Copper-catalyzed amidations of bromo substituted furans and thiophenes

Article abstract of DOI:10.1016/S0040-4039(02)01725-2

The C-N cross-coupling reaction between aromatic halides and amides has now been applied to 2- and 3-substituted bromofurans and bromothiophenes. Catalytic CuI in the presence of N,N′-dimethylethylenediamine as a ligand and K₃PO₄ or K₂CO₃ as the base furnished 2- and 3-substituted amidofurans and thiophenes ranging from 11 to 99% depending on the particular amide source used.

Full text of DOI:10.1016/S0040-4039(02)01725-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7365–7368
Copper-catalyzed amidations of bromo substituted furans and
thiophenes
Kenneth R. Crawford and Albert Padwa*
Department of Chemistry, Emory University, Atlanta, GA 30322, USA
Received 4 June 2002; revised 11 July 2002; accepted 16 August 2002
Abstract—The CꢀN cross-coupling reaction between aromatic halides and amides has now been applied to 2- and 3-substituted
bromofurans and bromothiophenes. Catalytic CuI in the presence of N,N%-dimethylethylenediamine as a ligand and K3PO4 or
K2CO3 as the base furnished 2- and 3-substituted amidofurans and thiophenes ranging from 11 to 99% depending on the
particular amide source used. © 2002 Published by Elsevier Science Ltd.
The stereoselective construction of nitrogen heterocy-
cles constitutes an area of considerable interest in
organic chemistry.1 In connection with a current project
dealing with the Diels–Alder cycloaddition of 2-amido
substituted furans for alkaloid synthesis,2 we required a
diverse range of stable secondary and tertiary amido-
furans. No broadly applicable method exists for the
synthesis of this class of compounds. Previously, we
had used a Curtius reaction to prepare various furano
carbamate derivatives via a transient isocyanate inter-
mediate (Scheme 1).3 Although formation of the
furanyl carbamate proceeded in excellent yield, our
efforts to trap the initially formed isocyanate 3 with
numerous organometallic reagents only afforded low
yields of the desired amide 5.
Disconnection of the CꢀN bond in 5 between the
furan carbon and amide nitrogen represents an alter-
nate and very appealing approach to this system. CꢀN
cross-coupling of aryl halides with amines has been the
subject of intense studies in recent years, primarily by
the groups of Buchwald4 and Hartwig.5 Application of
this methodology to various heteroaromatic com-
pounds is still
a
relatively unexplored process.6
Although there existed some precedence for the transi-
tion-metal promoted cross-coupling of azoles,6 there
were only limited reports on the coupling of
thiophenes7 and, to the best of our knowledge, no
examples using furans. The first reported case of a
Pd-catalyzed amination of a bromothiophene involved
coupling with diarylamines using a Pd(OAc)2/P(t-Bu)3
Scheme 1.
* Corresponding author. Fax: 404-727-6586; e-mail: chemap@emory.edu
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)01725-2

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K. R. Crawford, A. Padwa / Tetrahedron Letters 43 (2002) 7365–7368
catalyst system.8 These reactions required a strong base
(NaOt-Bu) at 120°C, making it incompatible with the
broader range of functionality we required. More
recently, the Buchwald group demonstrated that the
CuI-catalyzed amidation of aryl and heteroaryl halides
provides an excellent complement to the Pd-catalyzed
methodology.7a Since the scope of this method toward
heteroaromatics was quite limited when we started our
work, we became interested in determining whether the
tandem cross-coupling/cycloaddition sequence outlined
in Scheme 2 could be used to prepare various hexahy-
droindole alkaloids. Herein we detail our CꢀN cross
coupling results using several bromo substituted thio-
phene and furans with a broad selection of useful
amido substrates.
After a thorough screening of various catalytic systems
(including several Pd(0) catalysts and bis-phosphine
ligand combinations), we found that Buchwald’s CuI
catalytic system gave the most consistent and promising
results.7a Thus, when a mixture of 3-bromothiophene
and 2-oxazolidone together with 1 mol% of air-stable
CuI, 10 mol% of N,N-dimethylethylenediamine, and
K3PO4 was heated at 110°C, the desired coupling
product 10a was formed in almost quantitative yield.
Encouraged by this facile union, a systematic study was
conducted to investigate the generality of the coupling
reaction, as well as its scope and limitations. As shown
in Table 1, both primary and secondary amides, includ-
ing lactams, as well as carbamates can be coupled to a
variety of thiophene halides in modest to excellent yield
Scheme 2.
Table 1. Copper-catalyzed amidation of thiophene halides

K. R. Crawford, A. Padwa / Tetrahedron Letters 43 (2002) 7365–7368
7367
Table 2. Copper-catalyzed amidation of furan halides
depending on the particular amide source used.9 In
general, 1–10 mol% of air-stable CuI in combination
with N,N-dimethylethylenediamine or racemic N,N-
dimethyl-trans-cyclo-hexanediamine was employed.10
As a base, either K3PO4 or K2CO3 was used with
dioxane as the solvent at 90–110°C for 12–24 h. As can
be seen in entries 10c–g, the presence of a formyl group
at the 5-position of the thiophene ring showed no
deleterious effect. Even 2-bromothiazole underwent a
related cross-coupling to give 10l in 58% yield.
using the 2-bromofuran isomer provided the desired
amides (i.e. 11j, 11k, 11l and 11m) in 67–99% yield
which bodes well for the planned cascade sequence
outlined in Scheme 2. Only when o-nitrobenzamide was
employed as the amide source were low yields (30%)
encountered.
In summary, 2- and 3-amido substituted thiophenes
and furans can be prepared from the CꢀN cross cou-
pling reaction of various bromo heteroaromatics with
amides, carbamates and lactams. The route is flexible
and allows for the preparation of highly substituted
amido heteroaromatic substrates. Efforts to improve
and expand upon the utility of the method and a study
of its application toward unsaturated furanyl amides
are currently in progress and will be reported in due
course.
The CꢀN cross coupling reaction of various 2-furanyl
bromides are detailed in Table 2. The reactions were
conducted under conditions similar to those used in
Table 1.11 As can be seen from Table 2, the efficiency of
the amidation of the 3-bromo isomer was very sensitive
to the substrates used. Reaction with tert-butyl carba-
mate afforded 11a in 97% yield. However, employing
benzyl carbamate as the source of nitrogen produced
11b in only 27% yield. With benzamide and o-tolu-
amide, the coupling products 11c and 11d were isolated
in 98 and 86% yields, respectively. However, when
benzanilide was used as the amide, carbamate 11i was
obtained in only 11% yield. The coupling of
pyrrolidone with 3-bromofuran furnished the expected
lactam in 80% yield. Increasing the ring size of the
lactam significantly diminished the yield of the cross-
coupled lactam [i.e. 11g (19%) and 11h (11%)]. Most
importantly, however, the CꢀN cross coupling reaction
Acknowledgements
We gratefully acknowledge support of this work by the
National Science Foundation (grant CHE-0132651).
References
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1 1998, 3493.

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K. R. Crawford, A. Padwa / Tetrahedron Letters 43 (2002) 7365–7368
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(IR, NMR, elemental analysis and/or HRMS).
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N,N-dimethyl-trans-cyclohexane diamine was employed.
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mol%) and K2CO3 (4.3 mmol) under argon was added
dioxane (3 mL) followed by N,N%-dimethyl ethylenedi-
amine (0.1 mmol, 10 mol%), 3-bromofuran (1.0 mmol)
and t-butyl carbamate (1.2 mmol). The reaction mixture
was stirred at 110°C for 24 h, cooled to 25°C, diluted
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1
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