Flexible palladium-catalysed amidation reactions for the synthesis of complex aryl amides

Article abstract of DOI:10.1016/j.tetlet.2010.03.051

This Letter describes the synthesis of complex aryl amides using palladium-catalysed amidation reactions. Use of these conditions allowed for the coupling of a variety of aryl halides and triflates with a host of primary amides in high yields.

Full text of DOI:10.1016/j.tetlet.2010.03.051

Tetrahedron Letters 51 (2010) 2685–2689
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Flexible palladium-catalysed amidation reactions for the synthesis
of complex aryl amides
Christopher Barfoot a, Gerald Brooks b, Pamela Brown b, Steven Dabbs a, David T. Davies b, Ilaria Giordano a,
b
b
a
c
Alan Hennessy a, , Graham Jones , Roger Markwell , Timothy Miles , Neil Pearson ,
*
Christian A. Smethurst b
a Antibacterial Discovery Performance Unit, Infectious Diseases CEDD, GlaxoSmithKline, Gunnels Wood Road, Stevenage, SG1 2NY, UK
b Antibacterial Discovery Performance Unit, Infectious Diseases CEDD, GlaxoSmithKline, Third Avenue, Harlow, CM19 5AW, UK
c Antibacterial Discovery Performance Unit, Infectious Diseases CEDD, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
This Letter describes the synthesis of complex aryl amides using palladium-catalysed amidation reac-
tions. Use of these conditions allowed for the coupling of a variety of aryl halides and triflates with a host
of primary amides in high yields.
Received 2 February 2010
Revised 26 February 2010
Accepted 12 March 2010
Available online 17 March 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Since the early publications on palladium-catalysed amidation
of aryl halides were reported (Buchwald, Shakespeare and Har-
twig), there has been an increasing use of these transformations
in academic and industrial groups.1,2 In this Letter, we describe
the use of this reaction for the formation of complex aryl-amides
1, which we required for our medicinal chemistry programme
(Scheme 1, Eq. 1). Amides of type 1 were used as intermediates to-
wards compounds with anti-bacterial activity against a range of
clinically relevant organisms.3 For our initial work towards target
2, we used a classical amide coupling strategy between amine 3
and carboxylic acid 4 (Scheme 1, Eq. 2). This coupling worked well
although it required more forcing conditions than typical amide
coupling reactions. However, this coupling depends on the avail-
ability of amine 3. These amines generally derive from the corre-
sponding aryl halide or triflate (Scheme 2) and all typically
required a linear multi-step synthesis.4 Of particular note is the
formation of 3 via the reaction of a precursor triflate with propyl-
amine hydrochloride under forcing conditions.5
We therefore decided to focus on an alternative disconnection
which would allow for the use of more synthetically accessible aryl
halides and/or triflates.
Another major issue in driving this change of approach was that
efficient though the HATU coupling was, switching to
acids led to a complex mixture of products.
a-hydroxy
O
O
Pd catalysis
Aryl Halide
O
HN
Ar
O
H2N
or
+
Aryl Triflate
(eq 1)
N
H
O
N
H
O
X
X
1: X = H, OH, OMe, F, etc
O
O
NH2
HATU, Et3N
DMF, 60 ºC
O
HN
N
O
N
O
HO
(eq 2)
O
N
+
N
O
60%
N
H
O
H
N
2
3
4
Scheme 1. Initial synthesis of aryl amides and the proposed retrosynthetic disconnection for more complex amides.
* Corresponding author. Tel.: +44 1438762654.
E-mail address: alan.j.hennessy@gsk.com (A. Hennessy).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.03.051

2686
C. Barfoot et al. / Tetrahedron Letters 51 (2010) 2685–2689
O
(1) methyl propiolate
methanol, rt, 48 h
(2) Dowtherm A
reflux, 20 min
We believed that this additional functionality was hindering an
already slow amide-coupling process allowing for numerous com-
petitive side-reactions to take place instead. We therefore required
a solution to our problem which would tolerate this functionality
and provide more efficient access to our complex aryl amide
targets.
N
O
N
O
N
H
NH2
34%, 2 steps
2,6-lutidine,
DMAP,Tf2O
rt, 2.5 h
After analysing the literature and following in-house experience
we investigated coupling conditions using a palladium-BINAP
complex formed in situ and caesium carbonate as a base. To our
delight the coupling reaction proceeded cleanly and in high yield.
These reactions were performed on a variety of scale from milli-
gram to multigram, thus outlining their robust nature. For our first
product 6, the yield was essentially quantitative and standard col-
umn chromatography removed all relevant impurities.
75%
NH2
N
OTf
N
propylamine.HCl
pyridine,
N
N
O
O
reflux, 4 h
63%
3
To our knowledge, this was the first example of a palladium-
catalysed coupling of an
a
-hydroxy amide in this manner.6 Exam-
Scheme 2. A typical synthesis of a triflate and an amino-naphthyridine.
Table 1
Amidation of a variety of aryl halides and triflates using amide 5aa
O
O
Pd2(dba)3, (+/-)-BINAP
Cs2CO3, 1,4-dioxane
85-105 ºC, 18-24 h
OH
OH
O
O
H2N
HN
Ar
Ar-X
+
N
O
N
H
O
X = Br or OTf
H
5a
6-23
Entry
1
Ar-X
Productb (yield %)
OTf
N
O
6 (>95)
N
OTf
N
2c
7 (79)
8 (65)
OTf
OTf
N
O
O
3
4
5
9 (53)
N
F
OTf
N
10 (72)
11 (40)
12 (72)
N
OTf
F
6
N
F
OTf
N
N
O
7c

C. Barfoot et al. / Tetrahedron Letters 51 (2010) 2685–2689
2687
Table 1 (continued)
Entry
Ar-X
Productb (yield %)
OTf
N
N
8
9
13 (90)
14 (25)
Br
N
O
O
Br
N
O
O
10
11
15 (13)
O
N
Br
N
O
16 (>95)
Br
O
12
13
17 (92)
18 (34)
N
Br
O
N
Br
N
O
14
19 (18)
Br
N
O
15
16
17
20 (74)
21 (94)
22 (84)
23 (94)
N
Br
N
Br
S
N
Br
N
N
18
a
Reaction conditions: aryl halide or triflate (1 equiv), amide (1.05 equiv), Pd2(dba)3 (3 mol %), ( )-BINAP (6 mol %), Cs2CO3 (2.5 equiv), 1,4-dioxane, 85–105 °C, 18–24 h.
Isolated yield.
Xantphos was used instead of ( )-BINAP.
b
c
ination of the reaction mixtures showed no evidence of competing
These coupling conditions proved to be general for a host of di-
verse aryl halides and triflates (Table 1). This was extremely bene-
ficial due to the wide availability of triflates (or their precursor
phenols) and aryl halides.
The synthesis of aryl triflates and aryl halides has been de-
scribed already and the preparation of primary amides of type
5a–f will be fully described as the subject of a future Letter.4,6
reactions such as arylation of the carbamate or hydroxy function-
alities. We reasoned that the primary amide should be the most
reactive functional group under typical palladium-catalysed ami-
dation conditions, mostly due to steric reasons.
We decided to use amide 5a as our standard amide coupling
partner for medicinal chemistry reasons.7

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C. Barfoot et al. / Tetrahedron Letters 51 (2010) 2685–2689
Table 2
Amidation of a variety of aryl halides and triflates using amides 5b–fa
Pd2(dba)3, (+/-)-BINAP
Cs2CO3, 1,4-dioxane
85-100 ºC, 18-24 h
O
O
Ar-X
+
HN
Ar
R
R
H2N
X = Cl or OTf
5b-f
24-28
Entry
1
Ar-X
Amide
Productb (yield %)
OTf
N
O
O
O
O
O
OH
O
N
O
O
O
O
O
H2N
H2N
H2N
H2N
H2N
24 (82)
N
H
O
O
O
O
O
5b
5c
Cl
N
2
3
25 (60)
26 (97)
27 (72)
28 (53)
N
H
OTf
F
O
N
N
H
N
5d
5e
5f
OTf
N
O
4c
N
H
OTf
N
OH
O
N
5d
N
H
a
b
c
Reaction conditions: aryl halide or triflate (1 equiv), amide (1.05 equiv), Pd2(dba)3 (3 mol %), ( )-BINAP (6 mol %), Cs2CO3 (2.5 equiv), 1,4-dioxane, 85–100 °C, 18–24 h.
Isolated yield.
Xantphos was used instead of ( )-BINAP.
Reaction temperature was kept at 60 °C.
d
The synthesis of these amides generally presented no more of
In conclusion, we have described a very general method for the
synthesis of -hydroxy aryl amides and related aryl amides using a
palladium-catalysed process, which may find future synthetic use.
an obstacle than that of the corresponding carboxylic acids.
As entries 1–18 show, this strategy successfully afforded
a
a
-hy-
droxy amides 6–23.8,9 In contrast to the HATU amide coupling con-
ditions, a clean reaction to give the product was observed. Entries
for aryl triflates (entries 1–8) show a similar range of yields to the
aryl bromides (entries 9–18). In some cases a minor by-product
was observed when using electron-withdrawing aryl triflates due
to some triflate hydrolysis. Entries 2 and 7 also show that Xantphos
was an equally efficient ligand for this process. As well as examin-
ing a range of substituted aryl halides and triflates, we also exam-
ined the effect of altering the primary amide.
We therefore looked at a series of primary amide variations,
taking in fluoro, methoxy, and various hydroxy functionalities as
dictated by our medicinal chemistry needs at the time (Table 2).
To our delight, the entries in Table 2 all showed reasonable
yields and good purities. The reaction is tolerant of various func-
tionalities on the amide synthon including hydroxy, methoxy, flu-
oro or alkene. No competing arylation of the carbamate, hydroxy
group or alkene (via Heck reaction) was observed. A temperature
of 60 °C was required in entry 5 in order to reduce the formation
of uncharacterized impurities. As entry 2 shows, an aryl chloride
was also suitable for this reaction.
Acknowledgements
Acknowledgment is given to Steve Richards for NMR support,
Bill Leavens for mass spectroscopy support and all the chemists
who have been involved in this work.
References and notes
1. For early intramolecular examples, see: (a) Wolfe, J. P.; Rennels, R. A.; Buchwald,
S. L. Tetrahedron 1996, 21, 7525; (b) Yang, B. H.; Buchwald, S. L. Org. Lett. 1999, 1,
35; (c) He, F.; Foxman, B. M.; Snider, B. B. J. Am. Chem. Soc. 1988, 120, 6417; For
early intermolecular examples, see: (d) Shakespeare, W. C. Tetrahedron Lett.
1999, 40, 2035; (e) Yin, J.; Buchwald, S. L. Org. Lett. 2000, 2, 1101; (f) Hartwig, J.
F.; Kawatsura, M.; Huack, S. L.; Shaughnessy, K. H.; Alcazar-Roman, L. M. J. Org.
Chem. 1999, 64, 5575.
2. For recent related Letters, see (a) Fors, B. P.; Dooleweerdt, K.; Zeng, Q.;
Buchwald, S. L. Tetrahedron 2009, 65, 6576; (b) Wallace, D. J.; Campos, K. R.;
Shultz, C. S.; Klapars, A.; Zewge, D.; Crump, B. R.; Phenix, B. D.; McWilliams, J.;
Krska, S.; Sun, Y.; Chen, C.; Spinder, F. Org. Process Res. Dev. 2009, 13, 84; (c)
Hunag, J.; Chen, Y.; King, A. O.; Dilmeghani, M.; Larsen, R. D.; Faul, M. M. Org.
Lett. 2008, 10, 2609; (d) Dallas, A. S.; Gothelf, K. V. J. Org. Chem. 2005, 70, 3321;
(e) Manley, P. J.; Bilodeau, M. T. Org. Lett. 2004, 6, 2433.

C. Barfoot et al. / Tetrahedron Letters 51 (2010) 2685–2689
2689
3. (a) For the syntheses of these compounds and experimental details for the
reactions in this Letter see: Brooks, G.; Davies, D. T.; Jones, G. E.; Markwell, R. E.;
Pearson, N. D.; WO2003087098; Chem. Abstr. 2003, 139, 337959; (b) Axten, J. M.;
Daines, R. A.; Davies, D. T.; Gallagher, T. F.; Jones, G. E.; Miller, W. H.; Pearson, N.
D.; Pendrak, I.; WO2004002992; Chem. Abstr. 2004, 140, 94053; (c) Davies, D. T.;
Elder, J. S.; Forrest, A. K.; Jarvest, R. L.; Pearson, N. D.; Sheppard, R. J.;
WO20040014361; Chem. Abstr. 2004, 140, 199210
4. Aryl bromides were generally made from precursor quinolinones and
naphthyridinones using PBr3 in DMF.
5. For an example of this reaction, see: Radinov, R.; Khaimova, M.; Simova, D.
Synthesis 1986, 11, 886.
acid 6-methoxy-[1,5]-naphthyridin-4-yl ester (0.64 g) (1 equiv) was added, and
the mixture was stirred at 85 °C for 18 h under argon. The mixture was cooled to
room temperature, filtered and the filtrate was evaporated and chromatographed
on silica gel, eluting with CHCl3, then (1–2%) MeOH–CH2Cl2 to afford 6 as a white
solid (0.85 g) (>95%); mp 165–167 °C; 1H NMR (600 MHz, DMSO-d6): d = 1.39 (s,
9H), 1.49–1.60 (m, 2H), 1.63–1.74 (m, 4H), 1.84–1.91 (m, 2H), 3.24–3.30 (m, 1H),
4.10 (s, 3H), 6.10 (s, 1H), 6.83 (br d, J = 9 Hz, 1H), 7.33 (d, J = 9.5 Hz, 1H), 8.28 (d,
J = 9.5 Hz, 1H), 8.44 (d, J = 6 Hz, 1H), 8.69 (d, J = 6 Hz, 1H), 11.10 (s, 1H).
13C NMR (151 MHz, DMSO-d6): d = 27.2, 28.3, 32.9, 48.5, 53.7, 73.8, 77.4, 109.6,
116.8, 131.5, 138.8, 140.7, 140.8, 149.0, 154.8, 161.0, 176.9. ESI-HRMS: m/z calcd
for C21H29N4O5: 417.2138; found 417.2139 [M+H]+.
6. This work originally appeared in the patents listed in references 3a–c. Related
copper-catalysed amidations have also been reported but have tended to require
aryl iodides as the coupling partner and failed to give any of the desired product
for our systems. For examples, see: (a) Klapars, A.; Huang, X.; Buchwald, S. L. J.
Am. Chem. Soc. 2002, 124, 7421; (b) Franz, A. K.; Dreyfuss, P. D.; Schreiber, S. L. J.
Am. Chem. Soc. 2007, 129, 1020; (c) Clive, D. L. J.; Peng, J.; Fletcher, S. P.; Ziffle, V.
E.; Wingert, D. J. Org. Chem. 2008, 73, 2330; (d) Some palladium-catalysed
couplings were also reported in the patent literature after our initial patent
publications, see: Herold, P.; Mah, R.; Stutz, S.; Stojanovic, A.; Tschinke, V.;
Jotterand, N.; WO2005061457; Chem. Abstr. 2005, 143, 115449; (e) Zhang, X. P;
Chen, Y.; Gao, G.; US2005124596; Chem. Abstr. 2003, 143, 37557
9. Selected analytical data:
Compound 9: White solid; mp 179–181 °C; 1H NMR (600 MHz, DMSO-d6):
d = 1.39 (s, 9H), 1.54–1.63 (m, 2H), 1.64–1.71 (m, 2H), 1.74–1.80 (m, 2H), 1.82–
1.91 (m, 2H), 3.23–3.30 (m, 1H), 3.95 (s, 3H), 5.96 (s, 1H), 6.82 (br d, J = 9 Hz,
1H), 7.09 (d, J = 1.5 Hz, 1H), 7.40 (dd, J = 10.5, 1.5 Hz, 1H), 8.20 (d, J = 6 Hz, 1H),
8.70 (d, J = 6 Hz, 1H), 10.03 (s, 1H).
13C NMR (151 MHz, DMSO-d6): d = 27.3, 28.2, 32.8, 48.5, 55.9, 73.7, 77.3, 96.9,
106.1, 113.5, 123.1, 134.7, 139.8, 148.3, 154.8, 156.8, 158.2, 176.5. ESI-HRMS: m/
z calcd for C22H29FN3O5: 434.2091; found 434.2087 [M + H]+.
Compound 21: White solid; mp 161–163 °C; 1H NMR (600 MHz, DMSO-d6):
d = 1.39 (s, 9H), 1.55–1.64 (m, 2H), 1.65–1.71 (m, 2H), 1.75–1.80 (m, 2H), 1.84–
1.90 (m, 2H), 3.24–3.30 (m, 1H), 3.94 (s, 3H), 5.96 (s, 1H), 6.82 (br d, J = 9.5 Hz,
1H), 7.33 (d, J = 3.5 Hz, 1H), 7.45 (dd, J = 9.0, 3.5 Hz, 1H), 7.93–7.96 (m, 2H), 8.66
(d, J = 6.5 Hz, 1H), 10.05 (s, 1H).
7. A Letter detailing the multiple routes and methods to access amides of type 5, is
in preparation.
8. General procedure for the palladium-catalysed amidation reaction, (Table 1, entry 1).
A mixture of amide (5a) (0.51 g) (1.05 equiv), caesium carbonate (0.818 g)
(2.5 equiv), tris(dibenzylideneacetone)dipalladium(0) (38 mg) (3%) and rac-2,20-
[bis(diphenylphosphino)]-1,10-binaphthyl (77.4 mg) (6%) in dry 1,4-dioxane
(20 ml) under argon was sonicated for 10 min. 1,1,1-Trifluoro-methanesulfonic
13C NMR (151 MHz, DMSO-d6): d = 27.5, 28.4, 33.0, 48.6, 55.7, 73.9, 77.5, 100.2,
112.6, 121.6, 122.1, 131.3, 139.6, 144.6, 148.3, 155.0, 157.3, 176.6. ESI-HRMS: m/
z calcd for C22H30N3O5: 416.2185; found 416.2191 [M+H]+.