Copper- and Cobalt-Catalyzed Syntheses of Thiophene-Based Tertiary Amines

Article abstract of DOI:10.1002/ejoc.201900276

Thienylzinc halides and related compounds prepared by deprotonation followed by transmetalation were used in copper-catalyzed amination using N-benzoyloxy secondary amines. By extending the reaction to 1,5-naphthyridine, it was showed that the competitive dimer formation observed in the case of thiophenes was linked with the low stability of some thienylamines rather than homocoupling. Interestingly, thienylzinc halides and related compounds prepared by transmetalation of thienylmagnesium halides, either prepared from their bromo-precursors or generated by deprotometalation, were satisfactorily employed in cobalt-catalyzed aminations. Finally, aminothiophenes were involved in copper-catalyzed mono- and di-N-arylations, affording differently substituted di- and triphenylamines.

Full text of DOI:10.1002/ejoc.201900276

A Journal of
Accepted Article
Title: Copper- and Cobalt-Catalyzed Syntheses of Thiophene-Based
Tertiary Amines
Authors: Salima BOUARFA, Simon Graβl, Maria Ivanova, Timothy
Langlais, Ghenia Bentabed-Ababsa, Frédéric LASSAGNE,
William ERB, Thierry ROISNEL, Vincent DORCET, Paul
KNOCHEL, and Florence Mongin
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using the Digital Object Identifier (DOI) given below. The VoR will be
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the VoR from the journal website shown below when it is published
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content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900276
Link to VoR: http://dx.doi.org/10.1002/ejoc.201900276
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10.1002/ejoc.201900276
European Journal of Organic Chemistry
FULL PAPER
Copper- and Cobalt-Catalyzed Syntheses of Thiophene-Based
Tertiary Amines
Salima Bouarfa,[a,b] Simon Graβl,[c] Maria Ivanova,[c] Timothy Langlais,[a,c] Ghenia Bentabed-Ababsa,*[b]
Frédéric Lassagne,[a] William Erb,[a] Thierry Roisnel,[a] Vincent Dorcet,[a] Paul Knochel*[c] and Florence
Mongin*[a]
Abstract: Thienylzinc halides and related compounds prepared by
deprotonation followed by transmetalation were used in copper-
catalyzed amination using N-benzoyloxy secondary amines. By
extending the reaction to 1,5-naphthyridine, it was showed that the
competitive dimer formation observed in the case of thiophenes was
linked with the low stability of some thienylamines rather than
homocoupling. Interestingly, thienylzinc halides and related
compounds prepared by transmetalation of thienylmagnesium
halides, either prepared from their bromo-precursors or generated by
deprotometalation, were satisfactorily employed in cobalt-catalyzed
aminations. Finally, aminothiophenes were involved in copper-
catalyzed mono- and di-N-arylations, affording differently substituted
di- and triphenylamines.
preferred over cyclizations of suitable substrates. As a
consequence, efficient methods to regio- and chemoselectively
introduce substituents onto thiophenes and related compounds
are required.
From the perspective of the pharmaceutical industry, one
current challenge of organic synthesis remains the introduction
of amines into drug molecules, if possible through C-H bond
activation, and more generally by formation of C-N bonds.[2]
Heteroaromatic C(sp2)-N bonds can be formed by transition
metal-catalyzed couplings from the corresponding halides,[3]
either using palladium-[4] or copper-catalysts.[5] Two
complementary approaches have since been developed for the
direct functionalization of heteroarenes,[6] oxidative reactions in
the presence of a suitable metal catalyst-oxidant combination,[7]
and
transition
metal-catalyzed
electrophilic
amination
reactions.[8]
Introduction
Among the methods used to introduce aliphatic amines onto
thiophenes, the oxidative nucleophilic substitution of hydrogen
has been described but remains limited to specific nitro
compounds;[9] therefore, most of the studies follow one of the
above-mentioned strategies. Zinc amidocuprates formed from
thienylzincs and lithium amides were involved in copper(I)-
mediated oxidative aminations.[10] Owing to a picolinamide
directing group, morpholine can be introduced onto thiophene in
Electron-rich thiophenes and related compounds are an
important class of five-membered aromatic heterocycles, notably
for various applications in the fields of medicinal chemistry and
materials.[1] Thiophene for example is found in the skeleton of
important pharmaceuticals such as duloxetine and olanzapine,
which respectively target major depressive disorder and
schizophrenia, and dorzolamide, an anti-glaucoma agent. The
thiophene scaffold is also present in many organic materials
among which we can cite light-emitting diodes, field effect
transistors and solar cells.[1] To access these aforementioned
scaffolds, the functionalization of thiophenes is in general
the presence of
a copper(II)-catalyst and PhI(OAc)2 as
oxidant.[11] The in situ formation of diaryl-λ3-iodanes followed by
copper(I)-catalyzed reaction with morpholine can be similarly
applied to thiophene in average yields.[12] Provided that a
carboxamide group is present, ruthenium(II)-catalyzed C-H
amination of thiophenes can be performed with N-
(benzoyloxy)morpholine in moderate yields.[13] The use of O-
benzoyl hydroxylamines (BzO-NR2) to intercept thienylmetals
under copper(I)-catalysis displays a broader substrate scope,
and has been developed from arylmetals prepared by C-H
[a]
[b]
[c]
S. Bouarfa, T. Langlais, F. Lassagne, Dr. W. Erb, Dr. T. Roisnel,
Dr. V. Dorcet, Prof. F. Mongin
Univ Rennes, CNRS, ISCR (Institut des Sciences Chimiques de
Rennes) - UMR 6226
F-35000 Rennes, France
lithiation-transalumination[14]
deprotozincation.[15]
and,
above
all,
by
E-mail: florence.mongin@univ-rennes1.fr
https://iscr.univ-rennes1.fr/corint/florence-mongin
S. Bouarfa, Prof. G. Bentabed-Ababsa
Laboratoire de Synthèse Organique Appliquée
Faculté des Sciences Exactes et Appliquées
Université Oran1 Ahmed Ben Bella, BP 1524 El M’Naouer
31000 Oran, Algeria
If copper was employed as catalyst in the Johnson
pioneered electrophilic amination of diarylzincs by BzO-NR2 in
2004,[16] cobalt can also be used to catalyze amination of
arylzincs.[8b] Indeed, we recently showed that both arylzinc
pivalates[17] and chlorides[18] can be involved in such an
amination in the presence of cobalt salts. In the present paper,
we report our studies on copper- and cobalt-catalyzed reactions
involving thienylzincs and O-benzoyl secondary hydroxylamines.
Our investigations on the copper-catalyzed mono and double N-
arylation of thienylamines by aromatic iodides to access
thiophene-based triarylamines are also presented.
E-mail: badri_sofi@yahoo.fr
https://scholar.google.com/citations?user=7c5-Bw8AAAAJ&hl=fr
S. Gral, Dr. M. Ivanova, T. Langlais, Prof. Dr. Paul Knochel
Department Chemie
Ludwig-Maximilians-Universitꢀt Mꢁnchen
Butenandtstrasse 5-13, Haus F, 81377 Mꢁnchen, Germany
E-mail: paul.knochel@cup.uni-muenchen.de
http://www.knochel.cup.uni-muenchen.de/
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201900276
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Results and Discussion
catalytic amount of copper(II) acetate. Under these conditions,
the expected product 1a was isolated in 51-52% yield in spite of
its propensity to turn into 2,2’-bi(benzothiophene) (1’; entries 1
and 2). These results suggest that lithium chloride and TMEDA,
that are both present, do not hamper the reaction. In contrast,
attempts to directly use benzothienyllithium (formed by reaction
with LiTMP) instead of the corresponding zinc compound did not
furnish 1a (entry 3). The presence of the electrophile and
catalyst during the addition of the base to the substrate similarly
We first studied a ‘deprotolithiation-transmetalation to zinc-
copper catalyzed amination’ sequence in THF (THF
tetrahydrofuran) by starting from benzothiophene (Table 1). In
order to generate the corresponding arylzinc halide, we
=
compared
deprotolithiation
ZnCl2·TMEDA[19]
two
methods,
followed
(TMEDA
(i)
butyllithium-mediated
by
transmetalation
using
N,N,N’,N’-
=
failed
(entry
4).
N-(benzoyloxy)dibutylamine,
N-
tetramethylethylenediamine; entry 1) and (ii) deprotolithiation
(benzoyloxy)morpholine and N-(benzoyloxy)piperidine were
used under the best reaction conditions to afford the expected
benzothienylamines 1b-d (entries 5-7; Figure 1, top).
using LiTMP (TMP
= 2,2,6,6-tetramethylpiperidino) in the
presence of ZnCl2·TMEDA as in situ trap (entry 2).[20] Amination
was next performed by using N-(benzoyloxy)diallylamine and a
Table 1. Optimization of the conversion of benzothiophene into 2-benzothienylamines 1.
Entry
1
Base (equiv), conditions
1) BuLi (1), ‒20 °C, 0.5 h
Product 1, Yield [%][a]
1a, 51[b]
2) ZnCl2·TMEDA (1), ‒20 °C, 0.5 h
1) ZnCl2·TMEDA (1)
2
1a, 52[b]
2) LiTMP (1), ‒20 °C, 0.5 h
3
4
1a, 0[c]
1a, 0[d]
LiTMP (1), ‒20 °C, 0.5 h
LiTMP (1) added to the solution of benzothiophene,
(allyl)2N-OCOPh and Cu(OAc)2 in THF, ‒20 °C, 0.5 h
1) BuLi (1), ‒20 °C, 0.5 h
5
1b, 63[b]
2) ZnCl2·TMEDA (1), ‒20 °C, 0.5 h
1) BuLi (1), ‒20 °C, 0.5 h
6
7
1c, 29[b]
1d, 68[b]
2) ZnCl2·TMEDA (1), ‒20 °C, 0.5 h
1) BuLi (1), ‒20 °C, 0.5 h
2) ZnCl2·TMEDA (1), ‒20 °C, 0.5 h
[a] After purification (see experimental part). [b] 2,2’-Bi(benzothiophene) (1’) was detected in the crude and proved to be
more or less difficult to separate, depending on both the polarity and the stability of the product 1. [c] Benzothiophene was
present in the crude (<20% yield) together with an unidentified product, but 1’ was not detected. [d] Benzothiophene was
present in the crude together with the same unidentified product.
Scheme 1. Extension of the sequence to 2-chlorothiophene and proposed mechanism to rationalize the degradation of 2a. [a] 5,5’-
Dichloro-2,2’-bithiophene (2a’) was also isolated in 32% yield.
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When the reaction was extended to 2-chlorothiophene, we
isolated both the expected diallylamine 2a in 49% yield and the
dimer 2a’ in 32% yield (Scheme 1). Interestingly we observed
that, upon storage in a fridge, isolated 2a turns dark blue in a
few days (or in a few minutes if dissolved in chloroform) while it
is converted into the dimer 2a’. This result tends to show that
dimerization is not related to a side homocoupling taking place in
the course of the reaction, but rather associated with the
thienylamine instability.[21] We thus decided to move to a
substrate for which the corresponding amines are stable.
The 1,5-naphthyridine heterocycle is present in numerous
compounds endowed with biological properties as well as in
OLED materials.[22] Besides direct introduction of an amino
group by a Chichibabin reaction,[23] its functionalization at C4
can be achieved by deprotometalation. The latter was performed
by using a lithium amide provided that a directing group is
present at C3.[24] However, from bare 1,5-naphthyridine, a
regioselective reaction at C4 was found possible after
precomplexation of the substrate with (TMP)2Mg·2LiCl, and
takes place in THF within 5 min at ‒78 °C.[22] In order to prepare
amines (Table 2), we first evaluated the ‘deprotolithiation-
transmetalation to zinc-copper catalyzed amination’ sequence,
this failure, we tested iodine as electrophile, and obtained the 4-
iodo 3-I and 4,8-diiodo 3’-I in respective yields of 34 and 6%
alongside with remaining starting material (Scheme 2, left).
Concerned by the potential low stability of the intermediate 4-
lithio compound, we next moved to more stable zinc amides.
After deprotozincation using TMPZnCl·LiCl[25] (1.1 equiv) at
room
temperature
for
2 h,
interception
with
N-
(benzoyloxy)diallylamine as before led to 3a in 64% yield (entry
3), a rather good result since trapping with iodine afforded 3-I in
72% yield (Scheme 2, left). (TMP)2Zn·2LiCl, prepared from
LiTMP and ZnCl2 in a 2:1 ratio, was similarly employed and
furnished the amine 3c after copper-catalyzed reaction with N-
(benzoyloxy)morpholine (entry 4). Interestingly, a magnesium
intermediate generated by TMPMgCl·LiCl[26] is tolerated,[27] as
evidenced by quenching with N-(benzoyloxy)diisopropylamine to
afford the amine 3b in 52% yield (entry 5).
Alternatively, the synthesis of the amines 3a-c can be
considered by nucleophilic substitution of the iodo 3-I. If such a
possibility efficiently worked by using morpholine as nucleophile,
the yield dropped to 17% with diallylamine, and the reaction
failed with diisopropylamine, a result probably due to important
steric hindrance in this case (Scheme 2, right). Thus,
deprotometalation-amination and deprotometalation-iodolysis-
substitution appear as being complementary to access 1,5-
naphthyridines 4-substituted by various amino groups.
successful
from
benzothiophene,
by
using
N-
(benzoyloxy)diallylamine as electrophile. However, under these
conditions, the expected amine 3a was isolated in a maximum
10% yield (entries 1 and 2). In order to understand the reason of
Table 2. Extension to 1,5-naphthyridine.
Entry
1
Base (equiv), conditions
Product 3, Yield [%][a]
1) ZnCl2·TMEDA (1)
3a, 0[b]
2) LiTMP (1.2), ‒30 °C, 0.5 h
1) ZnCl2·TMEDA (1)
2[c]
3
3a, 10[b]
3a, 64
2) LiTMP (2.2), ‒30 °C, 0.5 h
TMPZnCl·LiCl (1.1), r.t., 2 h
4
5
(TMP)2Zn·2LiCl (1.1), r.t., 2 h
3c, 52
3b, 52
TMPMgCl·LiCl (1.1), ‒40 °C, 1 h
[a] After purification (see experimental part). [b] The rest is starting material. [c] By using 2.2 equivalents of (allyl)2N-OCOPh.
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Scheme 2. Alternative way to access 1,5-naphthyridines 4-substituted by amino groups. [a] 4,8-Diiodo-1,5-naphthyridine (3’-I) was
also isolated in 6% yield.
We next involved thiophene-based and related organozinc
chlorides in cobalt-catalyzed amination reactions. First, arylzinc
compounds were prepared by transmetalation of the
corresponding arylmagnesium reagents obtained by LiCl-
favored reactions: 2-thienyl- and 2-benzothienylmagnesium
bromides by Grignard reaction (insertion method A;[28] Scheme
3, top), and 2-thiazolyl- and 2-benzothiazolylmagnesium
bromides by bromine/metal exchange (exchange method B,[29]
bottom). The amination step was successfully performed to
respectively afford 1c, 2c, 2e, 2f and 4c, 5e, 5f, 5g by using N-
(benzoyloxy) secondary amines in the presence of
CoCl2·2LiCl,[17] a combination that recently proved efficient to
functionalize organozincs prepared from other aryl halides.[17-18]
For atom economy reason and to avoid the use of costly aryl
bromides, we finally employed organozinc compounds prepared
by deprotometalation-transmetalation in this cobalt-catalyzed
amination (Scheme 4). This represents an additional challenge
as very few cobalt-catalyzed electrophilic trappings have been
achieved from arylzincs prepared by deprotometalation.[30]
To this purpose, we involved in the amination 2-thienylzinc
chlorides prepared from 2,2’-bithiophene and thieno[3,2-
b]thiophene by deprotomagnesiation using TMPMgCl·LiCl[26,31]
followed by transmetalation (top). Similarly, we performed the
amination of the organozinc chloride coming from 1,3-dithiole-2-
thione, generated by using the same base at low temperature[32]
followed by transmetalation (bottom). The reactions gave the
expected amines 6c, 7c, 7f, 7h and 8c, 8e, 8f, 8h in high yields
in the presence of TMEDA (0.2 equiv),[17] making this cobalt-
catalyzed ‘deprotonation-transmetalation-amination’ a general
way to obtain amino-substituted thiophenes and related
compounds.
Scheme 3. Cobalt-catalyzed amination of (benzo)thienylzinc and (benzo)thiazolylzinc chlorides prepared from the corresponding
halides. [a] Yields are given after purification (see experimental part).
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10.1002/ejoc.201900276
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[a]
Scheme 4. Cobalt-catalyzed amination of organozinc chlorides prepared by deprotonation-transmetalation. Yields are given after
purification (see experimental part).
We recently reported the use of 2-aminophenones as
substrates in copper-catalyzed N-arylation with aryl and
heteroaryl iodides.[36d] To achieve the reactions, we employed a
catalytic amount of activated copper and potassium carbonate
as a base at the reflux temperature of dibutylether. We chose
these conditions as starting point to investigate the reaction from
methyl 3-amino-2-thiophenecarboxylate and methyl 2-amino-3-
thiophenecarboxylate. Preliminary results led us to rapidly
realize that reproducibility of the reactions could be ensured by
using stoichiometric copper (5 x 0.2 equiv added every 2 h),
conditions that were kept to perform the whole study.
When methyl 3-amino-2-thiophenecarboxylate (Scheme 5)
was treated by 1.5 equivalents of iodobenzene, a mixture of the
mono- and diphenylated products 9a and 10a was formed in a
~1:1 ratio under these conditions. By reducing the amount of aryl
iodide to one equivalent, monoarylation was favored, affording
9a in 79% yield; only traces of 10a were observed in the crude,
and could be easily removed by purification over silica gel (top).
Conversely, increasing the amount of iodide to 2 equivalents
Figure 1. ORTEP diagrams (50% probability) of the compounds 1d and 10ab.
allowed 10a to be obtained in a high 88% yield; using 3-
iodothiophene instead of iodobenzene similarly furnished 10d
Apart from nucleophilic substitution reactions that require
(bottom left).
activated aryl halides and strong reaction conditions,[33] access
The formation of the monophenylated 9a in high yield using
to thiophene-based triarylamines is more readily possible by
applying the Buchwald-Hartwig approach. Thus, palladium-
catalyzed reactions have been used to N-arylate 2-amino-[33a,34]
and 3-amino-[35] thiophenes or benzothiophenes. To avoid the
use of expensive transition metal, and following our interest in N-
arylation reactions,[36] we next investigated the copper-catalyzed
N-arylation of thiophene-based anilines. Indeed, if copper has
been employed to catalyze N-arylation of an aminothiophene
with organoboron reagents,[37] aryl halides have to our
knowledge never been used in such reactions.
1 equivalent of iodide shows that 9a is less reactive than starting
3-amino-2-thiophenecarboxylate in the N-arylation reaction. It is
nevertheless possible, by using an excess of the iodide, to
prepare triarylamines, as shown with the products 10a and 10d.
Furthermore, a different aryl iodide could be used in the second
N-arylation reaction and, when 9a was treated by 4-iodoanisole
and 1-iodo-4-(trifluoromethyl)benzene under the same reaction
conditions, the differently substituted triarylamines 10ab (Figure
1, bottom) and 10ac were isolated in high yields (bottom right).
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Scheme 5. N-arylation of methyl 3-amino-2-thiophenecarboxylate to afford either 9 or 10. [a] Added by portions of 0.2 equivalent
every 2 h. [b] After purification (see experimental part).
Scheme 6. Compared reactivities of 4-iodoanisole and 1-iodo-4-(trifluoromethyl)benzene in the N-arylation of 9a.
A competitive reaction performed on 9a in the presence of
iodobenzene and 3-iodothiophene; bottom left). The N-arylation
two halides, 4-iodoanisole and 1-iodo-4-(trifluoromethyl)benzene, of 11a with 4-iodoanisole and 2-iodobenzofuran satisfactorily led
showed close reactivities, but in favor of more electron-rich 4-
iodoanisole (Scheme 6). When compared with works on both the
Goldberg reaction[38] and the copper-catalyzed N-arylation of
aniline with aryl bromides,[39] in which electron-withdrawing
substituents at the para position of the aryl halide facilitate the
reaction rates, our competition study revealed a different
behavior for the 4-trifluoromethylated iodide.
We next turned to the isomeric methyl 2-amino-3-
thiophenecarboxylate (Scheme 7). As observed for methyl 3-
amino-2-thiophenecarboxylate, reaction with 1.5 equivalents of
iodobenzene under the same reaction conditions led to a
mixture of the mono- and diphenylated products 11a and 12a in
respective yields of 59% and 30%. It proved easy to achieve
monophenylation by using 1 equivalent of iodobenzene (83%
yield; top). Though somewhat less efficient, diphenylation was
also possible (54% and 76% yield, respectively using
to two new thiophene-based triarylamines (bottom right).
We finally compared the reactivity of 2-aminothiophenes and
3-aminothiophenes in this N-arylation reaction (Scheme 8). To
this purpose, we chose 4-iodoanisole to first attempt
a
competitive
thiophenecarboxylate
reaction
between
and
methyl
methyl
3-amino-2-
2-amino-3-
thiophenecarboxylate (left). Even if the former also reacted, we
noticed a higher reactivity of the latter (a ~1:3 ratio was
recorded). As monophenylated 9a and 11a are less reactive
than their precursors (at the origin of the possible monoarylation
reactions), this reactivity difference towards 4-iodoanisole is
logically more pronounced between less reactive 9a and 11a
(right). It is difficult to rationalize such a reactivity difference, but
more studies will be performed in order to get general trends
and connect them with possible reaction mechanisms.
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Scheme 7. N-arylation of methyl 2-amino-3-thiophenecarboxylate to afford either 11 or 12. [a] Added by portions of 0.2 equivalent
every 2 h. [b] The diphenylated product 12a was also isolated in 6% yield. [c] After purification (see experimental part). [d] Starting
iodide and benzofuran were present in the crude, but no more aminothiophene.
Scheme 8. Left: Compared reactivities of methyl 3-amino-2-thiophenecarboxylate and methyl 2-amino-3-thiophenecarboxylate in the
N-arylation using 4-iodoanisole. Right: Compared reactivities of methyl 3-(phenylamino)-2-thiophenecarboxylate (9a) and methyl 2-
(phenylamino)-3-thiophenecarboxylate (11a) in the N-arylation using 4-iodoanisole.
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1.7 mmol) in THF (3 mL) and stirring for 5 min. If necessary, the solution
was titrated as reported previously.[26]
Conclusions
TMPZnCl·LiCl was prepared as follows.[25] A dry and argon flushed
250 mL Schlenk flask, equipped with a magnetic stirrer and a septum,
was charged with 2,2,6,6-tetramethylpiperidine (10.2 mL, 60 mmol) and
THF (60 mL). The solution was cooled to ‒40 °C before dropwise
addition of BuLi (2.4 M in hexane, 25 mL, 60 mmol). Then, the reaction
mixture was allowed to warm up slowly to ‒10 °C for 1 h. ZnCl2 (1.0 M in
THF, 66 mL, 66 mmol) was added dropwise and the resulting solution
was stirred for 0.5 h at ‒10 °C and then for 0.5 h at 25 °C. The solvents
were then removed under vacuum to afford a yellowish solid. Freshly
distilled THF was then slowly added under vigorous stirring until the salts
were completely dissolved. The freshly prepared TMPZnCl·LiCl solution
was titrated prior to use at 25 °C with benzoic acid using 4-
(phenylazo)diphenylamine1 as indicator.[42]
In the course of this study dedicated to the synthesis of
thiophene-based tertiary amines, we have developed three
approaches that are copper-catalyzed and cobalt-catalyzed
amination of thienylzinc halides or related compounds, and
copper-catalyzed arylation of aminothiophenes. The amination
allowed thienylzinc halides, obtained by bromine/metal
exchange but also by deprotometalation, to be functionalized;
the only limit seems to be the low stability of some of the
generated thienylamines. Concerning copper-catalyzed N-
arylation of aminothiophenes,
a single reaction can be
selectively achieved, but also diarylation using two different aryl
iodides. Such reactions will undoubtly find applications given the
interest for thiophenes and related compounds in the fields of
medicinal chemistry and materials.
(TMP)2Zn·2LiCl was prepared as follows in a nearly quantitative yield. A
dry and argon flushed 250 mL Schlenk flask, equipped with a magnetic
stirrer and a septum, was charged with 2,2,6,6-tetramethylpiperidine
(10.2 mL, 60 mmol) and THF (60 mL). The solution was cooled to ‒40 °C
before dropwise addition of BuLi (2.4 M in hexane, 25 mL, 60 mmol).
Then, the reaction mixture was allowed to warm up slowly to ‒10 °C for
1 h. ZnCl2 (1.0 M in THF, 30 mL, 30 mmol) was added dropwise and the
resulting solution was stirred for 0.5 h at ‒10 °C and then for 0.5 h at
25 °C. The solvents were then removed under vacuum. Freshly distilled
THF was then slowly added to the residue under vigorous stirring until
the salts were completely dissolved and an orange solution obtained.
Experimental Section
General
All reactions were carried out under an argon atmosphere in flame-dried
glassware. Syringes, which were used to transfer anhydrous solvents or
reagents, were purged with argon prior to use. THF was continuously
refluxed and freshly distilled from sodium-benzophenone under nitrogen
or argon and stored over molecular sieves. Column chromatography
separations were achieved on silica gel (40-63 μm) from Merck. Melting
points were measured on a Kofler apparatus. IR spectra were taken on a
Perkin-Elmer Spectrum 100 spectrometer. 1H and 13C Nuclear Magnetic
Resonance (NMR) spectra were recorded either on a Bruker Avance III
spectrometer at 300 MHz and 75 MHz respectively, or on a Bruker ARX-
400 spectrometer at 400 MHz and 101 MHz respectively. 1H chemical
shifts (δ) are given in parts per million (ppm) relative to the solvent
residual peak and 13C chemical shifts are relative to the central peak of
the solvent signal.[40] Mass spectra and high resolution mass spectra
(HRMS) were recorded using electron ionization (EI) except otherwise
noted. Gas-chromatographical analyses were performed on machines of
the types Hewlett-Packard 6890 or 5890 Series II (Hewlett Packard, 5%
phenylmethylpolysiloxane; length: 10 m, diameter: 0.25 mm; film
thickness: 0.25 μm).
TMPMgCl·LiCl was prepared as follows.[26] In a dry and argon flushed
Schlenk-flask, 2,2,6,6-tetramethylpiperidine (14.8 g, 105 mmol) was
added to iPrMgCl·LiCl (71.4 mL, 0.10 mol, 1.4 M in THF) at 25 °C and
the mixture was stirred for 3 days at 25 °C. The freshly prepared
TMPMgCl·LiCl was titrated prior to use at 0 °C with benzoic acid using 4-
(phenylazo)diphenylamine as indicator.[42]
CoCl2·2LiCl was prepared as follows.[17] A dry and argon-flushed 250 mL
Schlenk-flask, equipped with a magnetic stirring bar and a rubber septum,
was charged with anhydrous LiCl (5.9 g, 0.14 mol) and heated to 150 °C
under high vacuum for 5 h. After cooling to room temperature under
vacuum, anhydrous CoCl2 (9.1 g, 70 mmol) was added under argon. The
Schlenk-flask was further heated to 130 °C for 3 h under high vacuum,
cooled to 25 °C and charged with dry THF (70 mL). The mixture was
vigorously stirred until all solids were dissolved (ca. 8 h). The reagent
CoCl2·2LiCl (1 M in THF) is obtained as a dark blue solution.
1,5-Naphthyridine,[22] activated Cu,[43] methyl (2-aminothiophene-3-
carboxylate[44] and 2-iodobenzofuran[45] were prepared as reported
previously.
Starting materials
iPrMgCl·LiCl was purchased as a solution in THF from Albemarle and
titrated against iodine prior to use.[41]
All reagents not listed in the publication (main paper or supporting
information) were obtained from commercial sources.
ZnCl2 solution (1.0 M in THF) was prepared by drying ZnCl2 (136 g,
0.10 mol) in a Schlenk-flask under vacuum at 140 °C for 5 h. After
cooling, dry THF (100 mL) was added and stirring was continued until all
salts were dissolved (12 h). ZnCl2·TMEDA was prepared as reported
previously.[19a]
Crystallographic data
CCDC 1896366 (1d), 1896367 (2a’) and 1896368 (10ab) contain the
crystallographic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre.
After opening a new bottle of 2,2,6,6-tetramethylpiperidine, KOH pellets
were added and storage in a desiccator was necessary. LiTMP was
prepared by adding BuLi (about 1.6 M hexanes solution, 1.5 mmol) to a
stirred, cooled (‒10 °C) solution of 2,2,6,6-tetramethylpiperidine (0.28 mL,
The samples were studied with monochromatized Mo-K radiation ( =
0.71073 Å, multilayer monochromator). The X-ray diffraction data of the
compounds 1d, 2a’ and 10ab were collected at 150(2) K by using a D8
VENTURE Bruker AXS diffractometer equipped with a (CMOS) PHOTON
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10.1002/ejoc.201900276
European Journal of Organic Chemistry
FULL PAPER
100 detector. The structure was solved by dual-space algorithm using the
SHELXT program,[46] and then refined with full-matrix least-square
methods based on F2 (SHELXL-2014).[47] All non-hydrogen atoms were
refined with anisotropic atomic displacement parameters. H atoms were
finally included in their calculated positions and treated as riding on their
parent atom with constrained thermal parameters. The molecular
diagrams were generated by ORTEP-3 (version 2.02).[48]
yield (0.66 g) as a beige powder: mp 65 °C (lit.[50] 62.5-63 °C); IR (ATR):
428, 675, 713, 782, 850, 917, 1019, 1037, 1070, 1092, 1184, 1235, 1249,
1270, 1280, 1319, 1453, 1601, 1728, 2847, 2940 cm-1; 1H NMR (300
MHz, CDCl3)  1.00-1.59 (m, 6H), 2.55 (br s, 2H), 3.28 (br s, 2H), 7.18 (t,
2H, J = 7.7 Hz), 7.30 (t, 1H, J = 7.3 Hz), 7.79 (d, 2H, J = 7.8 Hz).
N-(Benzoyloxy)diisopropylamine.
General procedure
amines.
1 for the N-benzoyloxylation of secondary
The general procedure 1 using diisopropylamine (0.84 mL) gave N-
(benzoyloxy)diisopropylamine (eluent: hexanes-AcOEt 90:10; Rf = 0.30)
in 45% yield (0.50 g) as a yellow oil: IR (ATR): 644, 663, 708, 729, 874,
913, 1025, 1061, 1081, 1177, 1243, 1314, 1383, 1451, 1601, 1740, 2226,
2877, 2938, 2978 cm-1; 1H NMR (300 MHz, CDCl3)  1.03 (d, 12H, J =
6.3 Hz), 3.28 (hept, 2H, J = 6.2 Hz), 7.31 (t, 2H, J = 7.3 Hz), 7.43 (t, 1H, J
= 7.3 Hz), 7.91 (d, 2H, J = 7.7 Hz). The NMR data are as described
previously.[51] 13C NMR (75 MHz, CDCl3)  17.2 (br s, 2CH3), 20.1 (br s,
2CH3), 53.3 (2CH), 128.3 (2CH), 129.1 (C), 129.3 (2CH), 132.8 (CH),
166.1 (C, C=O).
To dibasic potassium phosphate (K2HPO4; 1.3 g, 7.5 mmol) and freshly
dried benzoyl peroxide (1.2 g, 5.0 mmol) in DMF (20 mL) under argon
was slowly added the secondary amine (6.0 mmol). The reaction mixture
was stirred at room temperature until disappearance of benzoyl peroxide
(about 12 h, as shown by TLC monitoring). After addition of saturated
aqueous ammonium chloride (30 mL), extraction was performed using
AcOEt (3x20 mL). The organic phase was washed with saturated
aqueous NaHCO3 (20 mL) and brine (20 mL), and then dried over
Na2SO4. Removal of the solvent and purification by chromatography on
silica gel (the eluent is given in the product description) led to the
expected compound.
N-(Benzoyloxy)di(2-methoxyethyl)amine.
The general procedure 1 using di(2-methoxyethyl)amine (0.89 mL) gave
N-(benzoyloxy)di(2-methoxyethyl)amine (eluent: hexanes-AcOEt 50:50)
in 76% yield (0.96 g) as a colorless oil: IR (ATR): 1022, 1056, 1116, 1198,
1241, 1450, 1740, 2888 cm-1; 1H NMR (400 MHz, CDCl3)  3.26 (t, 4H, J
= 5.6 Hz), 3.29 (s, 6H), 3.61 (t, 4H, J = 5.8 Hz), 7.43-7.45 (m, 2H), 7.57 (t,
1H, J = 7.4 Hz), 8.02 (dd, 2H, J = 8.3 and 1.2 Hz); 13C NMR (101 MHz,
CDCl3)  59.0 (2CH3), 59.4 (2CH2), 69.9 (2CH2), 128.5 (2CH), 129.6 (C),
129.7 (2CH), 133.2 (CH), 165.6 (C, C=O); MS (EI, 70 eV) m/z (%) 42
(87), 44 (36), 51 (10), 56 (10), 59 (13), 76 (37), 88 (16), 104 (100), 105
(11), 121 (19), 208 (29); HRMS (EI) m/z calcd for C13H19NO4: 253.1314;
found: 253.1307.
N-(Benzoyloxy)diallylamine.
The general procedure
1 using diallylamine (0.74 mL) gave N-
(benzoyloxy)diallylamine (eluent: hexanes-AcOEt 80:20; Rf = 0.67) in
76% yield (0.83 g) as a yellow oil. H NMR (300 MHz, CDCl3)  3.39 (d,
1
2H, J = 6.5 Hz), 4.90 (dd, 2H, J = 10.2 and 1.6 Hz), 5.00 (dd, 2H, J =
17.2 and 1.6 Hz), 5.76 (ddt, 2H, J = 16.8, 10.1 and 6.5 Hz), 7.12 (dd, 2H,
J = 8.3 and 6.9 Hz), 7.24 (tt, 1H, J = 7.4 and 1.9 Hz), 7.72 (dd, 2H, J =
8.3, 1.4 Hz). The analyses are as described previously.[17] 13C NMR (75
MHz, CDCl3)  61.7 (2CH2), 119.5 (2CH2), 128.3 (2CH), 129.2 (C), 129.4
(2CH), 132.5 (2CH), 133.0 (CH), 165.3 (C, C=O).
N-(Benzoyloxy)-1,4-dioxa-8-azaspiro[4.5]decane.
N-(Benzoyloxy)dibutylamine.
The general procedure
1
using 1,4-dioxa-8-azaspiro[4.5]decane
(0.77 mL) gave N-(benzoyloxy)-1,4-dioxa-8-azaspiro[4.5]decane (eluent:
hexanes-AcOEt 50:50) in 71% yield (0.93 g) as a white solid: IR (ATR):
1060, 1081, 1122, 1245, 1447, 1733, 2959 cm-1; 1H NMR (400 MHz,
CDCl3)  1.97 (t, 4H, J = 5.7 Hz), 3.27 (br s, 2H), 3.45 (br s, 2H), 4.00 (s,
4H, OCH2CH2O), 7.44 (t, 2H, J = 7.5 Hz), 7.57 (t, 1H, J = 7.5 Hz); 13C
NMR (101 MHz, CDCl3)  32.8 (2CH2), 54.1 (2CH2), 64.6 (2CH2), 106.3
(C), 128.5 (2CH), 129.6 (2CH), 129.6 (C), 133.1 (CH), 164.9 (C, C=O).
The NMR data are as described previously.[52] MS (EI, 70 eV) m/z (%) 42
(11), 43 (100), 45 (14), 50 (14), 61 (12), 77 (49), 88 (11), 87 (13), 122
(55); HRMS (EI) m/z calcd for C14H17NO4: 263.1158; found: 263.1156.
The general procedure
1 using dibutylamine (1.01 mL) gave N-
(benzoyloxy)dibutylamine (eluent: hexanes-AcOEt 95:5; Rf = 0.62) in
59% yield (0.74 g) as a colorless oil. 1H NMR (300 MHz, CDCl3)  0.86 (t,
3H, J = 7.3 Hz), 1.34 (sext, 2H, J = 7.3 Hz), 1.54 (ddd, 2H, J = 15.1, 8.7
and 6.1 Hz), 2.92 (d, 1H, J = 7.4 Hz), 2.94 (d, 1H, J = 7.4 Hz), 7.39 (t, 2H,
J = 7.4 Hz), 7.51 (tt, 1H, J = 7.4 and 1.9 Hz), 7.99 (d, J = 7.1 Hz, 1H).
The 1H NMR data are as described previously.[49] 13C NMR (75 MHz,
CDCl3)  13.9 (2CH3), 20.5 (2CH2), 29.0 (2CH2), 59.5 (2CH2), 128.4
(2CH), 129.4 (C), 129.5 (2CH), 132.9 (CH), 165.6 (C, C=O).
N-(Benzoyloxy)morpholine.
N-(Benzoyloxy)azepane.
The general procedure
1
using morpholine (0.52 mL) gave N-
The general procedure
1
using azepane (0.68 mL) gave N-
(benzoyloxy)morpholine (eluent: hexanes-AcOEt 50:50; Rf = 0.62) in
37% yield (0.39 g) as a white powder: mp 82 °C (lit.[50] 81-82 °C); IR
(ATR): 677, 708, 793, 857, 1008, 1023, 1049, 1066, 1083, 1100, 1247,
1316, 1386, 1453, 1600, 1728, 2849, 2966 cm-1; 1H NMR (300 MHz,
CDCl3)  2.99-3.01 (m, 2H), 3.39-3.41 (m, 2H), 3.78-3.91 (m, 4H), 7.40 (t,
2H, J = 7.6 Hz), 7.52 (t, 1H, J = 7.3 Hz), 7.97 (d, 2H, J = 7.2 Hz). 13C
NMR (75 MHz, CDCl3)  56.9 (2CH2), 65.8 (2CH2), 128.4 (2CH), 129.0
(C), 129.4 (2CH), 133.2 (CH), 164.5 (C, C=O).
(benzoyloxy)azepane as reported previously.[53] 1H NMR (400 MHz,
CDCl3)  1.68 (dt, 4H, J = 6.1 and 3.0 Hz), 1.82 (ddd, 4H, J = 6.8, 4.4 and
1.8 Hz), 3.33 (t, 4H, J = 5.5 Hz), 7.43 (t, 2H, J = 7.7 Hz), 7.55 (t, 1H, J =
7.4 Hz), 8.00 (dd, 2H, J = 8.3 and 1.4 Hz); 13C NMR (101 MHz, CDCl3) 
24.2 (2CH2), 26.5 (2CH2), 59.6 (2CH2), 128.5 (2CH), 129.5 (2CH), 129.8
(C), 133.0 (CH), 164.9 (C, C=O).
N-(Benzoyloxy)-1,2,3,4-tetrahydroisoquinoline.
N-(Benzoyloxy)piperidine.
The general procedure 1 using 1,2,3,4-tetrahydroisoquinoline (0.76 mL)
gave
N-(benzoyloxy)-1,2,3,4-tetrahydroisoquinoline
as
reported
The general procedure
1
using piperidine (0.59 mL) gave N-
previously.[18] 1H NMR (400 MHz, CDCl3)  3.12 (t, 2H, J = 6.0 Hz), 3.55
(br s, 2H), 4.43 (br s, 2H, H1’), 7.06 (d, 1H, J = 6.4 Hz), 7.12-7.23 (m, 3H),
(benzoyloxy)piperidine (eluent: hexanes-AcOEt 70:30; Rf = 0.75) in 64%
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10.1002/ejoc.201900276
European Journal of Organic Chemistry
FULL PAPER
7.42 (t, 2H, J = 7.7 Hz), 7.55 (t, 1H, J = 7.4 Hz), 8.00 (d, 2H, J = 7.1 Hz);
13C NMR (101 MHz, CDCl3)  26.7 (CH2), 53.4 (CH2), 58.1 (CH2), 126.3
(CH), 126.8 (CH), 126.9 (CH), 128.4 (CH), 128.4 (2CH), 129.3 (C), 129.5
(2CH), 132.3 (C), 132.9 (C), 133.1 (CH), 164.9 (C, C=O).
beige powder: mp 180 °C (lit.[10a] 180-181.5 °C); IR (ATR): 569, 592, 653,
723, 744, 780, 868, 901, 1013, 1065, 1116, 1186, 1212, 1250, 1264,
1303, 1375, 1437, 1455, 1527, 1557, 2850, 2958 cm-1; 1H NMR (300
MHz, CDCl3)  3.24 (t, 4H, J = 4.9 Hz), 3.86 (t, 4H, J = 4.8 Hz), 6.23 (s,
1H, H3), 7.10 (t, 1H, J = 7.6 Hz), 7.25 (t, 1H, J = 7.4 Hz), 7.48 (d, 1H, J =
7.9 Hz), 7.61 (d, 1H, J = 7.9 Hz); 13C NMR (75 MHz, CDCl3)  51.1
(2CH2), 66.4 (2CH2), 99.6 (CH), 121.2 (CH), 121.7 (CH), 121.8 (CH),
124.7 (CH), 132.8 (C), 140.4 (C), 157.9 (C). These data are as reported
previously.[10a]
General procedure 2 for the deprotolithiation-zincation-amination of
benzothiophene.
To
a stirred mixture of benzothiophene (0.20 g, 1.5 mmol) and
ZnCl2·TMEDA (0.39 g, 1.5 mmol) in THF (3 mL) at ‒20 °C was added
dropwise a THF-hexane solution of LiTMP (1.5 mmol) to a stirred, cooled
(0 °C) solution of 2,2,6,6-tetramethylpiperidine (0.28 mL, 1.7 mmol) in
THF (3 mL) and stirring for 5 min) cooled at ‒20 °C. After 0.5 h at ‒20 °C,
the solution was added dropwise to the N-benzoyloxy secondary amine
(1.2 mmol) and anhydrous copper(II) acetate (14 mg, 75 μmol) in THF
(3 mL) at ‒20 °C. The mixture was stirred overnight before addition of an
aqueous saturated solution of Na2CO3 (5 mL) and extraction with Et2O (3
x 20 mL). The combined organic layers were dried over MgSO4, filtered
and concentrated under reduced pressure. The crude product was
purified by chromatography over silica gel (the eluent is given in the
product description).
2-(Piperidino)benzothiophene (1d).
The general procedure 2 using N-(benzoyloxy)piperidine (0.25 g) gave
1d (eluent: hexanes-Et3N 98:2; Rf = 0.40) in 68% yield (0.18 g) as a white
powder: mp 102 °C (lit.[55] 99-100 °C); IR (ATR): 479, 558, 581, 641, 721,
734, 772, 812, 855, 1009, 1069, 1117, 1203, 1236, 1255, 1316, 1384,
1439, 1532, 1559, 1717, 2935, 3055 cm-1; H NMR (300 MHz, CDCl3) 
1
1.61-1.67 (m, 2H), 1.73-1.80 (m, 4H), 3.28 (t, 4H, J = 5.5 Hz), 6.18 (s, 1H,
H3), 7.08 (t, 1H, J = 7.5 Hz), 7.24 (t, 1H, J = 7.5 Hz), 7.46 (d, 1H, J = 7.6
Hz), 7.61 (d, J = 7.9 Hz, 1H); 13C NMR (75 MHz, CDCl3)  24.0 (CH2),
25.3 (2CH2), 52.1 (2CH2), 98.5 (CH), 120.7 (CH), 121.0 (CH), 121.6 (CH),
124.5 (CH), 132.7 (C), 141.0 (C), 158.6 (C). Crystal data for 1d.
C13H15NS, M = 217.32, triclinic, P -1, a = 6.0747(7), b = 12.9937(15), c =
14.7777(18) Å, α = 74.742(4), β = 82.826(4), γ = 86.354(4) °, V =
1115.9(2) Å3, Z = 4, d = 1.293 g cm-3, μ = 0.255 mm-1. A final refinement
on F2 with 5071 unique intensities and 297 parameters converged at
ωR(F2) = 0.0949 (R(F) = 0.0411) for 4457 observed reflections with I >
2σ(I). CCDC 1896366.
2-(Diallylamino)benzothiophene (1a).
The general procedure 2 using N-(benzoyloxy)diallylamine (0.26 g) gave
1a (eluent: hexanes-CH2Cl2 95:5; Rf = 0.42) in 52% yield (0.14 g) as a
yellow oil: IR (ATR): 566, 704, 736, 794, 863, 923, 1016, 1065, 1184,
1258, 1355, 1416, 1439, 1540, 1563, 1640, 2962 cm-1; 1H NMR (300
MHz, CDCl3)  3.97 (dt, 4H, J = 5.6 and 1.5 Hz), 5.26 (dd, 2H, J = 8.9
and 1.5 Hz), 5.33 (dd, 2H, J = 17.3 and 1.6 Hz), 5.92 (ddt, 2H, J = 17.0,
10.1 and 5.6 Hz), 6.06 (s, 1H, H3), 7.06 (t, 1H, J = 7.6 Hz), 7.24 (t, 1H, J
2-Chloro-5-(diallylamino)thiophene (2a).
= 7.6 Hz), 7.43 (dd, 1H, J = 8.0 and 1.1 Hz), 7.59 (d, 1H, J = 7.9 Hz); 13
C
The general procedure 2, from 2-chlorothiophene (0.18 g) instead of
thiophene, using N-(benzoyloxy)diallylamine (0.26 g) gave 2a (eluent:
hexanes-Et3N 95:5; Rf = 0.50) in 49% yield (0.13 g) as a colorless oil of
low stability (e.g. a solution in CDCl3 becomes dark after a few minutes):
1H NMR (300 MHz, CDCl3)  3.77 (d, 1H, J = 5.8 Hz), 5.20 (dd, 2H, J =
10.0 and 1.3 Hz), 5.22 (dd, 2H, J = 17.2 and 1.5 Hz), 5.71 (d, 1H, J = 4.0
Hz), 5.83 (ddt, 2H, J = 16.0, 10.4 and 5.8 Hz), 6.53 (d, 1H, J = 4.0 Hz).
Before the IR spectra and 13C NMR could be recorded, degradation to
give allylated products was noticed and formation of 5,5’-dichloro-2,2’-
bithiophene (2a’) was identified by NMR: 1H NMR (300 MHz, CDCl3) 
6.82 (d, 2H, J = 3.9 Hz), 6.85 (d, 2H, J = 3.9 Hz); 13C NMR (75 MHz,
CDCl3)  123.2 (2CH), 127.0 (2CH), 129.3 (2C), 135.2 (2C). These NMR
data are similar to those reported previously.[56] Crystal data for 2a’.
C8H4Cl2S2, M = 235.13, orthorhombic, P c c n, a = 7.3894(12), b =
21.610(3), c = 5.7035(9) Å, V = 910.8(2) Å3, Z = 4, d = 1.715 g cm-3, μ =
1.104 mm-1. A final refinement on F2 with 1041 unique intensities and 55
parameters converged at ωR(F2) = 0.1336 (R(F) = 0.0682) for 904
observed reflections with I > 2σ(I). CCDC 1896367.
NMR (75 MHz, CDCl3)  54.9 (2CH2), 96.5 (CH), 117.4 (2CH2), 120.0
(CH), 120.3 (CH), 121.2 (CH), 124.4 (CH), 131.8 (C), 133.0 (2CH), 141.4
(C), 155.7 (C). HRMS (EI) m/z calcd for C14H15NS: 229.0925; found:
229.0921. 2,2’-Bi(benzothiophene) (1’) was also isolated. This compound
could be obtained in 25% yield by performing the same procedure
without O-benzoyl hydroxylamine: white powder; mp 262 °C (lit.[54] 260-
261 °C); IR (ATR): 476, 557, 722, 736, 814, 937, 1013, 1067, 1177, 1250,
1420, 1451, 1711, 1944, 2851, 2923, 3053 cm-1; 1H NMR (300 MHz,
CDCl3)  7.30-7.39 (m, 4H), 7.52 (s, 2H), 7.74-7.84 (m, 4H); 13C NMR (75
MHz, CDCl3)  121.6 (CH), 122.3 (CH), 123.9 (CH), 124.9 (CH), 125.1
(CH), 137.4 (C), 139.6 (C), 140.3 (C).
2-(Dibutylamino)benzothiophene (1b).
The general procedure 2 using N-(benzoyloxy)dibutylamine (0.30 g) gave
1b (eluent: hexanes-Et3N 95:5; Rf = 0.67) in 63% yield (0.25 g) as a
yellow oil: IR (ATR): 726, 756, 919, 1018, 1065, 1111, 1133, 1194, 1243,
1279, 1311, 1369, 1440, 1539, 1562, 2861, 2928, 2955 cm-1; 1H NMR
(300 MHz, CDCl3)  0.96 (t, 6H, J = 7.3 Hz, CH3), 1.38 (dq, 4H, J = 14.6
and 7.0 Hz, CH2), 1.65 (quintuplet, 4H, J = 7.5 Hz, CH2), 3.28 (t, 4H, J =
7.5 Hz, CH2), 5.88 (s, 1H, H3), 6.97 (t, 1H, J = 7.5 Hz), 7.18 (t, 1H, J =
7.5 Hz), 7.36 (d, 1H, J = 7.9 Hz), 7.53 (d, 1H, J = 7.9 Hz); 13C NMR (75
MHz, CDCl3)  14.0 (2CH3), 20.4 (2CH2), 29.5 (2CH2), 53.2 (2CH2), 94.9
(CH), 119.6 (CH), 119.8 (CH), 121.3 (CH), 124.5 (CH), 131.6 (C), 141.9
(C), 156.3 (C). HRMS (EI) m/z calcd for C16H23NS: 261.1551; found:
261.1549.
4-(Diallylamino)-1,5-naphthyridine (3a) by deprotometalation-
amination of 1,5-naphthyridine.
To a stirred mixture of 1,5-naphthyridine (0.13 g, 1.0 mmol) in THF
(3 mL) at room temperature was added dropwise
a solution of
TMPZnCl·LiCl (1.04 M THF solution; 1.1 mmol). After 2 h at this
temperature, the mixture was treated dropwise by a solution of N-
(benzoyloxy)diallylamine (0.18 g, 0.8 mmol) and anhydrous copper(II)
acetate (9 mg, 50 μmol) in THF (3 mL). It was stirred overnight before
addition of an aqueous saturated solution of NH4Cl (4 mL) and extraction
with AcOEt (3 x 10 mL). The combined organic layers were washed by
aqueous saturated solutions of NaHCO3 (4 mL) and brine (4 mL), dried
over MgSO4, filtered and concentrated under reduced pressure to afford,
2-(Morpholino)benzothiophene (1c).
The general procedure 2 using N-(benzoyloxy)morpholine (0.25 g) gave
1c (eluent: hexanes-Et3N 98:2; Rf = 0.30) in 29% yield (76 mg) as a
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10.1002/ejoc.201900276
European Journal of Organic Chemistry
FULL PAPER
after chromatography over silica gel (eluent: AcOEt; Rf = 0.50), 3a in
64% yield (0.11 g) as a yellow oil: IR (ATR): 555, 610, 657, 712, 790, 823,
919, 993, 1111, 1171, 1232, 1249, 1288, 1347, 1411, 1480, 1504, 1563,
1639, 2910, 2980, 3075 cm-1; 1H NMR (300 MHz, CDCl3)  4.42 (dd, 4H,
J = 4.3 and 2.8 Hz, H1’), 5.19-5.25 (m, 4H, H3’), 6.04 (ddt, 2H, J = 17.8,
9.9 and 5.5 Hz, H2’), 6.69 (d, 1H, J = 5.5 Hz, H3), 7.50 (dd, 1H, J = 8.5
and 4.0 Hz, H7), 8.23 (dd, 1H, J = 8.5 and 1.8 Hz, H8), 8.50 (d, 1H, J =
5.5 Hz, H2), 8.73 (dd, 1H, J = 4.1 and 1.7 Hz, H6); 13C NMR (75 MHz,
CDCl3)  54.7 (2CH2), 107.1 (CH), 117.4 (2CH2), 123.8 (CH), 134.0
(2CH), 137.4 (CH), 137.9 (C), 145.3 (C), 146.0 (CH), 150.8 (CH), 152.5
(C). HRMS (EI) m/z calcd for C14H15N3: 225.1266; found: 225.1268.
A degassed sealed tube containing 4-iodo-1,5-naphthyridine (3-I; 96 mg,
0.375 mmol) and morpholine (0.195 mL, 2.25 mmol) in isopropanol
(1 mL) was heated at 110 °C for 72 h. The cooled residue was poured
onto brine and extracted with AcOEt (3 x 10 mL). The combined organic
layers were dried over Na2SO4, filtered and concentrated under reduced
pressure. The crude product was purified by chromatography over silica
gel (eluent: AcOEt; Rf = 0.30) to afford 3c in 70% yield (57 mg) as a
white powder: mp 116-118 °C; IR (ATR): 1026, 1111, 1249, 1265, 1305,
1372, 1414, 1477, 1503, 1566, 1604, 2864, 2966, 3205, 3350 cm-1; 1H
NMR (300 MHz, CDCl3)  3.68-3.71 (m, 4H, 2CH2), 3.97-4.01 (m, 4H,
2CH2), 6.84 (d, 1H, J = 5.1 Hz, H3), 7.55 (dd, 1H, J = 8.5 and 4.1 Hz, H7),
8.30 (dd, 1H, J = 8.5 and 1.8 Hz, H8), 8.68 (d, 1H, J = 5.1 Hz, H2), 8.81
(dd, 1H, J = 4.1 and 1.7 Hz, H6); 13C NMR (75 MHz, CDCl3)  51.1
(2CH2), 66.9 (2CH2), 109.0 (CH), 124.0 (CH), 138.0 (CH), 138.6 (C),
145.1 (C), 147.4 (CH), 151.5 (CH), 154.9 (C). HRMS (EI) m/z calcd for
C12H13N3O: 215.1059; found: 215.1055.
4-(Diisopropylamino)-1,5-naphthyridine (3b) by deprotometalation-
amination of 1,5-naphthyridine.
To a stirred mixture of 1,5-naphthyridine (0.13 g, 1.0 mmol) in THF
(3 mL) at ‒40 °C was added dropwise a solution of TMPMgCl·LiCl
(1.07 M THF solution; 1.1 mmol). After 1 h at this temperature, the
General procedure 3 for the preparation of 2-thienylzinc chloride or
2-benzothienylzinc chloride (insertion method A),[28] and
subsequent amination.[17]
mixture
was
treated
dropwise
by
a
solution
of
N-
(benzoyloxy)diisopropylamine (0.18 g, 0.8 mmol) and anhydrous
copper(II) acetate (9 mg, 50 μmol) in THF (3 mL). It was slowly warmed
to room temperature and stirred overnight before addition of an aqueous
saturated solution of NH4Cl (4 mL) and extraction with AcOEt (3 x 10 mL).
The combined organic layers were washed by aqueous saturated
solutions of NaHCO3 (4 mL) and brine (4 mL), dried over MgSO4, filtered
and concentrated under reduced pressure to afford, after
chromatography over silica gel (eluent: AcOEt; Rf = 0.27), 3b in 52%
yield (95 mg) as a yellow oil: 1H NMR (400 MHz, CDCl3)  1.42 (d, 12H, J
= 6.8 Hz, CH3), 4.57 (septuplet, 2H, J = 6.8 Hz), 6.95 (d, 1H, J = 5.6 Hz,
H3), 7.46 (dd, 1H, J = 8.5 and 4.0 Hz, H7), 8.20 (dd, 1H, J = 8.5 and 1.7
Hz, H8), 8.46 (d, 1H, J = 5.6 Hz, H2), 8.71 (dd, 1H, J = 4.0 and 1.7 Hz,
H6); 13C NMR (101 MHz, CDCl3)  21.9 (4CH3), 50.5 (2CH), 110.2 (CH),
123.6 (CH), 137.2 (CH), 139.7 (C), 145.6 (CH), 145.8 (C), 149.8 (CH),
152.9 (C). Note that 3b is contaminated with impurities.
A dry and argon flushed Schlenk flask equipped with a magnetic stirring
bar and a septum was charged with magnesium turnings (0.30 g,
12.5 mmol), LiCl (0.32 g, 7.5 mmol) and THF (15 mL). The aromatic
bromide (5.0 mmol) was added dropwise. If necessary, the Schlenk flask
was placed in a water bath for cooling during the initial heat evolution of
the insertion reaction. The progress of the insertion reaction was
monitored by GC-analysis of reaction aliquots quenched with an aqueous
saturated NH4Cl solution and/or iodine. Upon completion of the insertion,
ZnCl2 (1.0 M) solution (6.0 mL, 6.0 mmol) was added dropwise. The
organozinc reagent was titrated using iodine solution (1.0 M in THF)
before use in the amination reaction. A dry and argon flushed flask
equipped with a magnetic stirring bar and a septum was charged with the
N-benzoyloxy secondary amine (0.50 mmol) and THF (2 mL). To the
mixture CoCl2·2LiCl (50 μmol) was added as a 1.0 M solution in THF.
Then, the prepared organozinc chloride (0.55 mmol) in THF was added
dropwise. The solution was stirred for 2 h at room temperature and the
reaction progress checked by thin layer chromatography. Upon
completion of starting material (approximately less than 2 h), the reaction
was quenched with saturated aqueous NH4Cl solution (1 mL) and the
product was extracted with AcOEt (3 x 15 mL). The combined organic
layers were washed with saturated aqueous NaHCO3 solution (15 mL)
and brine (15 mL), dried over MgSO4, filtered and concentrated under
reduced pressure. The crude product was purified by chromatography
over silica gel (the eluent is given in the product description).
4-Iodo-1,5-naphthyridine (3-I).
To a stirred mixture of 1,5-naphthyridine (0.26 g, 2.0 mmol) in THF
(4 mL) at room temperature was added dropwise
a solution of
TMPZnCl·LiCl[22] (1.04 M THF solution; 2.4 mmol). After 2 h at room
temperature, a solution of iodine (0.76 g, 3.0 mmol) in THF (3 mL) was
added. The resulting mixture was stirred overnight before addition of an
aqueous saturated solution of Na2S2O3 (5 mL) and extraction with AcOEt
(3 x 10 mL). The combined organic layers were washed with brine (5 mL),
dried over Na2SO4, filtered and concentrated under reduced pressure.
The crude product was purified by chromatography over silica gel
(eluent: hexanes-AcOEt 60:40) to afford 3-I in 72% yield (0.37 g) as a
whitish powder: mp 91-93 °C; 1H NMR (300 MHz, CDCl3)  7.70 (dd, 1H,
J = 8.5 and 4.2 Hz, H7), 8.28 (d, 1H, J = 4.5 Hz), 8.37 (dd, 1H, J = 8.4
and 1.6 Hz, H8), 8.53 (d, 1H, J = 4.5 Hz), 9.06 (dd, 1H, J = 4.2 and 1.6
Hz, H6); 13C NMR (75 MHz, CDCl3)  116.4 (C, C-I), 125.5 (CH), 135.4
(CH), 138.4 (CH), 143.9 (C), 144.0 (C), 150.8 (CH), 152.2 (CH). These
data are similar to those described previously.[22] Using procedure 3 led
to both 3-I (34% yield) and 4,8-diiodo-1,5-naphthyridine 3’-I. The latter
was isolated in 6% yield as a white powder: mp > 260 °C; IR (ATR): 491,
590, 630, 683, 851, 1031, 1079, 1167, 1210, 1257, 1325, 1358, 1376,
1398, 1459, 1578, 1695, 1957, 2851, 2921 cm-1; 1H NMR (300 MHz,
CDCl3)  8.32 (d, 2H, J = 4.5 Hz), 8.58 (d, 2H, J = 4.5 Hz); 13C NMR (75
MHz, CDCl3)  116.6 (2C, C4 and C8), 136.4 (2CH, C3 and C7), 143.6
(2C), 151.5 (2CH, C2 and C6).
2-(Morpholino)benzothiophene (1c).
The general procedure 3 using 2-bromobenzothiophene (1.1 g) and N-
(benzoyloxy)morpholine (0.10 g) gave 1c (eluent: hexanes-AcOEt 90:10)
in 96% yield (0.10 g) as a white powder: IR (ATR): 900, 1012, 1090,
1263, 1298, 1374, 1435, 1526, 1666, 2838 cm-1; 1H NMR (400 MHz,
CDCl3)  3.24 (t, 4H, J = 4.9 Hz), 3.86 (t, 4H, J = 4.8 Hz), 6.23 (s, 1H, H3),
7.10 (t, 1H, J = 7.6 Hz), 7.25 (t, 1H, J = 7.4 Hz), 7.48 (d, 1H, J = 7.9 Hz),
7.61 (d, 1H, J = 7.9 Hz); 13C NMR (101 MHz, CDCl3)  51.1 (2CH2), 66.4
(2CH2), 99.6 (CH), 121.2 (CH), 121.7 (CH), 121.8 (CH), 124.7 (CH),
132.8 (C), 140.4 (C), 157.9 (C). These data are as reported
previously.[10a] MS (EI, 70 eV) m/z (%) 69 (12), 89 (44), 121 (17), 133
(14), 134 (72), 147 (50), 160 (100), 161 (99), 219 (19); HRMS (EI) m/z
calcd for C12H13NOS: 219.0718; found: 219.0711.
4-Morpholino-1,5-naphthyridine (3c).
2-Morpholinothiophene (2c).
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900276
European Journal of Organic Chemistry
FULL PAPER
The general procedure 3 using 2-bromothiophene (0.82 g) and N-
(benzoyloxy)morpholine (0.10 g) gave 2c (eluent: hexanes-AcOEt 90:10)
in 80% yield (68 mg) as a brown oil: IR (ATR): 928, 1028, 1090, 1208,
1269, 1293, 1374, 1443, 1466, 1528, 2853 cm-1; 1H NMR (400 MHz,
CDCl3)  3.12-3.14 (m, 4H), 3.83-3.85 (m, 4H), 6.16 (dd, 1H, J = 3.7 and
1.4 Hz, H3), 6.64 (dd, 1H, J = 5.2 and 1.1 Hz, H5), 6.80 (dd, 1H, J = 5.4
and 3.8 Hz, H4); 13C NMR (101 MHz, CDCl3)  52.2 (2CH2), 66.7 (2CH2),
105.9 (CH), 113.1 (CH), 126.4 (CH), 159.5 (C). These data are as
reported previously.[57] MS (EI, 70 eV) m/z (%) 110 (33), 111 (61), 154
(11), 169 (100); HRMS (EI) m/z calcd for C8H11NOS: 169.0561; found:
169.0554.
and brine (15 mL), dried over MgSO4, filtered and concentrated under
reduced pressure. The crude product was purified by chromatography
over silica gel (the eluent is given in the product description).
2-Morpholinothiazole (4c).
The general procedure
4 using 2-bromothiazole (0.16 g) and N-
(benzoyloxy)morpholine (0.10 g) gave 4c (eluent: hexanes-AcOEt 90:10)
in 76% yield (65 mg) as a brown oil: IR (ATR): 905, 1034, 1140, 1229,
1270, 1373, 1447, 1511, 2852 cm-1; 1H NMR (400 MHz, CDCl3)  3.46-
3.48 (m, 4H), 3.81-3.83 (m, 4H), 6.60 (d, 1H, J = 3.6 Hz), 7.22 (d, 1H, J =
3.7 Hz); 13C NMR (101 MHz, CDCl3)  48.9 (2CH2), 66.1 (2CH2), 108.1
(CH), 139.8 (CH), 172.6 (C). These data are as reported previously.[58]
MS (EI, 70 eV) m/z (%) 58 (18), 85 (49), 86 (15), 99 (14), 100 (33), 101
(11), 111 (19), 112 (34), 113 (88), 125 (32), 126 (13), 139 (42), 151 (12),
155 (20), 168 (22), 169 (23), 170 (100); HRMS (EI) m/z calcd for
C7H10N2OS: 170.0514; found: 170.0506.
2-[Di(2-methoxyethyl)amino]thiophene (2e).
The general procedure 3 using 2-bromothiophene (0.82 g) and N-
(benzoyloxy)di(2-methoxyethyl)amine (0.13 g) gave 2e (eluent: hexanes-
AcOEt 90:10) in 52% yield (56 mg) as a brown oil: IR (ATR): 1012, 1100,
1
1185, 1360, 1446, 1533, 1639, 2922 cm-1; H NMR (400 MHz, CDCl3) 
3.35 (s, 6H, OMe), 3.49 (td, 4H, J = 5.8 and 0.7 Hz, CH2), 3.57 (td, 4H, J
= 5.8 and 0.85 Hz, CH2), 5.90 (dd, 1H, J = 3.7 and 1.3 Hz, H3), 6.42 (dd,
1H, J = 5.4 and 1.4 Hz, H5), 6.75 (dd, 1H, J = 5.5 and 3.7 Hz, H4); 13C
NMR (101 MHz, CDCl3)  54.3 (2CH2), 59.1 (2CH3), 70.2 (2CH2), 102.3
(CH), 109.3 (CH), 126.7 (CH), 157.3 (C); MS (EI, 70 eV) m/z (%) 112
(10), 138 (12), 170 (100), 215 (31); HRMS (EI) m/z calcd for
C10H17NO2S: 215.0980; found: 215.0974.
2-[Di(2-methoxyethyl)amino]benzothiazole (5e).
The general procedure 4 using 2-bromobenzothiazole (0.21 g) and N-
(benzoyloxy)di(2-methoxyethyl)amine (0.13 g) gave 5e (eluent: hexanes-
AcOEt 90:10) in 56% yield (74 mg) as a yellow oil: IR (ATR): 749, 1111,
1
1309, 1442, 1549, 1560, 1702, 2875 cm-1; H NMR (400 MHz, CDCl3) 
3.40 (s, 6H, OMe), 3.70 (t, 4H, J = 5.5 Hz), 3.82 (t, 4H, J = 5.5 Hz), 7.04
(ddd, 1H, J = 7.8, 7.3 and 1.2 Hz), 7.27 (ddd, 1H, J = 8.6, 7.4 and 1.3 Hz),
7.53 (ddd, 1H, J = 8.1, 1.0 and 0.4 Hz), 7.59-7.61 (ddd, 1H, J = 7.8, 1.2
and 0.4 Hz); 13C NMR (101 MHz, CDCl3)  52.3 (2CH2), 59.3 (2CH3),
70.8 (2CH2), 119.1 (CH), 120.9 (CH), 121.3 (CH), 126.2 (CH), 131.1 (C),
153.4 (C), 168.2 (C). These data are as reported previously.[59] MS (EI,
70 eV) m/z (%) 136 (16), 150 (21), 163 (100), 178 (25), 191 (43), 208
(36), 221 (20); HRMS (EI) m/z calcd for C13H18N2O2S: 266.1089; found:
266.1079.
2-[8-(1,4-Dioxa-8-azaspiro[4.5]decyl)]thiophene (2f).
The general procedure 3 using 2-bromothiophene (0.82 g) and N-
(benzoyloxy)-1,4-dioxa-8-azaspiro[4.5]decane (0.13 g) gave 2f (eluent:
hexanes-AcOEt 90:10) in 78% yield (88 mg) as a brown oil: IR (ATR):
1035, 1100, 1141, 1226, 1363, 1454, 1527, 2955 cm-1; 1H NMR (400
MHz, CDCl3)  1.85 (t, 4H, J = 5.9 Hz), 3.28 (t, 4H, J = 5.8 Hz), 3.98 (s,
4H, OCH2CH2O), 6.12 (dd, 1H, J = 3.8 and 1.4 Hz, H3), 6.59 (dd, 1H, J =
5.5 and 1.4 Hz, H5), 6.76 (dd, 1H, J = 5.5 and 3.8 Hz, H4); 13C NMR (101
MHz, CDCl3)  34.2 (2CH2), 50.5 (2CH2), 64.5 (2CH2), 106.1 (CH), 106.8
(C, C5’), 112.5 (CH), 126.2 (CH), 159.1 (C); MS (EI, 70 eV) m/z (%) 110
(25), 111 (67), 138 (21), 164 (13), 180 (12), 225 (100), 226 (11); HRMS
(EI) m/z calcd for C11H15NO2S: 225.0823; found: 225.0816.
2-[8-(1,4-Dioxa-8-azaspiro[4.5]decyl)]benzothiazole (5f).
The general procedure 4 using 2-bromobenzothiazole (0.21 g) and N-
(benzoyloxy)-1,4-dioxa-8-azaspiro[4.5]decane (0.13 g) gave 5f (eluent:
hexanes-AcOEt 90:10) in 88% yield (0.12 g) as a yellow oil: IR (ATR):
922, 1099, 1291, 1446, 1543, 1595, 2925 cm-1; 1H NMR (400 MHz,
CDCl3)  1.83 (t, 4H, J = 5.9 Hz), 3.75 (dd, 4H, J = 6.6 and 5.1 Hz), 4.02
(s, 4H, OCH2CH2O), 7.06 (td, 1H, J = 7.6 and 1.1 Hz), 7.28 (ddd, 1H, J =
8.5, 7.4 and 1.3 Hz), 7.54 (dd, 1H, J = 8.1 and 0.6 Hz), 7.58-7.60 (m,
1H); 13C NMR (101 MHz, CDCl3)  34.7 (2CH2), 47.1 (2CH2), 64.8 (2CH2),
107.2 (C, C5’), 119.3 (CH), 121.0 (CH), 121.7 (CH), 126.3 (CH), 131.3
(C), 153.2 (C), 168.6 (C). These data are as reported previously.[60] MS
(EI, 70 eV) m/z (%) 99 (20), 108 (14), 134 (12), 135 (46), 136 (12), 149
(59), 161 (13), 162 (13), 163 (77), 175 (89), 176 (39), 177 (25), 189 (12),
203 (12), 207 (16), 276 (100); HRMS (EI) m/z calcd for C14H16N2O2S:
276.0932; found: 276.0922.
General procedure 4 for the preparation of 2-thiazolylzinc chloride
or 2-benzothiazolylzinc chloride (exchange method B),[29] and
subsequent amination.[17]
A dry and argon flushed 10 mL flask, equipped with a magnetic stirrer
and a septum, was charged with iPrMgCl·LiCl (1.0 mL, 1.05 mmol,
1.05 M in THF). The neat aryl bromide (1.0 mmol) was added at room
temperature. The reaction mixture was stirred for 0.5 h, and the
completion of the Br/Mg exchange was checked by GC-analysis using
tetradecane as internal standard. Upon completion of the exchange,
ZnCl2 (1.0 M) solution (1.2 mL, 1.2 mmol) was added dropwise. The
organozinc reagent was titrated using iodine solution (1.0 M in THF)
before use in the amination reaction. A dry and argon flushed flask
equipped with a magnetic stirring bar and a septum was charged with the
N-benzoyloxy secondary amine (0.50 mmol) and THF (2 mL). To the
mixture CoCl2·2LiCl (50 μmol) was added as a 1.0 M solution in THF.
Then, the prepared organozinc chloride (0.55 mmol) in THF was added
dropwise. The solution was stirred for 2 h at room temperature and the
reaction progress checked by thin layer chromatography. Upon
completion of starting material (approximately less than 2 h), the reaction
was quenched with saturated aqueous NH4Cl solution (1 mL) and the
product was extracted with AcOEt (3 x 15 mL). The combined organic
layers were washed with saturated aqueous NaHCO3 solution (15 mL)
2-(1-Azepanyl)benzothiazole (5g).
The general procedure 4 using 2-bromobenzothiazole (0.21 g) and N-
(benzoyloxy)azepane (0.11 g) gave 5g (eluent: hexanes-AcOEt 90:10) in
89% yield (0.10 g) as a yellow oil: IR (ATR): 748, 1249, 1299, 1359, 1441,
1560, 2923 cm-1; 1H NMR (400 MHz, CDCl3)  1.61-1.64 (m, 4H), 1.85-
1.91 (m, 4H), 3.69 (t, 4H, J = 6.0 Hz), 7.03 (td, 1H, J = 7.6 and 1.1 Hz),
7.28 (ddd, 1H, J = 8.2, 7.4 and 1.3 Hz), 7.55 (ddd, 1H, J = 8.0, 1.0 and
0.4 Hz), 7.59 (ddd, 1H, J = 7.8, 1.2 and 0.4 Hz)); 13C NMR (101 MHz,
CDCl3)  27.9 (2CH2), 28.2 (2CH2), 51.1 (2CH2), 118.7 (CH), 120.7 (CH),
120.9 (CH), 126.2 (CH), 130.9 (C), 153.7 (C), 168.5 (C). These data are
as reported previously.[61] MS (EI, 70 eV) m/z (%) 98 (11), 135 (17), 136
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900276
European Journal of Organic Chemistry
FULL PAPER
(31), 149 (38), 150 (49), 162 (23), 163 (46), 175 (37), 177 (14), 189 (65),
199 (23), 203 (18), 217 (27), 232 (100), 233 (14); HRMS (EI) m/z calcd
for C13H16N2S: 232.1034; found: 232.1030.
The general procedure 5 using thieno[3,2-b]thiophene (70 mg) and N-
(benzoyloxy)-1,4-dioxa-8-azaspiro[4.5]decane (0.13 g) gave 7f (eluent:
hexanes-CH2Cl2 80:20) in 85% yield (0.12 g) as a green powder: IR
(ATR): 1066, 1115, 1297, 1442, 1520, 2926 cm-1; 1H NMR (400 MHz,
CDCl3)  1.87 (t, 4H, J = 5.9 Hz), 3.32 (t, 4H, J = 5.8 Hz), 4.00 (s, 4H,
OCH2CH2O), 6.32 (s, 1H), 7.08 (s, 2H); 13C NMR (101 MHz, CDCl3) 
34.2 (2CH2), 50.4 (2CH2), 64.6 (2CH2), 98.9 (CH), 106.8 (C, C5’), 119.6
(CH), 121.9 (CH), 128.2 (C), 138.4 (C), 160.7 (C); MS (EI, 70 eV) m/z
(%) 140 (22), 166 (20), 167 (100), 207 (38), 209 (21), 225 (48), 281 (34);
HRMS (EI) m/z calcd for C13H15NO2S2: 281.0544; found: 281.0537.
General procedure 5 for the preparation of 5-(2-thienyl)-2-thienylzinc
chloride
or
2-(thieno[3,2-b]thienyl)zinc
chloride
(deprotometalation)[31] and subsequent amination.[17]
A dry and argon flushed Schlenk flask, equipped with a magnetic stirrer
and septum, was charged with the starting bithiophene or
a
thienothiophene (0.50 mmol) in THF (approximately 1.0 M solution) at
room temperature. A solution of TMPMgCl·LiCl (0.55 mmol) in THF was
added dropwise and the reaction mixture stirred for 1 h (the completion of
the reaction was checked by GC analysis of reaction aliquots quenched
with a solution of I2 in THF). Upon completion of the deprotonation, ZnCl2
(1.0 M) solution (0.60 ml, 0.60 mmol) was added dropwise. The
organozinc reagent was titrated using iodine solution (1.0 M in THF)
before use in the amination reaction. A dry and argon flushed flask
equipped with a magnetic stirring bar and a septum was charged with the
N-benzoyloxy secondary amine (0.50 mmol) and THF (about 2 mL).
CoCl2·2LiCl (50 μmol; 1.0 M solution in THF) and TMEDA (15 μL,
0.10 mmol) were added to the mixture. Then, the prepared organozinc
chloride (0.55 mmol) in THF was added dropwise. The solution was
stirred for 2 h at room temperature and the reaction progress checked by
thin layer chromatography. Upon completion of starting material
(approximately less than 2 h), the reaction was quenched with saturated
aqueous NH4Cl solution (1 mL) and the product was extracted with
AcOEt (3 x 15 mL). The combined organic layers were washed with
saturated aqueous NaHCO3 solution (15 mL) and brine (15 mL), dried
over MgSO4, filtered and concentrated under reduced pressure. The
crude product was purified by chromatography over silica gel (the eluent
is given in the product description).
2-[2-(1,2,3,4-tetrahydroisoquinolyl)]thieno[3,2-b]thiophene (7h).
The general procedure 5 using thieno[3,2-b]thiophene (70 mg) and N-
(benzoyloxy)-1,2,3,4-tetrahydroisoquinoline (0.13 g) gave 7h (eluent:
hexanes-CH2Cl2 80:20) in 88% yield (0.12 g) as a green powder: IR
(ATR): 928, 1196, 1380, 1454, 1519, 2831 cm-1; 1H NMR (400 MHz,
CDCl3)  3.04 (t, 2H, J = 6.0 Hz), 3.54 (t, 2H, J = 6.0 Hz), 4.41 (s, 2H,
H1’), 6.40 (s, 1H), 7.08 (d, 1H, J = 5.2 Hz), 7.11 (d, 1H, J = 5.2 Hz), 7.14-
7.23 (m, 4H); 13C NMR (101 MHz, CDCl3)  28.8 (CH2), 49.6 (CH2), 53.1
(CH2), 97.9 (CH), 119.6 (CH), 121.8 (CH), 126.3 (CH), 126.5 (CH), 126.7
(CH), 127.6 (C), 128.9 (CH), 133.1 (C), 134.0 (C), 138.6 (C), 160.1 (C);
MS (EI, 70 eV) m/z (%) 73 (13), 77 (12), 78 (15), 88 (11), 91 (16), 103
(16), 104 (58), 115 (24), 117 (49), 139 (17), 166 (68), 270 (30), 271 (100),
272 (21), 273 (13), 277 (22); HRMS (EI) m/z calcd for C15H13NS2:
271.0489; found: 271.0498. This compound is quite instable in CDCl3.
General procedure
6 for the preparation of 2-thiooxo-4-(1,3-
dithiolyl)zinc chloride (deprotometalation),[32] and subsequent
amination.[17]
A dry and argon flushed Schlenk flask was charged with a solution of 1,3-
dithiole-2-thione (0.50 mmol) in anhydrous THF (approximately 0.5 M
solution). A solution of TMPMgCl·LiCl (0.55 mmol) in THF was added
dropwise at –78 °C and the mixture was stirred at this temperature for
0.5 h. The completion of the reaction was checked by GC analysis of
reaction aliquots quenched with I2. Upon completion of the deprotonation,
a ZnCl2 (0.60 mL, 0.60 mmol) solution (1.0 M in THF) was added
dropwise. The organozinc reagent was titrated using iodine solution
(1.0 M in THF) before use in the amination reaction. A dry and argon
flushed flask equipped with a magnetic stirring bar and a septum was
charged with the N-benzoyloxy secondary amine (0.50 mmol) and THF
(about 2 mL). CoCl2·2LiCl (50 μmol; 1.0 M solution in THF) and TMEDA
(15 μL, 0.10 mmol) were added to the mixture. Then, the prepared
organozinc chloride (0.55 mmol) in THF was added dropwise. The
solution was stirred for 2 h at room temperature and the reaction
progress checked by thin layer chromatography. Upon completion of
starting material (approximately less than 2 h), the reaction was
quenched with saturated aqueous NH4Cl solution (1 mL) and the product
was extracted with AcOEt (3 x 15 mL). The combined organic layers
were washed with saturated aqueous NaHCO3 solution (15 mL) and
brine (15 mL), dried over MgSO4, filtered and concentrated under
reduced pressure. The crude product was purified by chromatography
over silica gel (the eluent is given in the product description).
5-Morpholino-2,2’-bithiophene (6c).
The general procedure 5, but without TMEDA, using 2,2’-bithiophene
(83 mg) and N-(benzoyloxy)morpholine (0.10 g) gave 6c (eluent:
hexanes-AcOEt 90:10) in 72% yield (90 mg) as a yellow powder: IR
(ATR): 899, 1115, 1296, 1450, 1535, 1594, 2925 cm-1; 1H NMR (400
MHz, CDCl3)  3.15-3.16 (m, 4H), 3.85-3.87 (m, 4H), 6.08 (d, 1H, J = 3.9
Hz), 6.88 (d, 1H, J = 3.7 Hz), 6.96 (dd, 1H, J = 5.1 and 3.6 Hz, H4’), 6.99
(dd, 1H, J = 3.6 and 1.2 Hz, H3’), 7.11 (dd, 1H, J = 5.0 and 1.3 Hz, H5’);
13C NMR (101 MHz, CDCl3)  51.6 (2CH2), 66.6 (2CH2), 106.0 (CH),
122.1 (CH), 123.1 (CH), 123.2 (CH), 124.6 (C), 127.9 (CH), 138.5 (C),
158.5 (C). These data are as reported previously.[62] MS (EI, 70 eV) m/z
(%) 121 (16), 179 (12), 191 (38), 193 (77), 251 (100); HRMS (EI) m/z
calcd for C12H13NOS2: 251.0439; found: 251.0435.
2-(Morpholino)thieno[3,2-b]thiophene (7c).
The general procedure 5 using thieno[3,2-b]thiophene (70 mg) and N-
(benzoyloxy)morpholine (0.10 g) gave 7c (eluent: hexanes-CH2Cl2 80:20)
in 92% yield (0.10 g) as a white powder: IR (ATR): 925, 1100, 1217,
1261, 1374, 1442, 1509, 2831 cm-1; 1H NMR (400 MHz, CDCl3)  3.16-
3.18 (m, 4H), 3.85-3.88 (m, 4H), 6.37 (s, 1H), 7.10 (d, 1H, J = 5.2 Hz),
7.12 (d, 1H, J = 5.2 Hz); 13C NMR (101 MHz, CDCl3)  52.1 (2CH2), 66.4
(2CH2), 99.5 (CH), 119.6 (CH), 122.8 (CH), 128.6 (C), 138.1 (C), 160.1
(C). MS (EI, 70 eV) m/z (%) 69 (10), 122 (12), 139 (10), 140 (46), 153
(23), 166 (47), 167 (99), 207 (13), 223 (16), 225 (100); HRMS (EI) m/z
calcd for C10H11NOS2: 225.0282; found: 225.0276.
4-Morpholino-1,3-dithiole-2-thione (8c).
The general procedure 6 using N-(benzoyloxy)morpholine (0.10 g) gave
8c (eluent: hexanes-AcOEt 90:10) in 73% yield (80 mg) as a yellow
powder: IR (ATR): 867, 1000, 1111, 1214, 1273, 1375, 1442, 1531, 2834
cm-1; 1H NMR (400 MHz, CDCl3)  3.07-3.10 (m, 4H), 3.79-3.81 (m, 4H),
5.63 (s, 1H, H5); 13C NMR (101 MHz, CDCl3)  51.0 (2CH2), 66.1 (2CH2),
98.8 (CH, C5), 155.2 (C, C4), 207.9 (C, C=S); MS (EI, 70 eV) m/z (%) 48
2-[8-(1,4-Dioxa-8-azaspiro[4.5]decyl)]thieno[3,2-b]thiophene (7f).
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900276
European Journal of Organic Chemistry
FULL PAPER
(27), 49 (100), 50 (12), 52 (25), 60 (15), 73 (11), 75 (14), 84 (30), 115
(11), 143 (31); HRMS (EI) m/z calcd for C7H9NOS3: 219.9846; found:
219.9902.
(CH, C4), 141.5 (C, C1’), 151.5 (C, C3), 165.2 (C, C=O). These data are
similar to those described previously.[35a]
General procedure 7 for the bis-N-arylation of methyl 3-amino-2-
4-[Di(2-methoxyethyl)amino]-1,3-dithiole-2-thione (8e).
thiophenecarboxylate using the same iodide.
The general procedure 6 using N-(benzoyloxy)di(2-methoxyethyl)amine
(0.13 g) gave 8e (eluent: hexanes-AcOEt 90:10) in 95% yield (0.13 g) as
a red oil: IR (ATR): 942, 1054, 1099, 1363, 1455, 1534, 2978 cm-1; 1H
NMR (400 MHz, CDCl3)  3.35 (s, 6H, OMe), 3.43 (t, 4H, J = 6.0 Hz),
3.54 (t, 4H, J = 6.0 Hz), 5.39 (s, 1H); 13C NMR (101 MHz, CDCl3)  53.9
(2CH2), 59.2 (2CH3), 70.1 (2CH2), 93.1 (CH, C5), 153.6 (C, C4), 206.7 (C,
C=S); MS (EI, 70 eV) m/z (%) 76 (100), 78 (10), 207 (13), 225 (11);
HRMS (EI) m/z calcd for C9H15NO2S3: 265.0265; found: 265.0264.
To the required iodide (2.0 mmol) in Bu2O (1.5 mL) were successively
added activated Cu (13 mg, 0.20 mmol), methyl 3-amino-2-
thiophenecarboxylate (0.16 g, 1.0 mmol) and K2CO3 (0.28 g, 2.0 mmol).
The mixture was degassed and heated at 140 °C under argon for 24 h.
During this time, activated Cu (4 x 13 mg, 4 x 0.20 mmol) was added
after 2, 4, 6 and 8 h of heating. After cooling to room temperature, the
mixture was concentrated. Addition of H2O (25 mL), extraction with
AcOEt (3 x 10 mL), drying over Na2SO4, removal of the solvent and
purification by chromatography on silica gel (the eluent is given in the
product description) led to the expected compound.
4-[8-(1,4-Dioxa-8-azaspiro[4.5]decyl)]-1,3-dithiole-2-thione (8f).
Methyl 3-(diphenylamino)-2-thiophenecarboxylate (10a).
The
general
procedure
6
using
N-(benzoyloxy)-1,4-dioxa-8-
azaspiro[4.5]decane (0.13 g) gave 8f (eluent: hexanes-AcOEt 90:10) in
98% yield (0.13 g) as a yellow powder: IR (ATR): 920, 1022, 1099, 1145,
1365, 1455, 1532, 2950 cm-1; 1H NMR (400 MHz, CDCl3)  1.78 (t, 4H, J
= 5.9 Hz, 2CH2), 3.20 (t, 4H, J = 5.9 Hz, 2CH2), 3.94 (s, 4H, OCH2CH2O),
5.55 (s, 1H, H5); 13C NMR (101 MHz, CDCl3)  33.9 (2CH2), 49.5 (2CH2),
64.6 (2CH2), 98.5 (CH, C5), 106.0 (C, C5’), 155.1 (C, C4), 208.2 (C,
C=S); MS (EI, 70 eV) m/z (%) 43 (100), 45 (14), 61 (19), 70 (14), 98 (13),
275 (50); HRMS (EI) m/z calcd for C10H13NO2S3: 275.0108; found:
275.0100.
The general procedure 7 using iodobenzene (0.22 mL) gave 10a (eluent:
hexanes-AcOEt 95:5; Rf = 0.35) in 88% yield (0.27 g) as a yellow oil; IR
(ATR): 503, 583, 637, 674, 694, 754, 776, 853, 951, 1041, 1074, 1094,
1175, 1226, 1253, 1394, 1418, 1438, 1481, 1524, 1567, 1592, 1667,
1714, 2950 cm-1; 1H NMR (300 MHz, CDCl3)  3.53 (s, 3H, OMe), 6.81 (d,
1H, J = 5.3 Hz, H4), 7.00 (t, 2H, J = 7.2 Hz, H4’), 7.04 (d, 4H, J = 8.1 Hz,
H2’ and H6’), 7.23 (t, 4H, J = 7.8 Hz, H3’ and H5’), 7.42 (d, 1H, J = 5.3
Hz, H5); 13C NMR (75 MHz, CDCl3)  51.7 (CH3), 121.1 (C, C2), 122.7
(4CH, C2’ and C6’), 122.9 (2CH, C4’), 128.6 (CH), 129.1 (4CH, C3’ and
C5’), 130.3 (CH), 147.7 (2C, C1’), 149.8 (C, C3), 161.3 (C, C=O). HRMS
(EI) m/z calcd for C18H15NO2S: 309.0823; found: 309.0820.
4-[2-(1,2,3,4-tetrahydroisoquinolyl)]-1,3-dithiole-2-thione (8h).
The
general
procedure
6
using
N-(benzoyloxy)-1,2,3,4-
Methyl 3-(di(3-thienyl)amino)-2-thiophenecarboxylate (10d).
tetrahydroisoquinoline (0.13 g) gave 8h (eluent: hexanes-AcOEt 90:10) in
96% yield (0.13 g) as a yellow powder: IR (ATR): 842, 1038, 1179, 1381,
1448, 1532, 2921 cm-1; 1H NMR (400 MHz, CDCl3)  2.98 (t, 2H, J = 5.5
Hz), 3.46 (t, 2H, J = 6.0 Hz), 4.33 (s, 2H, H1’), 5.57 (s, 1H, H5), 7.11 (dd,
1H, J = 5.2 and 3.6 Hz), 7.16 (dd, 1H, J = 5.3 and 3.8 Hz), 7.20-7.24 (m,
2H); 13C NMR (101 MHz, CDCl3)  28.6 (CH2), 49.1 (CH2), 52.0 (CH2),
96.3 (CH, C5), 126.4 (CH), 126.7 (CH), 127.2 (CH), 128.9 (CH), 131.9
(C), 133.5 (C), 154.3 (C, C4), 207.5 (C, C=S); MS (EI, 70 eV) m/z (%) 42
(42), 75 (11), 91 (16), 103 (12), 104 (15), 115 (24), 117 (81), 118 (18),
132 (14), 156 (21), 188 (57), 189 (15), 265 (100), 267 (14); HRMS (EI)
m/z calcd for C12H11NS3: 265.0054; found: 265.0048.
The general procedure 7 using 3-iodothiophene (0.20 mL) gave 10d
(eluent: hexanes-AcOEt 90:10; Rf = 0.52) in 87% yield (0.28 g) as a
yellow oil; IR (ATR): 605, 626, 649, 726, 749, 761, 841, 914, 986, 1042,
1073, 1099, 1151, 1188, 1214, 1297, 1375, 1401, 1423, 1437, 1520,
1
1692, 1713, 2947, 3105 cm-1; H NMR (300 MHz, CDCl3)  3.59 (s, 3H,
OMe), 6.58 (dd, 2H, J = 3.1 and 1.2 Hz, H2’), 6.86 (dd, 2H, J = 5.2 and
1.2 Hz, H4’), 6.88 (d, 1H, J = 5.6 Hz, H4), 7.18 (dd, 2H, J = 5.2, 3.2 Hz,
H5’), 7.40 (d, 1H, J = 5.3 Hz, H5); 13C NMR (75 MHz, CDCl3)  51.8
(CH3), 109.7 (2CH), 120.0 (C), 123.3 (2CH), 124.8 (2CH), 127.3 (CH),
130.2 (CH), 146.8 (2C, C3’), 149.9 (C), 161.4 (C, C=O). HRMS (EI) m/z
calcd for C14H11NO2S3: 320.9952; found: 320.9957. Methyl 3-(3-
thienylamino)-2-thiophenecarboxylate (9d) was similarly isolated
(eluent: hexanes-AcOEt 90:10; Rf = 0.575) in <10% yield as a yellow oil:
IR (ATR): 455, 584, 610, 722, 770, 840, 958, 1035, 1083, 1238, 1350,
1402, 1424, 1444, 1556, 1571, 1661, 2949, 3103, 3330 cm-1; 1H NMR
(300 MHz, CDCl3)  3.86 (s, 3H, OMe), 6.82 (dd, 1H, J = 3.2, 1.4 Hz, H2’),
6.95 (dd, 1H, J = 5.2, 1.4 Hz, H4’), 7.03 (d, 1H, J = 5.5 Hz, H4), 7.27 (dd,
1H, J = 5.1, 3.1 Hz, H5’), 7.36 (d, 1H, J = 5.5 Hz, H5), 8.75 (br s, 1H,
NH); 13C NMR (75 MHz, CDCl3)  51.5 (CH3), 102.0 (C), 109.1 (CH),
118.0 (CH), 123.4 (CH), 125.5 (CH), 132.1 (CH), 140.4 (C), 152.4 (C),
165.3 (C).
Methyl 3-(phenylamino)-2-thiophenecarboxylate (9a).
To iodobenzene (0.11 mL, 1.0 mmol) in Bu2O (1.5 mL) were successively
added activated Cu (13 mg, 0.20 mmol), methyl 3-amino-2-
thiophenecarboxylate (0.16 g, 1.0 mmol) and K2CO3 (0.28 g, 2.0 mmol).
The mixture was degassed and heated at 140 °C under argon for 24 h.
During this time, activated Cu (4 x 13 mg, 4 x 0.20 mmol) was added
after 2, 4, 6 and 8 h of heating. After cooling to room temperature, the
mixture was concentrated. Addition of H2O (25 mL), extraction with
AcOEt (3x10 mL), drying over Na2SO4, removal of the solvent and
purification by chromatography on silica gel (eluent: hexanes-AcOEt
95:5; Rf = 0.525) afforded 5a in 79% yield (0.18 g) as a yellow powder:
mp 68 °C (lit.[35a] 66-67 °C); IR (ATR): 692, 754, 772, 1090, 1226, 1254,
1394, 1418, 1435, 1566, 1593, 1667, 2948, 3309 cm-1; 1H NMR (300
MHz, CDCl3)  3.88 (s, 3H, OMe), 7.06 (t, 1H, J = 7.4 Hz, H4’), 7.10 (d,
1H, J = 5.5 Hz, H4), 7.18 (d, 2H, J = 7.7 Hz, H2’ and H6’), 7.33 (t, 2H, J =
7.7 Hz, H3’ and H5’), 7.35 (d, 1H, J = 5.3 Hz, H5), 8.80 (br s, 1H, NH);
13C NMR (75 MHz, CDCl3)  51.5 (CH3), 103.0 (C, C2), 118.0 (CH),
120.3 (2CH, C2’ and C6’), 123.1 (CH), 129.4 (2CH, C3’ and C5’), 131.8
General procedure 8 for the N-arylation of methyl 3-(phenylamino)-
2-thiophenecarboxylate (9a).
To the required iodide (1.0 mmol) in Bu2O (1.5 mL) were successively
added activated Cu (13 mg, 0.20 mmol), methyl 3-(phenylamino)-2-
thiophenecarboxylate (9a, 0.23 g, 1.0 mmol) and K2CO3 (0.28 g,
2.0 mmol). The mixture was degassed and heated at 140 °C under argon
for 24 h. During this time, activated Cu (4 x 13 mg, 4 x 0.20 mmol) was
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900276
European Journal of Organic Chemistry
FULL PAPER
added after 2, 4, 6 and 8 h of heating. After cooling to room temperature,
the mixture was concentrated. Addition of H2O (25 mL), extraction with
AcOEt (3 x 10 mL), drying over Na2SO4, removal of the solvent and
purification by chromatography on silica gel (the eluent is given in the
product description) led to the expected compound.
General procedure 9 for the bis-N-arylation of methyl 2-amino-3-
thiophenecarboxylate using the same iodide.
To the required iodide (2.0 mmol) in Bu2O (1.5 mL) were successively
added activated Cu (13 mg, 0.20 mmol), methyl 2-amino-3-
thiophenecarboxylate (0.16 g, 1.0 mmol) and K2CO3 (0.28 g, 2.0 mmol).
The mixture was degassed and heated at 140 °C under argon for 24 h.
During this time, activated Cu (4 x 13 mg, 4 x 0.20 mmol) was added
after 2, 4, 6 and 8 h of heating. After cooling to room temperature, the
mixture was concentrated. Addition of H2O (25 mL), extraction with
AcOEt (3 x 10 mL), drying over Na2SO4, removal of the solvent and
purification by chromatography on silica gel (the eluent is given in the
product description) led to the expected compound.
Methyl
N-(4-methoxyphenyl)-N-phenyl-3-amino-2-
using 4-
thiophenecarboxylate (10ab). The general procedure
8
iodoanisole (0.23 g) gave 10ab (eluent: hexanes-AcOEt 95:5; Rf = 0.27)
in 91% yield (0.31 g) as a yellow powder: mp 122 °C; IR (ATR): 665, 693,
720, 747, 769, 779, 789, 805, 836, 1026, 1041, 1073, 1098, 1225, 1247,
1258, 1442, 1489, 1505, 1594, 1709, 2922, 2957 cm-1; 1H NMR (300
MHz, CDCl3)  3.53 (s, 3H, OMe), 3.79 (s, 3H, OMe), 6.77 (d, 1H, J = 5.4
Hz, H4), 6.81 (d, 2H, J = 9.0 Hz), 6.90-6.95 (m, 3H, H2’, H4’ and H6’),
7.03 (d, 2H, J = 8.9 Hz), 7.19 (t, 2H, J = 7.9 Hz, H3’ and H5’), 7.39 (d, 1H,
J = 5.4 Hz, H5); 13C NMR (75 MHz, CDCl3)  51.7 (CH3), 55.6 (CH3),
114.6 (2CH), 119.9 (C), 121.1 (2CH), 122.0 (CH), 125.8 (2CH), 128.3
(CH), 129.0 (2CH), 130.2 (CH), 140.8 (C), 148.6 (C), 150.2 (C), 156.3 (C),
161.3 (C); HRMS (EI) m/z calcd for C19H17NO3S: 339.0929; found:
339.0926. Crystal data for 10ab. C19H17NO3S, M = 339.39, triclinic, P -1,
a = 9.2351(10), b = 9.7922(11), c = 9.9542(11) Å, α = 102.222(4), β =
96.641(4), γ = 108.875(4) °, V = 815.80(16) Å3, Z = 2, d = 1.382 g cm-3, μ
= 0.215 mm-1. A final refinement on F2 with 3725 unique intensities and
219 parameters converged at ωR(F2) = 0.0824 (R(F) = 0.0333) for 3289
observed reflections with I > 2σ(I). CCDC 1896368.
Methyl 2-(diphenylamino)-3-thiophenecarboxylate (12a).
The general procedure 9 using iodobenzene (0.22 mL) gave 12a (eluent:
hexanes-AcOEt 95:5; Rf = 0.27) in 54% yield (0.17 g) as a yellow
powder: mp 110 °C; 1H NMR (300 MHz, CDCl3)  3.52 (s, 3H, OMe),
6.98 (d, 1H, J = 5.9 Hz), 7.03 (t, 2H, J = 7.5 Hz, H4’), 7.08 (d, 4H, J = 7.9
Hz, H2’ and H6’), 7.25 (t, 4H, J = 7.8 Hz, H3’ and H5’), 7.33 (d, 1H, J =
5.9 Hz); 13C NMR (75 MHz, CDCl3)  51.4 (CH3), 120.1 (CH), 122.5
(4CH), 123.2 (2CH), 124.7 (C), 128.2 (CH), 129.1 (4CH), 147.9 (2C),
156.8 (C), 162.5 (C). HRMS (EI) m/z calcd for C18H15NO2S: 309.0823;
found: 309.0819.
Methyl
N-phenyl-N-(4-(trifluoromethyl)phenyl)-3-amino-2-
Methyl 2-(di(3-thienyl)amino)-3-thiophenecarboxylate (12d).
thiophenecarboxylate (10ac). The general procedure 8 using 1-iodo-4-
(trifluoromethyl)benzene (0.15 mL) gave 10ac (eluent: hexanes-AcOEt
95:5; Rf = 0.40) in 94% yield (0.35 g) as a yellow oil: IR (ATR): 508, 522,
611, 646, 684, 698, 732, 749, 769, 838, 951, 1011, 1040, 1066, 1110,
1161, 1183, 1226, 1279, 1297, 1316, 1396, 1438, 1490, 1515, 1528,
The general procedure 9 using 3-iodothiophene (0.20 mL) gave 12d
(eluent: hexanes-AcOEt 90:10; Rf = 0.52) in 76% yield (0.24 g) as a
yellow oil: IR (ATR): 472, 601, 630, 637, 668, 694, 734, 761, 782, 829,
836, 846, 871, 970, 997, 1072, 1083, 1129, 1148, 1185, 1237, 1256,
1285, 1383, 1395, 1453, 1522, 1537, 1695, 2949, 3104 cm-1; 1H NMR
(300 MHz, CDCl3)  3.59 (s, 3H, OMe), 6.64 (d, 2H, J = 2.4 Hz, H2’), 6.89
(d, 2H, J = 5.2 Hz, H4’), 6.93 (d, 1H, J = 5.9 Hz), 7.18 (dd, 2H, J = 5.1
and 3.2 Hz, H5’), 7.32 (d, 1H, J = 5.9 Hz); 13C NMR (75 MHz, CDCl3) 
51.3 (CH3), 109.9 (2CH), 119.4 (CH), 122.7 (2CH), 123.6 (C), 124.8
(2CH), 127.9 (CH), 146.7 (C), 156.5 (C), 162.2 (C). HRMS (EI) m/z calcd
for C14H11NO2S3: 320.9952; found: 320.9948.
1591, 1614, 1715, 2951 cm-1; H NMR (300 MHz, CDCl3)  3.59 (s, 3H,
1
OMe), 6.87 (d, 1H, J = 5.3 Hz, H4), 7.03 (d, 2H, J = 8.5 Hz), 7.09-7.15 (m,
3H), 7.31 (t, 2H, J = 7.8 Hz, H3’ and H5’), 7.45 (d, 2H, J = 8.6 Hz), 7.50
(d, 1H, J = 5.3 Hz, H5); 13C NMR (75 MHz, CDCl3)  51.8 (CH3), 119.9
(2CH), 123.1 (C), 123.2 (q, C, J = 32.4 Hz, C4”), 124.2 (2CH), 124.5 (CH),
124.6 (q, C, J = 269 Hz, CF3), 126.2 (q, 2CH, J = 3.7 Hz, C3” and C5”),
128.7 (CH), 129.4 (2CH), 130.9 (CH), 146.2 (C), 148.5 (C), 150.8 (d, C, J
= 1.3 Hz), 160.9 (C). HRMS (EI) m/z calcd for C19H14F3NO2S: 377.0697;
found: 377.0698.
General procedure 10 for the N-arylation of methyl 2-(phenylamino)-
3-thiophenecarboxylate (11a)
Methyl
2-(phenylamino)-3-thiophenecarboxylate
(11a).
To
iodobenzene (0.11 mL, 1.0 mmol) in Bu2O (1.5 mL) were successively
added activated Cu (13 mg, 0.20 mmol), methyl 2-amino-3-
thiophenecarboxylate (0.16 g, 1.0 mmol) and K2CO3 (0.28 g, 2.0 mmol).
The mixture was degassed and heated at 140 °C under argon for 24 h.
During this time, activated Cu (4 x 13 mg, 4 x 0.20 mmol) was added
after 2, 4, 6 and 8 h of heating. After cooling to room temperature, the
mixture was concentrated. Addition of H2O (25 mL), extraction with
AcOEt (3 x 10 mL), drying over Na2SO4, removal of the solvent and
purification by chromatography on silica gel (eluent: hexanes-AcOEt
95:5; Rf = 0.50) afforded 11a in 83% yield (0.19 g) as a white powder: mp
64 °C (lit.[37] 59-60 °C); IR (ATR): 490, 503, 661, 684, 751, 782, 1012,
1084, 1154, 1193, 1241, 1337, 1382, 1407, 1440, 1498, 1509, 1553,
To the required iodide (1.0 mmol) in Bu2O (1.5 mL) were successively
added activated Cu (13 mg, 0.20 mmol), methyl 2-(phenylamino)-3-
thiophenecarboxylate (11a, 0.23 g, 1.0 mmol) and K2CO3 (0.28 g,
2.0 mmol). The mixture was degassed and heated at 140 °C under argon
for 24 h. During this time, activated Cu (4 x 13 mg, 4 x 0.20 mmol) was
added after 2, 4, 6 and 8 h of heating. After cooling to room temperature,
the mixture was concentrated. Addition of H2O (25 mL), extraction with
AcOEt (3 x 10 mL), drying over Na2SO4, removal of the solvent and
purification by chromatography on silica gel (the eluent is given in the
product description) led to the expected compound.
1
1592, 1670, 2948, 3213 cm-1; H NMR (300 MHz, CDCl3)  3.87 (s, 3H,
Methyl
N-(4-methoxyphenyl)-N-phenyl-2-amino-3-
OMe), 6.31 (d, 1H, J = 5.7 Hz), 7.07 (t, 1H, J = 7.1 Hz, H4’), 7.15 (d, 1H,
J = 5.8 Hz), 7.31 (d, 2H, J = 7.6 Hz, H2’ and H6’), 7.37 (t, 2H, J = 7.8 Hz,
H3’ and H5’), 9.91 (br s, 1H, NH); 13C NMR (75 MHz, CDCl3)  51.3
(CH3), 107.1 (CH), 107.5 (C), 118.2 (2CH), 122.9 (CH), 125.4 (CH),
129.5 (2CH), 140.9 (C), 158.5 (C), 166.4 (C). These data are similar to
those described previously.[37]
thiophenecarboxylate (12ab).
The general procedure 10 using 4-iodoanisole (0.23 g) gave 12ab
(eluent: hexanes-AcOEt 90:10; Rf = 0.25) in 86% yield (0.29 g) as a red
oil: IR (ATR): 533, 570, 614, 632, 645, 694, 750, 823, 910, 1003, 1033,
1084, 1108, 1144, 1191, 1238, 1284, 1387, 1438, 1463, 1490, 1506,
1531, 1594, 1704, 2835, 2949 cm-1; 1H NMR (300 MHz, CDCl3)  3.55 (s,
3H, OMe), 3.79 (s, 3H, OMe), 6.86 (d, 2H, J = 8.9 Hz, H2” and H6”), 6.91
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(d, 1H, J = 5.9 Hz), 6.95-6.99 (m, 3H), 7.15 (d, 2H, J = 8.9 Hz, H3” and
H5”), 7.18-7.24 (m, 2H), 7.32 (d, 1H, J = 5.9 Hz); 13C NMR (75 MHz,
CDCl3)  51.2 (CH3), 55.4 (CH3), 114.5 (2CH), 119.3 (CH), 120.3 (2CH),
121.9 (CH), 123.4 (C), 125.8 (2CH), 128.0 (CH), 128.9 (2CH), 140.7 (C),
148.6 (C), 156.6 (C), 157.5 (C), 162.3 (C) ; HRMS (EI) m/z calcd for
C19H17NO3S: 339.0929; found: 339.0932.
S. Chang, ACS Catal. 2016, 6, 2341-2351; e) J. Jiao, K. Murakami, K.
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The general procedure 10 using 2-iodobenzofuran (0.24 g) gave 12ae
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1492, 1536, 1582, 1709, 2949, 3062 cm-1; H NMR (300 MHz, CDCl3) 
1
3.61 (s, 3H, OMe), 6.11 (s, 1H, H3”), 7.09 (d, 1H, J = 5.9 Hz), 7.11-7.22
(m, 5H), 7.31-7.39 (m, 3H), 7.42-7.45 (m, 2H); 13C NMR (75 MHz, CDCl3)
 51.6 (CH3), 91.8 (CH), 110.7 (CH), 119.8 (CH), 121.1 (2CH), 121.2
(CH), 122.8 (CH), 123.1 (CH), 124.0 (CH), 125.9 (C), 128.2 (CH), 129.2
(2CH), 129.3 (C), 145.6 (C), 151.3 (C), 152.5 (C), 155.2 (C), 162.2 (C).
HRMS (EI) m/z calcd for C20H15NO3S: 349.0773; found: 349.0770.
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Acknowledgements
[17] Y.-H. Chen, S. Graβl, P. Knochel, Angew. Chem. 2018, 130, 1120-
1124; Angew. Chem. Int. Ed. 2018, 57, 1108-1111. See Supporting
Information for a suggestion concerning the role of TMEDA in the
reactions displayed in Scheme 4.
We thank the Université de Rennes 1, and the Centre National
de la Recherche Scientifique (F. M.). We acknowledge the
Fonds Européen de Développement Régional (FEDER; D8
VENTURE Bruker AXS diffractometer) and Thermofisher
(generous gift of 2,2,6,6-tetramethylpiperidine). This research
has been partly performed as part of the CNRS PICS project
“Bimetallic synergy for the functionalization of heteroaromatics”.
Maria Ivanova thanks the Alexander von Humboldt foundation
for a fellowship.
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Entry for the Table of Contents
Key topic: Thiophene aminations
FULL PAPER
Salima Bouarfa, Simon Graβl, Maria
Ivanova, Timothy Langlais, Ghenia
Bentabed-Ababsa,* Frédéric Lassagne,
William Erb, Thierry Roisnel, Vincent
Dorcet, Paul Knochel* and Florence
Mongin*
Page No. – Page No.
Both copper- and cobalt-catalyzed aminations of arylzincs using N-benzoyloxy
amines are possible. Thus, thienylzincs prepared by transmetalation from
thienylmagnesium halides obtained by various methods including deprotometalation
were aminated with success. In addition, triarylamines were prepared from
aminothiophenes by consecutive copper-catalyzed N-arylations using iodoarenes.
Copper- and Cobalt-Catalyzed
Syntheses of Thiophene-Based
Tertiary Amines
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