Palladium catalysed amination of electron deficient halothiophenes

Article abstract of DOI:10.1016/S0040-4039(00)01307-1

A range of functionalised aminothiophenes has been prepared via palladium-catalysed aminations. The reaction proceeds in high yield when the halide is conjugated to an electron-withdrawing group and is suitable for a wide variety of amines. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01307-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 7731–7735
Palladium catalysed amination of electron deficient
halothiophenes
Tim J. Luker,a,* Haydn G. Beaton,a Mat Whiting,b Antonio Metea and
David R. Cheshirea
aAstraZeneca R&D Charnwood, Medicinal Chemistry, Bakewell Road, Loughborough, LE11 5RH, UK
bSchool of Chemistry, University of Nottingham, University Park, Nottingham, NG7 2RD, UK
Received 19 June 2000; accepted 31 July 2000
Abstract
A range of functionalised aminothiophenes has been prepared via palladium-catalysed aminations. The
reaction proceeds in high yield when the halide is conjugated to an electron-withdrawing group and is
suitable for a wide variety of amines. © 2000 Elsevier Science Ltd. All rights reserved.
Functionalised thiophenes form an integral part of numerous natural products1 and pharma-
ceuticals.2 They are often used within medicinal chemistry as phenyl ring isosteres, allowing fine
tuning of the properties of potential drug molecules.3 As part of a drug discovery program, we
required a diverse range of stable secondary- and tertiary-aminothiophenes. These needed to
contain useful functionality, both appended onto the nitrogen and on the aryl ring itself, to
allow further molecular diversification. No broadly applicable methodology existed for the
synthesis of this class of compound. The Gewald reaction is the most well established route,4 but
is limited to the synthesis of 2-aminothiophenes containing very unreactive primary-amines
(often vinylogous amides) which are difficult to functionalise further. Certain halothiophenes
undergo nucleophilic aromatic substitution with amines, however this reaction is limited to very
electron deficient aromatics containing nitro- and occasionally aldehyde-substituents.5 The
palladium-catalysed amination of halobenzenes has been thoroughly delineated over the last
decade, primarily by the groups of Buchwald6 and Hartwig,7 allowing the coupling of most
classes of amine with virtually any halobenzene. Application of this methodology to other
heterocyclic aromatics is still relatively unexplored.8 Watanabe recently reported the first
Pd-catalysed bromothiophene amination, showing that relatively electron rich mono- and
di-bromothiophenes could be coupled with diarylamines using a Pd(OAc)2/P(tBu)3 catalyst
system.9 These reactions required a strong base (NaOtBu) at 120°C, making them incompatible
* Corresponding author. Tel: +44(0)1509645457, fax: +44(0)1509645507; e-mail: tim.luker@astrazeneca.com
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01307-1

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with the broader range of functionality we required. To the best of our knowledge, this is the
only reported application of Pd-catalysed amination methodology to halothiophenes. Herein we
detail initial Pd-catalysed cross coupling results obtained with functionalised halothiophenes and
a broad selection of useful amines.
The cross coupling of 3-bromothiophene-2-carboxylic acid methyl ester with n-butylamine
was selected for optimisation of reaction conditions. Palladium source, ligand, solvent, base,
temperature and stoichiometry were optimised, eventually leading to the General Conditions A
which afforded a 94% isolated yield of the expected product (Table 1, entry 1).10 Several details
are worthy of comment. Firstly, no reaction occurred in the absence of catalyst. BINAP was a
superior ligand to other chelating phosphines such as DPPF and DPPP. In addition to Pd2dba3,
Pd(OAc)2 was also an effective palladium source, crucial in couplings of some of our other
halothiophenes (vide infra). Toluene and dioxane were useful solvents. No other metal carbon-
Table 1
Palladium-catalysed amination halothiophenes
Entry
Thiophene
Br
Amine
Product
Conditionsa Yieldb
NHBu
A
B
94 (100)
78 (85)
1
BuNH2
CO2Me
CO2Me
S
S
S
S
S
S
S
S
S
S
2
3
4
5
6
7
PhNHMe
BuNH2
CO2Me
CO2Me
NHBu
Br
Ph(Me)N
Br
A
A or B
A
89 (100)
- (0)
CN
CN
Br
Ph(Me)N
PhNHMe
BuNH2
CN
CN
S
S
S
S
Br
Cl
NHBu
- (7)
Cl
Cl
NHBu
A or B
A or B
- (68)
- (96)
BuNH2
CO2Me
CO2Me
NHBu
OTf
BuNH2
CO2Me
CO2Me
(a) Reaction conditions: 1.0 eq thiophene, 1.2 eq amine, 1.4 eq Cs2CO3, 5 Mol% Pd2dba3 (General
Conditions A) or 10 Mol% Pd(OAc)2, (General Conditions B), 10 Mol% BINAP, toluene (0.1 M),
110 oC, 20 h under N2.
(b) Isolated yield of compounds >95% pure by HPLC analysis, GC yield in parenthesis.

7733
Table 2
Pd-catalysed amination of 3-bromothiophene-2-carboxylic acid methyl estera
Br
NRR'
Pd(0)
RR'NH
CO2Me
CO2Me
S
S
Entry
Amine
Yieldb
Entry
1
Amine
Yieldb
tBuNH2
40 (50)c
PhNH2
98 (100)
- (100)
- (83)
6
7
NH2
2
3
4
PhNHMe
BnNHMe
67 (72)
93 (-)
TBSO
O
NH2
8
O
BOCNH
tBuO2C
NH2
NH2
- (100)
92 (-)
9
83 (-)
MeN
NH
10
11
85 (100)
- (19)d
5
Ph
NH2
Et2NH
(a) Reaction conditions: General conditions A (see table 1).
(b) Isolated yield of compounds >95% pure by HPLC analysis, GC yield in parenthesis.
(c) 36 h. (d) 40% DPPF used in place of BINAP.
ate or tertiary amine base was as effective as caesium carbonate, and stronger bases (NaOtBu)
resulted solely in amide formation. Finally, later experiments showed similar levels of conversion
could be obtained in the presence of catalyst loadings down to 0.1 mol% Pd.
Aminations of a range of other halothiophenes were investigated11 (Table 1). The structure of
the halothiophene was found to have a profound effect on the reaction yield. When the halogen
is conjugated to the electron-withdrawing group (2,3- or 2,5-isomers) an excellent yield of the
desired product is obtained (entries 1–3). Surprisingly, changing the palladium source to
Pd(OAc)2 (General Conditions B), lead to vastly improved reaction yields with the 2,5-isomer.
By contrast, the coupling reaction of the 2,4-isomer completely fails (entry 4). Moderately
electron deficient thiophenes are required (entry 5), and finally, chloride and triflate are both
useful leaving groups in this reaction (entries 6–7). Our ability to synthesise moderately electron
deficient aminothiophenes for the first time compliments the results of Watanabe9 (more electron
rich analogues), and nucleophilic aromatic substitutions5 (highly electron deficient analogues).
Table 2 shows the cross coupling results obtained with 3-bromothiophene-2-carboxylic acid
methyl ester and a diverse selection of amines.12 Virtually all classes of amine were successfully
coupled in excellent yield. The reaction was relatively inert to steric encumbrance within the
t
amine component (entries 1–6), and only when butylamine was used did the reaction rate slow
significantly. A wide range of functionality useful for further elaboration was well tolerated
(entries 7–10). The only obvious limitation was our inability to couple secondary acyclic amines
in high yield (entry 11). These have also been the most demanding examples in the analogous
reaction of the halobenzenes, requiring the development of new ligand systems. Unfortunately,
these ligands (such as PPFA6a and (o-biphenyl)PCy2 6c), as well as more established catalytic

7734
systems, were all equally ineffective with the halothiophenes investigated. The best conversion
(19%) we have been able to achieve with diethylamine utilised DPPF as the ligand, however the
reaction also afforded significant quantities of the desbromothiophene dimer (entry 11). The
failure of the less electron releasing ligand (PPFA) may be attributable to its poor performance
when coupling secondary amines with ortho-substituted aryl bromides.13 The failure of the more
electron rich ligand (o-biphenyl)PCy2) may be due to the fact that it would be expected to
reduce the acidity of NH proton in the ArPd(II)Br-amine catalytic intermediate, perhaps
inhibiting its removal by the weaker caesium carbonate base.14
In conclusion, we have shown for the first time that the palladium catalysed amination of
electron deficient halothiophenes is a generally useful reaction for the synthesis of a broad range
of functionalised aminothiophenes. These results compliment those obtained previously with
more electron rich thiophenes and give access to a number of building blocks useful within the
pharmaceutical industry. Future work will include efforts to circumvent the current limitations
(non-conjugated halides and secondary acyclic amines) and will be reported in due course.
Acknowledgements
We thank Professor Nigel Simpkins and Dr. Steve Clark (University of Nottingham) for their
interest in this project.
References
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2. Source: World Drug Index, Derwent Information 2000 (www.derwent.co.uk).
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D. G. Bioorg. Med. Chem. Lett. 1999, 9, 443–448.
4. (a) Gronowitz, S. Thiophene and it’s Derivatives, Wiley Interscience, New York, 1985. (b) Pinto, I. L.; Jarvest, R.
L.; Serafinowska, H. T. Tetrahedron Lett. 2000, 41, 1597–1600.
5. Prim, D.; Kirsch, G.; Nicoud, J.-F. Synlett 1998, 383–384 and references cited therein.
6. (a) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. Acc. Chem. Res. 1998, 31, 805–818. (b) Wolfe, J.
P.; Buchwald, S. L. J. Org. Chem. 2000, 65, 1144–1157. (c) Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J.;
Buchwald, S. L. J. Org. Chem. 2000, 65, 1158–1174 and references cited therein.
7. (a) Hartwig, J. F. Angew. Chem., Int. Ed. Engl. 1998, 37, 2046–2067. (b) Hartwig, J. F.; Kawatsura, M.; Hauck,
S. I.; Shaughnessy, K. H.; Alcazar-Roman, L. M. J. Org. Chem. 1999, 64, 5575–5580 and references cited therein.
8. For halopyridines see references 6a,c.
9. Watanabe, M.; Yamamoto, T.; Nishiyama, M. J. Chem. Soc., Chem Commun. 2000, 133–134.
10. General Conditions A: To the halothiophene (1 mmol), Cs2CO3 (1.4 mmol), Pd2(dba)3 (0.05 mmol, 10 mol% Pd)
and BINAP (0.1 mmol, 10 mol%) under nitrogen were added toluene (10 ml) followed by the amine (1.2 mmol),
and the reaction was stirred at 110°C for 20 h. After cooling to room temperature (and GC–MS analysis), the
reaction mixture was pre-absorbed onto silica and purified by flash chromatography to yield the aminothiophene
product. For Table 1, entry 1, flash chromatography (33% DCM in iso-hexane) afforded 3-butylaminothiophene-
2-carboxylic acid methyl ester as a colourless oil (201 mg, 94%). IR: wmax 1663 cm−1 1H NMR: (300 MHz,
.
CDCl3) l 7.32 (1H, d, J=6 Hz), 6.75 (1H, s), 6.63 (1H, d, J=6 Hz), 3.81 (3H, s), 3.26 (2H, q, J=7 Hz),
1.56–1.66 (2H, m), 1.41 (2H, sextet, J=7 Hz), 0.95 (3H, t, J=7 Hz). MS (EI): m/z 213 (M+). HRMS: calcd for
C10H15NO2S: 214.0902. Found: 214.0910. General Conditions B were as A but used Pd(OAc)2 (10 mol%) as the
palladium source.
11. Isolated yields refer to pure compounds (>95% by HPLC) characterised by NMR, IR, HPLC–MS and
combustion analysis (solids) or HRMS (oils).

7735
12. Initial experiments reveal these amines react similarly with the corresponding 2-bromothiophene-5-carboxylic acid
methyl ester.
13. This effect was originally noted for the analogous PPF–OMe ligand: Marcouw, J.-F.; Wagaw, S.; Buchwald, S.
L. J. Org. Chem. 1997, 62, 1568–1569.
14. Some indirect evidence for this does exist—Hartwig found when using the electron rich ligand (P(tBu)3) to
mediate Pd-catalysed coupling between p-bromotoluene and dibutylamine the reaction proceeded in 4 h at room
temperature with a strong base (NaOtBu), whereas with caesium carbonate the reaction required 12 h at 100°C
(see reference 7b).
.