–918
219.0 (MC, 65), 188.1 (100), 91.1 (97), 77.0 (37), 175.0
(21), 189.1 (14), 104.1 (13), 220.1 (11), 65.1 (11), 173.1
(10). IR (neat, cmK1) 3364, 3066, 3037, 2929, 2880, 1596,
1537, 1496, 1460, 1436, 1365, 1339, 1281, 1241, 1208,
1178, 1089, 1034, 843, 748, 690.
condenser and sealed with a septum. Air was removed and
replaced with nitrogen. The reaction mixture was stirred at
75–80 8C under nitrogen positive pressure until the 2,5-
dibromothiophene was consumed (usually 48 h, additional
50 mg Cu metal may be added if the conversion is not
completed). After the reaction cooled to room temperature,
50 ml of water was added and the mixture was extracted
with diethyl ether (3!120 ml). The combined organic
layers were then washed with brine and dried over
anhydrous MgSO4. Solvent was removed in vacuum, and
the residue was purified by flash chromatography on silica
gel pretreated with 3% triethylamine in hexane. The column
was first eluted with hexane and then hexane/ethyl acetate
(97:3). 2-Piperidinothiophene was eluented first (0.53 g,
26%). The 2,5-dipiperidinothiophene was obtained as
yellow crystals, 1.38 g, 46% yield. Mp 47.8–48.8 8C
(hexane). 1H NMR (300 MHz, CDCl3) d 5.86 (s, 2H),
2.98 (t, JZ5.6 Hz, 8H), 1.72–1.64 (m, 8H), 1.55–1.49 (m,
4H). 13C NMR (75 MHz, CDCl3) d 150.52, 105.90, 54.27,
25.83, 24.02. GC–MS (EI) 250.1 (MC, 100), 180.3 (64),
207.2 (53), 208.2 (47), 181.2 (35), 84.2 (25), 251.2 (16),
194.3 (11). Anal. Calcd C14H22N2S2: C, 67.15; H, 8.86; N,
11.19; S, 12.81. Found: C, 66.87; H, 9.02; N, 11.27; S,
12.63. HRMS (EI) calcd for C14H22N2SNa: 273.1401 (MC
Na), found: 273.1400. IR (neat, cmK1) 2927, 2850, 2818,
1556, 1528, 1463, 1446, 1381, 1324, 1230, 1189, 1126,
1120, 1019, 891, 858, 740, 717, 606.
3.1.17. 2-Piperidino-5-methylthiophene (Table 2, entry
13). 2-Bromo-5-methylthiophene (0.95 g, 5.4 mmol), piper-
idine (1.0 g, 12 mmol), Cu (32 mg, 0.5 mmol), CuI (50 mg,
0.25 mmol), K3PO4$H2O (3.9 g, 15 mmol) and deanol
(10 ml) were added to a flask fitted with a magnetic stirbar,
a condenser and sealed with a septum. The reaction mixture
was stirred at 80 8C for 24 h under nitrogen positive
pressure. After the reaction cooled to room temperature,
20 ml of water was added and the mixture was extracted
with diethyl ether (3!80 ml). The combined organic layers
were then washed with brine. Solvent was removed in
vacuo, and the residue was purified by flash chromatography
on silica gel eluted with hexane. The product was obtained
as a white solid, 0.67 g, 71% yield. Mp 31.2–32.0 8C
(hexane). 1H NMR (300 MHz, CDCl3) d 6.41–6.39 (m, 1H),
5.90 (d, JZ3.6 Hz, 1H), 3.05 (t, JZ5.5 Hz, 4H), 2.36 (d,
JZ0.8 Hz, 3H), 1.75–1.66 (m, 4H), 1.58–1.50 (m, 2). 13C
NMR (75 MHz, CDCl3) d 158.35, 126.72, 123.46, 105.29,
53.39, 25.64, 24.01, 15.47. GC–MS (EI) 181.1 (MC, 100),
180.1 (75), 97.0 (20), 124.1 (17), 112.1 (15), 182.1 (15),
111.1 (15), 166.1 (14). HRMS (EI) calcd for C10H16NS:
182.1003 (MCHC), found: 182.1001. IR (neat, cmK1
)
3.1.20. 5-Piperidino-2,20-bithiophene (compound 7).10
5-Bromo-2,20-bithiophene (1.25 g, 5 mmol), piperidine
(0.65 g, 8 mmol), Cu (32 mg, 0.5 mmol), CuI (50 mg,
0.25 mmol), and K3PO4$H2O (2.3 g, 10 mmol) and deanol
(7 ml) were added to a flask fitted with a magnetic stirbar, a
condenser and sealed with a septum. Air was removed and
replaced with nitrogen. The reaction mixture was stirred at
80 8C under nitrogen positive pressure until the 5-bromo-
2,20-bithiophene was consumed (36 h). After the reaction
cooled to room temperature, 50 ml of water was added and
the mixture was extracted with diethyl ether (3!60 ml).
The combined organic layers were then washed with brine
and dried over anhydrous MgSO4. Solvent was removed in
vacuum, and the residue was purified by flash chromato-
graphy on silica gel first eluted with hexane and then
hexane/ethyl acetate (97:3). The product was obtained as
yellow crystals, 0.78 g, 63% yield. Mp 59.8–60.0 8C
(hexane). Lit 59–60 8C.10 1H NMR (300 MHz, CDCl3) d
7.10–7.07 (m, 1H), 6.97–6.95 (m, 1H), 6.87 (d, JZ3.9 Hz,
1H), 5.98 (d, JZ3.9 Hz, 1H), 3.15 (t, JZ5.6 Hz, 4H), 1.76–
1.68 (m, 4H), 1.61–1.53 (m, 2H). 13C NMR (75 MHz,
CDCl3) d 159.21, 138.80, 127.74, 123.31, 122.55, 121.51,
105.16, 52.58, 25.38, 23.88. GC–MS (EI) 249.1 (MC, 100),
179.0 (25), 248.2 (24), 96.0 (24), 207.0 (20), 194.1 (20),
180.0 (19), 250.1 (18), 193.1 (18), 121.0 (16), 69.0 (14).
HRMS (EI) calcd for C13H16NS2: 250.0724 (MCHC),
found: 250.0708. IR (neat, cmK1) 3104, 3068, 2939, 2853,
2830, 1510, 1485, 1459, 1444, 1380, 1256, 1242, 1219,
1192, 1127, 1067, 1012, 860, 824, 809, 758, 692, 679.
3089, 3033, 2933, 2854, 2823, 1559, 1506, 1444, 1381,
1233, 1195, 1158, 1126, 1015, 886, 862, 840, 832, 758.
3.1.18.
5-(Piperidino)thiophene-2-carboxaldehyde
(Table 2, entry 14). 5-Bromo-2-thiophenecarboxaldehyde
(0.96 g, 5 mmol), piperidine (1.7 g, 20 mmol), Cu (32 mg,
0.5 mmol), CuI (50 mg, 0.25 mmol), and K3PO4$H2O
(2.3 g, 10 mmol) and deanol (10 ml) were added to a flask
fitted with a magnetic stirbar, a condenser and sealed with a
septum. Air was removed and replaced with nitrogen. The
reaction mixture was stirred at 65 8C under nitrogen positive
pressure until the 5-bromo-2-thiophenecarboxaldehyde was
consumed (up to 48 h). After the reaction cooled to room
temperature, 100 ml of water was added and the mixture
was extracted with diethyl ether (3!100 ml). The com-
bined organic layers were then washed with brine. Solvent
was removed in vacuum, and the residue was purified by
flash chromatography on silica gel eluted with hexane/ethyl
acetate (3:1). The product was obtained as orange crystals,
1
0.75 g, 77% yield. Mp 92.8–93.5 8C (hexane). H NMR
(300 MHz, CDCl3) d 9.51 (s, 1H), 7.47 (d, JZ4.4 Hz, 1H),
6.06 (d, JZ4.4 Hz, 1H), 3.34 (t, JZ5.5 Hz, 4H), 1.72–1.63
(m, 6H). 13C NMR (75 MHz, CDCl3) d 180.53, 168.63,
140.45, 126.75, 104.06, 51.07, 25.08, 23.68. GC–MS (EI)
195.1 (MC, 100), 194.1 (85), 138.0 (22), 196.1 (16), 166.2
(12), 154.1 (10), 111.1 (15), 180.1 (10). IR (neat, cmK1
)
3050, 3032, 2937, 2855, 2728, 1619, 1536, 1474, 1442,
1380, 1264, 1129, 1121, 1063, 1039, 1011, 890, 857, 763,
752, 742.
3.1.19. 2,5-Dipiperidinothiophene (compound 4). 2,5-
Dibromothiophene (2.90 g, 12 mmol), piperidine (6.0 g,
70 mmol), Cu (100 mg, 1.56 mmol), CuI (100 mg,
0.50 mmol), and K3PO4$H2O (11.0 g, 48 mmol) and deanol
(16 ml) were added to a flask fitted with a magnetic stirbar, a
3.1.21. 5,50-Dipe0ridino-2,20-bithiophene (compound 8).
5,50-Dibromo-2,2 -bithiophene (1.62 g, 5 mmol), piperidine
(1.62 g, 20 mmol), Cu (32 mg, 0.5 mmol), CuI (50 mg,
0.25 mmol), and K3PO4$H2O (4.6 g, 20 mmol) and deanol
(8 ml) were added to a flask fitted with a magnetic stirbar, a

Z. Lu, R. J. Twieg / Tetrahedron 61 (2005) 903–918
915
condenser and sealed with a septum. Air was removed and
replaced with nitrogen. The reaction mixture was stirred at
80 8C under0 nitrogen positive pressure until all the 5,50-
dibromo-2,2 -bithiophene (48 h) was consumed. After the
reaction cooled to room temperature, 50 ml of water was
added and the mixture was extracted with diethyl ether (3!
150 ml). The combined organic layers were then washed
with brine and dried over anhydrous MgSO4. Solvent was
removed in vacuum, and the residue was purified by flash
chromatography on silica gel first eluted with hexane an0d
then hexane/ethyl acetate (50:1 to 10:1). 5-Piperidino-2,2 -
bithiophene was isolated as a major product. It was obtaine0d
as yellow crystals, 0.68 g, 54.5% yield. The targeted 5,5 -
dipiperidino-2,20-bithiophene was also isolated as orange
crystals. Mp 189.6–190.0 8C (ethyl acetate). 0.24 g, 14.5%
reaction system and filled with nitrogen. The reaction
mixture was stirred at 80 8C for 40 h under nitrogen positive
pressure. After the reaction cooled to room temperature,
60 ml of water was added and the mixture was extracted
with diethyl ether (3!100 ml). The combined organic
layers were then washed with brine and dried over
anhydrous MgSO4. Solvent was removed in vacuo, and
the residue was purified by flash chromatography on silica
gel, eluted with hexane/triethylamine/EtOAc (94:2:4). The
product was obtained as a red-brown liquid (3.16 g, 86%
1
yield). H NMR (300 MHz, CDCl3) d 7.47–7.37 (m, 5H),
7.20 (dd, JZ5.2, 3.0 Hz, 1H), 6.68 (dd, JZ5.2, 1.7 Hz, 1H),
6.02 (dd, JZ3.0, 1.7 Hz, 1H), 4.31 (s, 2H), 4.03 (s, br, 1H).
13C NMR (75 MHz, CDCl3) d 148.70, 139.50, 128.82, 127.94,
127.53, 125.41, 120.14, 96.26, 50.83.MS(EI)(%) 189.1 (MC,
1
yield. H NMR (300 MHz, CDCl3) d 6.60 (s, br, 2H), 5.95
(s, br, 2H), 3.11 (s, br, 8H), 1.74–1.67 (m, 8H), 1.59–1.53
(m, 4H). (Note: The H NMR resonances of the aromatic
57), 91 (100), 188.1 (25), 65.0 (25), 50.7 (17). IR (neat, cmK1
)
3384, 3101, 3061, 3028, 2923, 2836, 1558, 1493, 1452, 1424,
1232, 1186, 1076, 1028, 864, 840, 800, 745, 697.
1
protons and the protons on the carbons connected to
nitrogen of the piperidine ring were either very broad or
sometimes disappeared entirely. The CDCl3 solution turns
red and eventually purple. The 13C NMR spectrum was
normal). 13C NMR (75 MHz, CDCl3) d 158.06, 124.90,
120.91, 105.24, 52.76, 25.47, 23.93. MS (ASCI) 333.2 (MC
1). Anal. Calcd C18H24N2S2: C, 65.02; H, 7.27; N, 8.42; S,
19.29. Found: C, 64.66; H, 7.40; N, 8.47; S, 19.33. HRMS
(EI) calcd for C18H24N2S2Na: 355.1279 (MCNa), found:
355.1284. IR (neat, cmK1) 3084, 3023, 2933, 2853, 2819,
1527, 1477, 1459, 1442, 1377, 1297, 1232, 1188, 1120,
1065, 1041, 1013, 892, 858, 822, 753.
3.1.24. 3-N-(Heptylamino)thiophene (Table 3, entry 3).
2-Bromothiophene (1.65 g, 10 mmol), n-heptylamine
(1.73 g, 15 mmol), Cu (32 mg, 0.5 mmol), CuI (100 mg,
0.5 mmol), K3PO4$H2O (4.6 g, 20 mmol) and deanol
(10 ml) were added to a flask fitted with a magnetic stirbar,
a condenser and sealed with a septum. Air was removed
from the reaction system and replaced with nitrogen. The
reaction mixture was stirred at 80 8C for 45 h under nitrogen
positive pressure. After the reaction cooled to room
temperature, 60 ml of water was added and the mixture
was extracted with diethyl ether (3!100 ml). The com-
bined organic layers were then washed with brine and dried
over anhydrous MgSO4. Solvent was removed in vacuo, and
the residue was purified by flash chromatography on silica
gel, eluted with hexane/triethylamine (98:2). The product
was obtained as a yellow liquid (1.6 g, 83% yield) that turns
red quickly on exposure to air. 1H NMR (300 MHz, CDCl3)
d 7.15 (dd, JZ5.2, 3.0 Hz, 1H), 6.62 (dd, JZ5.2, 1.7 Hz,
1H), 5.96 (dd, JZ3.0, 1.7 Hz, 1H), 3.59 (s, br, 1H), 3.08 (t,
JZ7.0 Hz, 2H), 1.66–1.59 (m, 2H), 1.44–1.29 (m, 8H), 0.92
(t, JZ7.0 Hz, 3H). 13C NMR (75 MHz, CDCl3) d 149.07,
125.18, 120.11, 95.36, 46.58, 32.03, 29.81, 29.36, 27.40,
22.82, 14.30. MS (EI) (%) 197.1 (MC, 27), 112.0 (100),
85.0 (23), 133.0 (13), 154.1 (8).
3.1.22. 3-N-(Butylamino)thiophene (Table 3, entry 1).
2-Bromothiophene (3.3 g, 20 mmol), n-butylamine (2.2 g,
30 mmol), Cu (64 mg, 1 mmol), CuI (190 mg, 1 mmol),
K3PO4$H2O (9.2 g, 40 mmol) and deanol (30 ml) were
added to a flask fitted with a magnetic stirbar, a condenser
and sealed with a septum. Air was removed from the
reaction system and replaced with nitrogen. The reaction
mixture was stirred at 80 8C for 36 h under nitrogen positive
pressure. After the reaction cooled to room temperature,
60 ml of water was added and the mixture was extracted
with diethyl ether (3!100 ml). The combined organic
layers were then washed with brine and dried over
anhydrous MgSO4. Solvent was removed in vacuo, and
the residue was purified by flash chromatography on silica
gel, eluted with hexane/triethylamine (98:2). The product
was obtained as a yellow liquid (2.54 g, 84.5% yield) that
3.1.25. 3-(Pyrrolidino)thiophene (Table 3, entry 4).15
3-Bromothiophene (1.65 g, 10 mmol), pyrrolidine (1.1 g,
150 mmol), Cu (32 mg, 0.5 mmol), CuI (100 mg,
0.5 mmol), K3PO4$H2O (4.6 g, 20 mmol) and deanol
(15 ml) were added to a flask fitted with a magnetic stirbar,
a condenser and sealed with a septum. Air was removed
from the reaction system and replaced with nitrogen. The
reaction mixture was stirred at 80 8C for 48 h under nitrogen
positive pressure. After the reaction cooled to room
temperature, 60 ml of water was added and the mixture
was extracted with diethyl ether (3!100 ml). The com-
bined organic layers were then washed with brine and dried
over anhydrous MgSO4. Solvent was removed in vacuo, and
the residue was purified by flash chromatography on silica
gel, eluted with hexane/ethylacetate (99:1). The product was
obtained as a yellow liquid (1.3 g, 85% yield) that turns red
on exposure to air. 1H NMR (300 MHz, CDCl3) d 7.22 (dd,
JZ5.2, 3.0 Hz, 1H), 6.72 (dd, JZ3.0, 1.7 Hz, 1H), 5.81 (dd,
JZ5.2, 1.7 Hz, 1H), 3.28–3.24 (m, 4H), 2.01–1.97 (m, 4H).
1
turns red quickly on exposure to air. H NMR (300 MHz,
CDCl3) d 7.16 (dd, JZ5.2, 3.0 Hz, 1H), 6.62 (dd, JZ5.2,
1.7 Hz, 1H), 5.95 (dd, JZ3.0, 1.7 Hz, 1H), 3.56 (s, br, 1H),
3.08 (t, JZ7.0 Hz, 2H), 1.67–1.57 (m, 2H), 1.50–1.38 (m,
2H), 0.97 (t, JZ7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3) d
149.07, 125.18, 120.07, 95.39, 46.24, 31.90, 20.50, 14.08.
MS (EI) (%) 155.1 (MC, 26), 112.0 (100), 85.0 (27), 50.8
(14), 113.1(11). IR(neat)3390, 3101, 2957, 2928, 2861, 1560,
1478, 1425, 1366, 1229, 1191, 1077, 868, 834, 743, 623.
3.1.23. 3-(N-Benzylamino)thiophene (Table 3, entry 2).
2-Bromothiophene (3.3 g, 20 mmol), benzylamine (3.2 g,
30 mmol), Cu (64 mg, 1 mmol), CuI (190 mg, 1 mmol),
K3PO4$H2O (9.2 g, 40 mmol) and deanol (30 ml) were
added to a flask fitted with a magnetic stirbar, a condenser
and sealed with a septum. Air was removed from the

916
Z. Lu, R. J. Twieg / Tetrahedron 61 (2005) 903–918
13C NMR (75 MHz, CDCl3) d 149.99, 125.20, 118.66,
93.88, 49.99, 25.47. MS (EI) 153.1 (MC, 63), 152.1 (100),
97.0 (31), 110.1 (27), 154.0 (11). IR (neat, cmK1) 3106,
2967, 2884, 2823, 1552, 1487, 1460, 1426, 1398, 1356,
1286, 1217, 1171, 1150, 1085, 997, 846, 737, 616.
(10 ml) were added to a flask fitted with a magnetic stirbar, a
condenser and sealed with a septum. Air was removed and
replaced with nitrogen. The reaction mixture was stirred at
85 8C under nitrogen positive pressure for 60 h. After the
reaction cooled to room temperature, 150 ml of water was
added and the mixture was extracted with diethyl ether (3!
150 ml). The combined organic layers were then washed
with brine. Solvent was removed in vacuum, and the residue
was purified by silica gel column and eluted with hexane
and hexane: ethyl acetate (50:1). The product was obtained
as a liquid, 0.24 g, 15% yield. 1H NMR (300 MHz, CDCl3)
d. 13C NMR (75 MHz, CDCl3) d 7.20 (dd, JZ3.0, 5.2 Hz,
1H), 6.77 (dd, JZ1.7, 5.2 Hz, 1H), 5.90 (dd, JZ1.7, 3.0 Hz,
1H), 3.25 (q, JZ7.0 Hz, 4H), 1.13 (t, JZ1.13 Hz). 13C
NMR (75 MHz, CDCl3) d 150.12, 124.00, 119.33, 95.95,
45.73, 12.48. GC–MS (EI) 155.1 (MC, 50), 140.1 (100),
112.0 (68), 85.0 (25), 110.0 (25), 97.1 (9). IR (neat, cmK1).
3112, 2969, 2930, 2897, 2870, 1547, 1460, 1447, 1427,
1375, 1362, 1347, 1290, 1255, 1228, 1177, 1137, 1115,
1090, 1076, 1017, 950, 849, 781, 738, 640.
3.1.26. 3-(Piperidino)thiophene (Table 3, entry 5).55
2-Bromothiophene (3.3 g, 20 mmol), piperidine (2.6 g,
30 mmol), Cu (64 mg, 1 mmol), CuI (190 mg, 1 mmol),
K3PO4$H2O (9.2 g, 40 mmol) and deanol (30 ml) were
added to a flask with a magnetic stirbar, a condenser and
sealed with a septum. Air was removed from the reaction
system and replaced with nitrogen. The reaction mixture
was stirred at 80 8C for 40 h under nitrogen positive
pressure. After the reaction cooled to room temperature,
60 ml of water was added and the mixture was extracted
with diethyl ether (3!100 ml). The combined organic
layers were then washed with brine and dried over
anhydrous MgSO4. Solvent was removed in vacuo, and
the residue was purified by flash chromatography on silica
gel, eluted with hexane/triethylamine/EtOAc (92:2:6). The
product was obtained as a yellow liquid (2.38 g, 73.3%
3.1.29. 3-[N-Methyl-(N-2-hydroxy)amino]thiophene
(Table 3, entry 8). 3-Bromothiophene (1.65 g, 10 mmol),
2-(methylamino)ethanol 15 ml (also solvent), Cu metal
(K45 mm powder, 32 mg, 0.5 mmol), CuI (100 mg,
0.5 mmol), and K3PO4$H2O (4.6 g, 20 mmol) were added
to a flask with a magnetic stirbar, a condenser and sealed
with a septum. The reaction mixture was stirred at 80 8C for
24 h under nitrogen positive pressure. After the reaction
cooled to room temperature, 20 ml of water was added and
the mixture was extracted with diethyl ether (3!150 ml).
The combined organic layers were then washed with brine
and dried over anhydrous MgSO4. Solvent was removed in
vacuo, and the residue was purified by flash chromatography
on silica gel eluted with hexane/EtOAc (1:1). The product
was obtained as a liquid, 1.40 g, 90% yield. 1H NMR
(300 MHz, CDCl3) d 7.21 (dd, JZ5.2, 3.0 Hz, 1H), 6.81
(dd, JZ5.2, 1.7 Hz, 1H), 6.02 (dd, JZ3.0, 1.7 Hz, 1H), 3.74
(t, JZ5.5 Hz, 2H), 3.31 (t, JZ5.5 Hz, 2H), 2.87 (s, 3H),
2.36 (s, br, 1H). 13C NMR (75 MHz, CDCl3) d 152.26,
125.54, 119.62, 97.67, 59.97, 57.24, 40.06. MS (EI) 157.0
(22), 126.1 (100), 97.2 (14), 93.2 (13), 93.1 (12), 110.1 (12),
65.2 (11). IR (neat, cmK1) 3355, 3110, 2946, 2873, 2797,
1548, 1448, 1431, 1413, 1393, 1261, 1169, 1121, 1086,
1066, 1042, 986, 939, 864, 845, 830, 805, 742, 629.
1
yield). H NMR (300 MHz, CDCl3) d 7.22 (dd, JZ5.2,
3.0 Hz, 1H), 6.89 (dd, JZ5.2, 1.7 Hz, 1H), 6.18 (dd, JZ3.0,
1.7 Hz, 1H), 3.07 (t, JZ7.0 Hz, 4H), 1.76–1.68 (m, 4H),
1.60–1.52 (m, 2H). 13C NMR (75 MHz, CDCl3) d 153.53,
125.13, 120.70, 100.14, 51.93, 25.82, 24.27. MS (EI) (%)
167.1 (MC, 65), 166.1 (100), 110.0 (36), 138.1 (18), 152.1
(14), 111.1 (13), 168.1 (12). IR (neat) 3112, 2933, 2853,
2802, 1538, 1450, 1421, 1385, 1255, 1216, 1190, 1132,
1088, 959, 882, 866, 837, 799, 749, 677.
3.1.27. 3-(Morpholino)thiophene (Table 3, entry 6).20
3-Bromothiophene (1.65 g, 10 mmol), morpholine (1.5 g,
30 mmol), Cu (32 mg, 0.5 mmol), CuI (100 mg, 0.5 mmol),
K3PO4$H2O (4.6 g, 20 mmol) and deanol (15 ml) were
added to a flask fitted with a magnetic stirbar, a condenser
and sealed with a septum. Air was removed from the
reaction system and replaced with nitrogen. The reaction
mixture was stirred at 80 8C for 40 h under nitrogen positive
pressure. After the reaction cooled to room temperature,
60 ml of water was added and the mixture was extracted
with diethyl ether (3!100 ml). The combined organic
layers were then washed with brine and dried over
anhydrous MgSO4. Solvent was removed in vacuo, and
the residue was purified by flash chromatography on silica
gel, eluted with hexane/triethylamine/EtOAc (92:2:6). The
product was obtained as a yellow liquid (0.4 g, 23% yield).
1H NMR (300 MHz, CDCl3) d 7.26 (dd, JZ5.2, 3.0 Hz,
1H), 6.86 (dd, JZ5.2, 1.7 Hz, 1H), 6.20 (dd, JZ3.0, 1.7 Hz,
1H), 3.84 (t, JZ5.0 Hz, 4H), 3.09 (t, JZ5.0 Hz 4H). 13C
NMR (75 MHz, CDCl3) d 152.59, 125.74, 119.77, 100.58,
66.82, 50.90. MS (EI) (%) 169.1 (MC, 90), 100.0 (100),
111.0 (94), 154.0 (63), 84 (20), 112.1 (17), 170.1 (10).
HRMS (EI) calcd for C8H12NOS: 170.0639 (MCHC),
found: 170.0639. IR (neat, cmK1) 3112, 2933, 2853, 2802,
1538, 1450, 1421, 1385, 1255, 1216, 1190, 1132, 1088, 959,
882, 866, 837, 799, 749, 677.
3.1.30. 3-[N-Ethyl-(NK2-hydroxy)amino]thiophene
(Table 3, entry 9). 3-Bromothiophene (1.65 g, 10 mmol),
2-(ethylamino)ethanol 15 ml (also solvent), Cu metal
(K45 mm powder, 32 mg, 0.5 mmol), CuI (100 mg,
0.5 mmol), and K3PO4$H2O (4.6 g, 20 mmol) were added
to a flask with a magnetic stirbar, a condenser and sealed
with a septum. The reaction mixture was stirred at 80 8C for
45 h under nitrogen positive pressure. After the reaction
cooled to room temperature, 20 ml of water was added and
the mixture was extracted with diethyl ether (3!150 ml).
The combined organic layers were then washed with brine
and dried over anhydrous MgSO4. Solvent was removed in
vacuo, and the residue was purified by flash chromatography
on silica gel eluted with hexane/EtOAc (1:1). The product
was obtained as a yellow liquid (0.75 g, 45% yield) that
turns brown quickly on exposure to air. 1H NMR (300 MHz,
CDCl3) d 7.20 (dd, JZ5.2, 3.0 Hz, 1H), 6.79 (dd, JZ5.2,
3.1.28. 3-Diethylaminothiophene (Table 3, entry 7).13
3-Bromothiophene (1.63 g, 10 mmol), diethylamine
(2.95 g, 40 mmol), Cu (190 mg, 3 mmol), CuI (100 mg,
0.5 mmol), and K3PO4$H2O (4.6 g, 20 mmol) and deanol

Z. Lu, R. J. Twieg / Tetrahedron 61 (2005) 903–918
917
3. Fevig, T. L.; Phillips, W. G.; Lau, P. H. J. Org. Chem. 2001,
66, 2493–2497.
1.7 Hz, 1H), 5.99 (dd, JZ3.0, 1.7 Hz, 1H), 3.73 (t, JZ
5.5 Hz, 2H), 3.33–3.27 (m, 4H), 2.33 (s, br, 1H), 1.12 (t, JZ
7.0 Hz, 3H). 13C NMR (75 MHz, CDCl3) d 150.14, 125.34,
4. Wu¨rthner, F.; Yao, S.; Debaerdemaeker, T.; Wortmann, R.
J. Am. Chem. Soc. 2002, 124, 9431–9447.
119.71, 97.54, 60.08, 54.23, 47.55, 11.97. IR (neat, cmK1
)
3357, 3115, 2968, 2931, 2872, 1547, 1425, 1374, 1257,
1166, 1129, 1072, 1045, 1009, 845, 784, 739, 634. MS (EI)
(%) 171.1 (MC, 19.5), 140.0 (100), 112.0 (53), 50.8 (39.0),
85.1 (23.1) 110.0 (17.5).
5. Kiryanov, A. A.; Seed, A. J.; Sampson, P. Tetrahedron Lett.
2001, 42, 8797–8800.
6. Jen, A. K. Y.; Rao, V. P.; Wong, K. Y.; Drost, K. J. J. Chem.
Soc., Chem. Commun. 1993, 90–92.
7. Heyde, C.; Zug, I.; Hartmann, H. Eur. J. Org. Chem. 2000,
3273–3278.
3.1.31.
4-(Piperidino)thiophene-2-carboxaldehyde
(Table 3, entry 10). 4-Bromo-2-thiophenecarboxaldehyde
(0.96 g, 5 mmol), piperidine (1.7 g, 20 mmol), Cu metal
(32 mg, 0.5 mmol), CuI (50 mg, 0.25 mmol), and
K3PO4$H2O (2.3 g, 10 mmol) and deanol (10 ml) were
added to a flask fitted with a magnetic stirbar, a condenser
and sealed with a septum. Air was removed and replaced
with nitrogen. The reaction mixture was stirred at 65–75 8C
under nitrogen positive pressure until 4-bromo-2-thio-
phenecarboxaldehyde was consumed (up to 72 h). After
the reaction cooled to room temperature, 100 ml of water
was added and the mixture was extracted with diethyl ether
(3!100 ml). The combined organic layers were then
washed with brine. Solvent was removed in vacuo, and
the residue was purified by flash chromatography on silica
gel eluted with hexane/ethyl acetate (3:1). The product was
obtained as a liquid, 0.50 g, 53% yield. 1H NMR (300 MHz,
CDCl3) d 9.81 (d, JZ1, 2 Hz, 1H), 7.51 (d, JZ1.9 Hz, 1H),
6.62–6.61 (m, 1H), 3.09 (t, JZ5.5 Hz, 4H), 1.75–1.66 (m,
4H),1.60–1.52(m, 2H).13CNMR(75 MHz,CDCl3)d183.17,
154.03, 142.33, 127.79, 110.40, 51.41, 25.56, 23.98. GC–MS
(EI) 195.1 (MC, 86), 194.1 (100), 138.1 (30), 139.0 (16),
166.1 (16), 196.1 (12). IR (neat, cmK1) 3320, 3103, 2935,
2852, 2809, 1663, 1547, 1439, 1386, 1365, 1248, 1227, 1177,
1120, 1045, 1028, 976, 885, 861, 831, 803, 728, 667.
8. Tarasova, O. A.; Klyba, L. V.; Vvedensky, V. Y.; Nedolya,
N. A.; Trofimov, B. A.; Brandsma, L.; Verkruijsse, H. D. Eur.
J. Org. Chem. 1998, 253–256.
9. Pinto, I. L.; Jarvest, R. L.; Serafinowska, H. T. Tetrahedron
Lett. 2000, 41, 1597–1600.
10. Manuela, M.; Raposo, M.; Kirsch, G. Heterocycles 2001, 55,
1487–1498.
11. Norris, R. K. Aminothiophenes and their Derivatives in
Thiophene and its Derivatives. In Gronowitz, S., Ed.; The
Chemistry of Heterocyclic Compounds; Wiley: New York,
1985; Vol. 44, pp 631–799; part 2.
12. Reinecke, M. G.; Adickes, H. W. J. Am. Chem. Soc. 1968, 90,
511–513.
13. Outurquin, F.; Lerouge, P.; Paulmier, C. Bull. Soc. Chim. Fr.
1986, 259–266.
14. Prim, D.; Kirsch, G. Tetrahedron 1999, 55, 6511–6526.
¨
15. Hartmann, H.; Scheithauer, S. J. fur Prakt. Chem. (Leipzig)
1969, 311, 827–843.
16. Bernardi, P.; Dembech, P.; Fabbri, G.; Ricci, A.; Seconi, G.
J. Org. Chem. 1999, 64, 641–643.
17. Cane, F.; Brancaleoni, D.; Dembech, P.; Ricci, A.; Seconi, G.
Synthesis 1997, 545–548.
18. Watanabe, M.; Yamamoto, T.; Nishiyama, M. Chem. Com-
mun. 2000, 133–134.
19. Crawford, K. R.; Padwa, A. Tetrahedron Lett. 2002, 43,
7365–7368.
Acknowledgements
20. Hooper, M. W.; Utsunomiya, M.; Hartwig, J. F. J. Org. Chem.
2003, 68, 2861–2873.
Z.K.L. thanks Dr. S. D. Huang for support and Kent State
University for a University Fellowship. The assistance with
some NMR, MS and elemental analysis experiments
provided by Dr. M. Gangoda is greatly appreciated.
21. Binder, D.; Habison, G.; Noe, C. R. Synthesis 1977, 255–256.
22. Wu¨rthner, F. Synthesis 1999, 2103–2113.
23. Yamamoto, H.; Maruoka, K. J. Org. Chem. 1980, 45,
2739–2740.
24. Whitesides, G. M.; San Filippo, J. Jr.; Casey, C. P.; Panek, E. J.
J. Am. Chem. Soc. 1967, 89, 5302–5303.
25. Hartwig, J. F. In Handbook of Organopalladium Chemistry for
Organic Synthesis, 2002; Vol. 1, pp 1051–1096.
26. Muci, A. R.; Buchwald, S. L. In Cross-Coupling Reactions;
Springer: Berlin, 2002; Vol. 219; pp 131–209.
27. Ogawa, K.; Radke, K. R.; Rothstein, S. D.; Rasmussen, S. C.
J. Org. Chem. 2001, 66, 9067–9070.
Supplementary data
Copies of H and 13C NMR spectra for all new and some
known compounds are provided.
1
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tet.2004.11.017
28. Luker, T. J.; Beaton, H. G.; Whiting, M.; Mete, A.; Cheshire,
D. R. Tetrahedron Lett. 2000, 41, 7731–7735.
29. For recent reviews, see: (a) Kunz, K.; Scholz, U.; Ganzer, D.
Synlett 2003, 2428–2439. (b) Ley, S. V.; Thomas, A. W.
Angew. Chem. Int. Ed. 2003, 42, 5400–5449.
30. Bedworth, P. V.; Cai, Y. M.; Jen, A.; Marder, S. R. J. Org.
Chem. 1996, 61, 2242–2246.
References and notes
1. Matsuno, K.; Nakajima, T.; Ichimura, M.; Giese, N. A.; Yu,
J. C.; Lokker, N. A.; Ushiki, J.; Ide, S. I.; Oda, S.; Nomoto, Y.
J. Med. Chem. 2002, 45, 4513–4523.
31. King, F. D.; Walton, D. R. M. J. Chem. Soc., Chem. Commun.
1974, 256–257.
32. Padwa, A.; Crawford, K. R.; Rashatasakhon, P.; Rose, M.
J. Org. Chem. 2003, 68, 2609–2617.
33. Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2003, 5, 793–796.
2. Beers, S. A.; Malloy, E. A.; Wu, W.; Wachter, M.; Ansell, J.;
Singer, M.; Steber, M.; Barbone, A.; Kirchner, T.; Ritchie, D.;
Argentieri, D. Bioorg. Med. Chem. 1997, 5, 779–786.

918
Z. Lu, R. J. Twieg / Tetrahedron 61 (2005) 903–918
34. Lu, Z.; Twieg, R. J.; Huang, S. D. Tetrahedron Lett. 2003, 44,
6289–6292.
45. Lam, P. Y. S.; Deudon, S.; Averill, K. M.; Li, R. H.; He, M. Y.;
DeShong, P.; Clark, C. G. J. Am. Chem. Soc. 2000, 122,
7600–7601.
35. Jiang, L.; Job, G. E.; Klapars, A.; Buchwald, S. L. Org. Lett.
2003, 5, 3667–3669.
46. Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Averill,
K. M.; Chan, D. M. T.; Combs, A. Synlett 2000, 674–676.
47. Collman, J. P.; Zhong, M.; Zhang, C.; Costanzo, S. J. Org.
Chem. 2001, 66, 7892–7897.
36. Huang, X. H.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapars,
A.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 6653–6655.
37. Brandsma, L.; Vvedensky, V. Y.; Nedolya, N. A.; Tarasova,
O. A.; Trofimov, B. A. Tetrahedron Lett. 1998, 39,
2433–2436.
48. Cohen, T.; Cristea, I. J. Am. Chem. Soc. 1976, 98, 748–753.
49. Lockhart, T. P. J. Am. Chem. Soc. 1983, 105, 1940–1946.
50. Ribas, X.; Jackson, D. A.; Donnadieu, B.; Mahia, J.; Parella,
T.; Xifra, R.; Hedman, B.; Hodgson, K. O.; Llobet, A.; Stack,
T. D. P. Angew. Chem. Int. Ed. 2002, 41, 2991–2994.
51. DuBois, J. L.; Mukherjee, P.; Stack, T. D. P.; Hedman, B.;
Solomon, E. I.; Hodgson, K. O. J. Am. Chem. Soc. 2000, 122,
5775–5787.
38. Eck, D. L.; Stacy, G. W. J. Heterocycl. Chem. 1969, 6,
147–151.
39. Lupo, D.; Ringsdorf, H.; Schuster, A.; Seitz, M. J. Am. Chem.
Soc. 1994, 116, 10498–10506.
¨ ¨
40. Gotz, G.; Scheib, S.; Klose, R.; Heinze, J.; Bauerle, P. Adv.
Funct. Mater. 2002, 12, 723–728.
41. Chun, H.; Moon, I. K.; Shin, D. H.; Song, S.; Kim, N. J. Mater.
Chem. 2002, 12, 858–862.
52. Woodward, S. Chem. Soc. Rev. 2000, 29, 393–401.
¨
¨ ¨
53. Bauerle, P.; Wurthner, F.; Gotz, G.; Effenberger, F. Synthesis
42. Dapperheld, S.; Feldhues, M.; Litterer, H.; Sistig, F.; Wegener,
P. Synthesis 1990, 403–405.
1993, 1099–1103.
54. Ikemoto, N.; Estevez, I.; Nakanishi, K.; Berova, N. Hetero-
cycles 1997, 46, 489–501.
¨
55. Scheithauer, S.; Hartmann, H.; Mayer, R. Zeitschrift fuer
43. Hassan, J.; Lavenot, L.; Gozzi, C.; Lemaire, M. Tetrahedron
Lett. 1999, 40, 857–858.
44. Arnauld, T.; Barton, D. H. R.; Doris, E. Tetrahedron 1997, 53,
4137–4144.
Chemie 1968, 8, 181–183.