Pd-catalyzed C-N bond formation with heteroaromatic tosylates

Article abstract of DOI:10.1002/chem.200903235

A protocol for the palladium(0)-catalyzed amidation of heteroaromatic tosylates was successfully developed. The methodology proved to be effective for a variety of heteroaryl tosylates including the pyridine, pyrimidine, quinoline and quinoxaline ring systems. Successful carbon-nitrogen bond formation with these heteroaryl tosylates could be performed with a wide range of primary amides, oxazolidinones, lactams, anilines and indoles, including one cyclic urea. Moreover, this C-N bond forming reaction provided products with high structural diversity. The coupling reaction was also amenable to scale up applications.

Full text of DOI:10.1002/chem.200903235

FULL PAPER
DOI: 10.1002/chem.200903235
À
Pd-Catalyzed C N Bond Formation with Heteroaromatic Tosylates
Mette L. H. Mantel, Anders T. Lindhardt,* Daniel Lupp, and Troels Skrydstrup*[a]
Dedicated to Professor Anders Kjær on the occasion of his 90th birthday
Abstract: A protocol for the palladi-
um(0)-catalyzed amidation of heteroar-
omatic tosylates was successfully devel-
oped. The methodology proved to be
effective for a variety of heteroaryl to-
sylates including the pyridine, pyrimi-
dine, quinoline and quinoxaline ring
bond formation with these heteroaryl
tosylates could be performed with a
wide range of primary amides, oxazoli-
dinones, lactams, anilines and indoles,
including one cyclic urea. Moreover,
À
this C N bond forming reaction pro-
vided products with high structural di-
versity. The coupling reaction was also
amenable to scale up applications.
Keywords: aryl tosylates · hetero-
À
geneous catalysis · C N bond for-
mation · heterocycles · palladium
À
systems. Successful carbon nitrogen
Introduction
aryl tosylates, being easily accessible from the corresponding
alcohols, to undergo effective Pd-catalyzed Mizoroki–Heck
reactions with electron-rich alkenes, providing a rapid route
to precursors of benzylic amines and aryl ketones.[4] Further-
more, we demonstrated that the same substrates could par-
ticipate in Fe-mediated cross-coupling reactions with a vari-
ety of Grignard reagents.[5] In this paper, we expand the ap-
plication of these heteroaromatic tosylates to include Pd-
catalyzed amidation reactions with a variety of heteroaro-
matic tosylates. This protocol appears highly suitable for in-
troducing a wide range of amide structures, as well as other
related nitrogen-based nucleophiles such as anilines and in-
doles.
À
Palladium-catalyzed C N bond forming reactions represent
important transformations for the functionalization of aro-
matic ring systems with applications in both academia and
industry.[1] Whereas these reactions have traditionally been
performed with aryl halides and triflates, increasing efforts
have been undertaken in recent years to extrapolate these
transformations to other derivatives such as aryl tosylates.[2]
In particular, this latter class of starting materials has several
advantages such as 1) typically higher crystallinity compared
with triflates or halides, which facilitates their handling,
2) superior chemical stability compared with the triflates,
and 3) the generally greater accessibility of heteroaryl alco-
hols compared with the corresponding halides.
Nitrogen heterocycles are important constituents of many
pharmacologically active compounds and organic materials
and hence facile methods for the introduction of a range of
ring substituents are of high interest.[3] We have recently re-
ported the aptitude of 2-pyridyl tosylates and other hetero-
Results and Discussion
The work presented here began with the intention of devel-
oping general reaction conditions for the Mizoroki–Heck re-
action between heteroaromatic tosylates and electron-poor
olefins. Initial efforts in this line were not so successful and
after considerable screening the best results obtained in the
coupling of 2-pyridyl tosylate (1) with tert-butyl acrylamide
[a] M. L. H. Mantel, Dr. A. T. Lindhardt, D. Lupp,
Prof. Dr. T. Skrydstrup
(2) employed a palladium catalyst prepared from PdACHTUNGTRENNUNG(OAc)2
The Center for Insoluble Protein Structures (inSPIN)
Department of Chemistry and the
Interdisciplinary Nanoscience Center
Aarhus University, Langelandsgade 140, 8000 Aarhus C (Denmark)
Fax : (+45)8619-6199
and X-Phos, providing the desired coupling product 3 in ap-
proximately 30% yield (Scheme 1). Attempts to improve
the yield by replacing the acrylamide with the N-acryloyl ox-
azolidinone (4) were not rewarding, but interestingly the
amidation product 5 could be isolated in a 20% yield. Sus-
pecting that this product arose from the high-temperature
decomposition of the olefin 4 to 2-oxazolidinone (6) under
E-mail: lindhardt@chem.au.dk
ts@chem.au.dk
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200903235.
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5437

tion between 2-pyridyl tosylate (1) and 2-oxazolidinone (6)
and proved effective in promoting the reaction (entry 1).
Screening other diphosphine ligands disclosed that the
two ferrocene ligands, DiPrPF and DitBuPF, were equally
effective as DPPF (entries 8 and 9).[6] Diphosphines bridged
by aliphatic chains showed that a propyl spacer was more ef-
ficient than both ethyl and pentyl, suggesting that the bite
angle of the bidentate ligands is important for catalytic ac-
tivity (entries 2–4). Applying the nitrogen-based ligand phe-
nanthroline resulted in a complex mixture of products
(entry 5). On the other hand, BINAP and BDPPP also pro-
vided good coupling yields (entries 6 and 7), but still slightly
less efficient than that of the ferrocene based ligands. Con-
trol experiments conducted in the absence of catalyst or
ligand, resulted in no coupling yields (results not shown).
Changing the solvent to toluene lowered the yield to 74%
(result not shown). The amount of DPPF was successfully
lowered to 3 mol% (entry 10); however, 1 mol% of DPPF
resulted in a considerable drop in conversion (entry 11).
Likewise, the amount of 6 was lowered to 1.5 equivalents
(entries 12 and 13) and the lower limit for K2CO3 was found
to be 2 equivalents (entry 14). Switching the stoichiometry
of the two starting materials lowered slightly the yield of the
reaction to 95% (entry 15). Finally, two other bases were
tested for this amidation reaction. Na2CO3 resulted in a
comparable yield to K2CO3 (entry 16), whereas Cs2CO3
(entry 17) produced a complex mixture of products.
Scheme 1. Discovery of amidation protocol with heteroaromatic tosy-
lates.
the reaction conditions followed by a Pd0-catalyzed amida-
tion, we decided to pursue the possibility of using the het-
À
G
G
using the same reaction conditions and substituting 4 with 6,
the coupling yield of 5 could be improved to 50%.
In an effort to improve this amidation reaction, we exam-
ined other reaction conditions (ligand, base and solvent),
the results of which are depicted in Table 1. The combina-
tion of [Pd
G
The optimized conditions were then tested on a variety of
heteroaryl tosylates in combination with different types of
amides and similar nitrogen-based nucleophiles. Generally,
the amidations went to completion within 16 h and the prod-
ucts could be isolated by column chromatography in good to
excellent yields. At first, a number of primary amides were
applied in the amidation of heteroaromatic tosylates
(Table 2, entries 1–8). The steric bulk of the amide influ-
enced the yield in the coupling with 1, as shown in en-
tries 1–3. Whereas the isopentanoyl and isobutyryl amides
led to high yields, coupling with the pivaloyl amide provided
a 57% yield of the desired product. Other heteroaryl tosy-
lates including the pyrimidine, quinoline and quinoxaline
skeleton proved equally suitable for coupling with primary
amides including cyclopropanecarboxamide (entries 5–8).
In entries 9–11, it is shown that 2-oxazolidinones can also
be coupled to different heterocycles demonstrating the high
oxane as solvent was chosen as starting point for the reac-
Table 1. Optimization of amidation conditions.
Entry Ligand ([%])
1[c]
DPPF (5)
DPPP (5)
DPPE (5)
DPPPe (5)
2[c]
3[c]
4[c]
5[c]
1,10-phenanthroline (5) K2CO3 (3)
6[c]
BINAP (5)
BDPPP (5)
DiPrPF (5)
DtBuPF (5)
DPPF (3)
DPPF (1)
DPPF (3)
DPPF (3)
DPPF (3)
DPPF (3)
DPPF (3)
DPPF (3)
À
7[c]
efficiency of this coupling procedure for C N bond forma-
8[c]
tion with cyclic carbamates. Interestingly, the 2,4-ditosylated
quinoline underwent selective monocoupling at the 2-posi-
tion in a 91% isolated yield without formation of the
double coupled product (entry 12).
9[c]
10[c]
11[c]
12[d]
13[e]
14[d]
15[f]
16[d]
17[d]
While acyclic secondary amides failed to couple with the
heteroaromatic tosylates in satisfactory yields under the ap-
plied conditions, lactams demonstrated to be good nucleo-
philes for the amidations (entries 13–16).[7] Five- and seven-
membered lactams provided good yields of the amidation
products and, gratifyingly, even a b-lactam could be exploit-
[a] Yield of the isolated product. nd=not determined [b] Conversions in
parentheses are measured by H NMR analysis of crude reaction mixture.
[c] 3 equivalents of 6. [d] 1.5 equivalents of 6. [e] 1.2 equivalents of 6.
[f] 1 equivalent of 6, 1.5 equivalents of 1.
À
ed effectively for C N bond formation with a pyrimidyl to-
sylate (entry 16).
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À
Pd-Catalyzed C N Bond Formation
FULL PAPER
Table 2. Primary amides, lactames and oxazolidinones in the amidation
of heteroaromatic tosylates.
Table 2. (Continued)
Entry[a]
Product
Cpd.
Yield [%][b]
17
23
79[d]
Entry[a]
1
Product
Cpd.
Yield [%][b]
92
[a] 1.5 equivalents of nitrogen-based nucleophile. [b] Yield of the isolated
product. [c] Reaction performed on a 0.5 mmol scale with ditosylate
1.5 equiv and 6 1 equiv [d] Obtained as epimers.
7
2
3
4
8
99
57
86
The tolerance of a tertiary carbon next to the amide car-
bonyl (entry 2) led us to examine a dipeptide with a C-ter-
minal amide (entry 17). Its coupling with a substituted pyrid-
yl tosylate could be effectively promoted and no traces of
coupling products to the secondary amide or carbamate
were observed. Nevertheless, epimerization proved to be
problematic under this coupling protocol, which is undoubt-
edly related to the use of base at 1008C in dioxane.[8]
On the other hand, primary carbamates were sluggish
using this amidation protocol. However, a good yield of the
desired coupling products could be obtained upon modifying
the reaction conditions slightly and applying Xantphos as
the ligand (Scheme 2).[9]
9
10
5
6
11
12
99
99
7
8
13
14
65
94
9
15
16
98
95
10
Scheme 2. Couplings with primary carbamates.
Double amidation reactions were also quite effective as il-
lustrated with the products in Figure 1. Mono-substituted
urea derivatives failed to provide more than 65% conver-
sion (results not shown), however, the cyclic urea, 2-imida-
zolidinone, was applied in a double coupling with 1 provid-
ing the N,N’-disubstituted urea 27 in an excellent 99% yield.
Double coupling with oxamide provided the double amida-
11
12
17
18
97
91[c]
À
tion product 28 in a 76% yield. Two C N bond formations
13
14
19
20
83
94
with ditosylates as starting materials likewise produced the
double amidation products 29 and 30 in excellent yields.
We then tested the coupling protocol on aminations with
anilines as the nitrogen nucleophile (Figure 2).[10] Three ani-
lines with electron-donating and -withdrawing groups all
provided coupling products 31–33 in excellent yields. Even
indoles were satisfactory nucleophiles for these transforma-
tions as shown with the product 34 obtained in a 68%
yield.[11] In Scheme 3, it is demonstrated how three consecu-
tive transition-metal-catalyzed transformations can be ex-
15
16
21
22
97
69
À
ploited including the application of our C N bond protocol
for the synthesis of a highly functionalized indole skeleton.
We recently published a two-step AuI-catalyzed hydroami-
Chem. Eur. J. 2010, 16, 5437 – 5442
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5439

T. Skrydstrup, A. T. Lindhardt et al.
Table 3. Scale-up amidation.
Entry
Scale [mmol]
Catalytic
t [h]
Yield [%][a]
loading [%]
(conversion [%])
1
2
3
4
5
3
3
3
3
20
1
16[b]
1.25
1.5
48
99
99
99
0.5
0.1
0.01
0.1
(41)[c]
Figure 1. Double amidations.
1
96
[a] Yield of the isolated product. [b] Time not optimized. [c] Conversion
based on 6.
(entry 3). A catalytic loading of 0.01% resulted in 41% con-
version after a reaction time of 48 h (entry 4). Finally, the
scale was increased to 20 mmol of the pyrimidyl tosylate 39
and after one hour with 0.1% catalyst loading, the amida-
tion product 41 could be isolated in an excellent 96% yield
(3.7 g) (entry 5).
Finally, the possibility of applying pyridines with tosylates
either in 3- or 4-position was investigated and the prelimina-
ry results are discussed below. Whereas attempts to apply 3-
pyridyl tosylates in the amidation protocol failed, some in-
teresting results were obtained using 2-methyl-4-tosyl quino-
line.[2b] When this tosylate was subjected to the standard
conditions using 2-oxazolidinone as the coupling partner a
roughly 10% conversion was obtained (result not shown).
Changing the ligand to DtBuPF resulted in a 60% isolated
yield of 42 (Scheme 4). Also isobutyramide (44), a primary
amide, proved sufficiently reactive affording 43 in a 48%
isolated yield. Comparing 42 and 43 to the product obtained
in Table 2, entry 12, suggests the possibility of sequential
double couplings using 18 as reactant. Applying isobutyra-
mide DtBuPF only afforded approximately 13% isolated
yield of 45. On the other hand, switching to the JosiPhos
type ligand PPF-PtBu,[6] 45 could be secured in an accepta-
ble 46% isolated yield (Scheme 4).[13]
Figure 2. Indole and anilines as nucleophiles in the Pd-catalyzed amida-
tion.
Scheme 3. Synthesis of highly substituted indole with Au and Pd catalysis.
nation of anilines with ynamides followed by a Pd0-promot-
ed cyclization step.[12] Subsequent amination of the 2,3-sub-
stituted indole 38 with the pyrimidyl tosylate 39 furnished
the trisubstituted indole derivative 40 in a 99% yield.
Next, we decided to investigate the potential for scale-up
application of the amidation reaction, which is illustrated in
Table 3 for the coupling of the pyrimidyl tosylate 39 with 6.
Initial studies were conducted on a 3 mmol scale represent-
ing ten times the scale used in the previous couplings. Run-
ning these coupling reactions at a higher concentration and
lowering the catalytic loading to 1 and 0.5 mol% provided
41 in quantitative yield (entries 1 and 2). Even a catalyst
loading of 0.1% palladium and ligand provided 41 in quanti-
tative yield in 1.5 h, corresponding to a TON of 3000
Scheme 4. Couplings with 4-tosylated quinolines. [a] Reaction run with
PdACTHNUTRGEN(UNG OAc)2.
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À
Pd-Catalyzed C N Bond Formation
FULL PAPER
The reaction mixture was heated for 16 h at 1008C. The crude reaction
was filtered through Celite washing with CH2Cl2. After concentration in
vacuo, the crude product was purified by column chromatography.
Conclusion
We have successfully developed a protocol for the palladi-
um-catalyzed amidation of heteroaromatic tosylates where
the simple diphosphine ligand DPPF proved highly effec-
tive. A range of heteroaromatic tosylates including the pyri-
dine, pyrimidine, quinoline and quinoxaline ring systems
could be applied, in combination with a number of primary
amides, lactams, oxazolidinones, anilines and indoles. In-
creased catalytic activity was observed in a large-scale reac-
tion using catalyst loading of only 0.1%. Further efforts are
currently underway to increase the scope of this methodolo-
gy to include other heteroaromatic systems and to obtain an
optimized protocol for the 4-pyridyl tosylate derivatives.
This work will be reported in due course.
2-(4-Fluorophenylamino)-4,6-dimethylnicotinonitrile (32): 3-Cyano-4,6-
dimethyl-2-pyridinyl tosylate (90.7 mg, 0.30 mmol), p-fluoroaniline
(50.0 mg, 0.45 mmol), K2CO3 (82.9 mg, 0.60 mmol), DPPF (5.0 mg,
0.009 mmol) and [PdACTHNUTRGNEUNG(dba)2] (5.2 mg, 0.009 mmol) were dissolved in diox-
ane (2 mL) and reacted for 16 h at 1008C. The crude product was puri-
fied by flash chromatography on silica gel using CH2Cl2/pentane 33:67.
This afforded 70.5 mg of the title compound (97% yield) as a colorless
solid. M.p. 150–1518C; 1H NMR (400 MHz, CDCl3): d = 7.59 (dd, 2H,
J=8.8, 4.8 Hz), 7.04 (dd, 2H, J=8.8, 8.4 Hz), 6.89 (brs, 1H), 6.55 (s,
1H), 2.43 ppm (s, 6H); 13C NMR (100 MHz, CDCl3): d = 161.7, 159.0 (d,
J=241.2 Hz), 156.1, 153.0, 135.2, 122.2 (d, J=7.6 Hz), 116.4, 115.60,
115.59 (d, J=22.2 Hz), 90.7, 25.0, 20.6 ppm; 19F NMR (377 MHz, CDCl3):
d = À120.0 ppm. HRMS (ESI) m/z: calcd for C14H12FN3Na [M+Na+]:
264.0913, found: 264.0913.
Experimental Section
Acknowledgements
We thank the Danish National Research Foundation, the Danish Council
for Independent Research/Natural Science, the Lundbeck Foundation,
the Carlsberg Foundation, the iNANO Graduate School and Aarhus Uni-
versity for generous financial support of this work.
General procedure for amidations of heteroaromatic tosylates with
amides and carbamates: The pyridyl tosylate (1 equiv), amide/carbamate
(1.5 equiv), K2CO3 (2 equiv), DPPF (0.03 equiv) and [PdACHTNUTRGNEUNG(dba)2]
(0.03 equiv) were dissolved in dioxane (2 mL) and the sample vial was
fitted with a Teflon sealed screw cap and removed from the glove box.
The reaction mixture was heated for 16 h at 1008C. The crude reaction
was filtered through Celite washing with CH2Cl2. After concentration in
vacuo, the crude product was purified by column chromatography.
À
[1] For reviews on Pd-catalyzed C N bond formation, see: a) D. Surry,
S. L. Buchwald, Angew. Chem. 2008, 120, 6438–6461; Angew. Chem.
Int. Ed. 2008, 47, 6338–6361; b) L. Jiang, S. L. Buchwald in Metal-
Catalyzed Cross Coupling Reactions, Vol. 2, 2nd ed. (Eds.: A. de
Meijere, F. Diederich), Wiley-VCH, Weinheim, 2004, pp. 699–760;
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of Organic Synthesis, Vol. 1 (Eds.: E. I. Negishi, A. de Meijere),
Wiley, New York, 2002, pp. 1051–1096; e) A. R. Muci, S. L. Buch-
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pagne, D. Joseph, B. Andrioletti, Tetrahedron 2002, 58, 2041–2075;
g) J. F. Hartwig in Modern Amination Methods (Ed.: A. Ricci),
Wiley-VCH, New York, 2000, pp. 195–262; h) B. H. Yang, S. L.
Buchwald, J. Organomet. Chem. 1999, 576, 125–146; i) J. P. Wolfe, S.
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2615–2623.
N-(2,6-Dimethylpyrimidin-4-yl)-2-(2-oxopyrrolidin-1-yl)acetamide (11):
Compound 39 (83.5 mg, 0.30 mmol), 2-(2-oxopyrrolidin-1-yl)acetamide
(64.0 mg, 0.45 mmol), K2CO3 (82.9 mg, 0.60 mmol), DPPF (5.0 mg,
0.009 mmol) and [PdACHTUNGTRENNUNG(dba)2] (5.2 mg, 0.009 mmol) were dissolved in diox-
ane (2 mL) and reacted for 16 h at 1008C. The crude product was puri-
fied by flash chromatography on silica gel using MeOH/CH2Cl2 3:97.
This afforded 74.0 mg of the title compound (99% yield) as a colorless
1
solid. M.p. 169–1708C; H NMR (400 MHz, CDCl3): d = 8.55 (brs, 1H),
7.76 (s, 1H), 4.11 (s, 2H), 3.54 (t, 2H, J=7.2 Hz), 2.55 (s, 3H), 2.50 (t,
2H, J=8.0 Hz), 2.46 (s, 3H), 2.17–2.10 ppm (m, 2H); 13C NMR
(100 MHz, CDCl3): d = 176.6, 169.1, 167.7, 167.5, 156.9, 106.2, 48.6, 48.2,
30.3, 25.8, 24.6, 18.2 ppm; HRMS (ESI): m/z: calcd for C12H16N4O2Na:
271.1171, found: 271.1171 [M+Na+].
General procedure for double amidations: The diamide or ditosylate
(1 equiv), heteroaryl tosylate or amide (3 equiv), K2CO3 (4 equiv), DPPF
(0.06 equiv) and [PdACHTUNGTRENNUNG(dba)2] (0.06 equiv) were dissolved in dioxane (2 mL)
and the sample vial was fitted with a Teflon sealed screw cap and re-
moved from the glove box. The reaction mixture was heated for 16 h at
1008C. The crude reaction was filtered through Celite washing with
CH2Cl2. After concentration in vacuo, the crude product was purified by
column chromatography.
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0.3 mmol), 1 (224.4 mg, 0.9 mmol), DPPF (10.0 mg, 0.018 mmol) and [Pd-
ACHTUNGTRENNUNG(dba)2] (10.4 mg, 0.018 mmol) were dissolved in dioxane (2 mL) and re-
acted for 16 h at 1008C. The crude product was purified by flash chroma-
tography on silica gel using Et2O/CH2Cl2 3:97 as eluent. This afforded
71.5 mg of the title compound (99% yield) as a colorless solid. M.p. 182–
1838C; 1H NMR (400 MHz, CDCl3): d = 8.35–8.30 (m, 4H), 7.68 (ddd,
2H, J=8.4, 7.2, 1.6 Hz), 6.98 (ddd, 2H, J=7.2, 5.2, 1.2 Hz), 4.19 ppm (s,
4H); 13C NMR (100 MHz, CDCl3): d = 154.6, 152.3, 147.6, 137.5, 118.5,
113.5, 40.8 ppm; HRMS (ESI): m/z: calcd for C13H12N4ONa: 263.0909,
found: 263.0905 [M+Na+].
General procedure for aminations of heteroaromatic tosylates with ani-
À
lines and indoles: The pyridyl tosylate (1 equiv), indole/aniline
some recent examples of C N bond formation with heteroaromatic
(1.5 equiv), K2CO3 (2 equiv), DPPF (0.03 equiv) and [Pd
N
systems, see h) G. B. W. L. Ligthart, H. Ohkawa, R. P. Sijbesma,
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(0.03 equiv) were dissolved in dioxane (2 mL) and the sample vial was
fitted with a Teflon sealed screw cap and removed from the glove box.
Chem. Eur. J. 2010, 16, 5437 – 5442
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5441

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DPPP=1,3-bis(di-
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phenylphosphino)-1,1’-binaphthalene, BDPPP=bis(2-diphenylphos-
phinophenylether),
cene, DitBuPF=1,1’-bis(ditertbutylphosphino)ferrocene.
DiPrPF=1,1’-bis(diisopropylphosphino)ferro-
PPF-
PtBu=(2R)-1-[(1R)-1-[bis(1,1-dimethylethyl)phosphino]ethyl]-2-(di-
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[9] For recent papers on the use of Xantphos with carbamates, see:
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Received: November 26, 2009
Published online: April 6, 2010
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