α-Aminoamides as ligands in Goldberg amidations

Article abstract of DOI:10.1016/j.tetlet.2013.09.099

α-Aminoamides are shown to be useful as ligands in Goldberg amidations. A number of α-aminoamides are examined and the importance of substitution on the α-aminoamides is explored. Acetamide is focused on as the nucleophilic coupling partner due to its low cost, stability and convenience as a protecting group. The initial substrate scope for these catalysts is explored and includes electronically activated and deactivated aryl bromides, however o-substituted aryl bromides are problematic.

Full text of DOI:10.1016/j.tetlet.2013.09.099

Tetrahedron Letters 54 (2013) 6580–6583
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a
-Aminoamides as ligands in Goldberg amidations
⇑
Aurpon W. Mitra, Marvin M. Hansen, Michael E. Laurila, Stanley P. Kolis, Joseph R. Martinelli
Small Molecule Design and Development, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
a
-Aminoamides are shown to be useful as ligands in Goldberg amidations. A number of
a-aminoamides
Received 13 August 2013
Revised 18 September 2013
Accepted 21 September 2013
Available online 28 September 2013
are examined and the importance of substitution on the -aminoamides is explored. Acetamide is
a
focused on as the nucleophilic coupling partner due to its low cost, stability and convenience as a protect-
ing group. The initial substrate scope for these catalysts is explored and includes electronically activated
and deactivated aryl bromides, however o-substituted aryl bromides are problematic.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Amidation
Aminoamide
Cross-coupling
Cu catalysis
Acetamide
Buchwald–Hartwig C–N bond forming cross-coupling reactions
are among the most powerful transformations utilized by organic
chemists for the synthesis of pharmaceuticals and agrochemicals.1
There are a number of versatile catalysts based on Pd or Cu that of-
fer advantages for different substrate combinations. The comple-
mentariness of these two different systems has been outlined
recently by Beletskaya,2 and in general, the simplicity and afford-
ability of Cu-based catalyst systems make them very attractive
especially for amidation reactions, commonly referred to as the
Goldberg coupling.3
F
F
F
NH
Me
Cu / Ligand /
F
H
I
KI / base
O
imp1
Ar-I
Br
O
F
F
F
F
H2N
Me
N
NH2
L
O
Me
imp2
imp3
imp4
Scheme 1. Cu-catalyzed cross-coupling of acetamide and 4-bromofluorobenzene.
Through the course of our process development, we became
interested in the coupling of acetamide with various aryl bromides.
We realized there were only scattered examples of this species in
the cross-coupling literature.4 This may be attributed, in part, to
the apparent simplicity of acetamide as a substrate and in part to
the known toxicity issues with acetamide.5 In fact, acetamide can
be a surprisingly problematic substrate due to the enolizable pro-
tons and the ease with which residual water can hydrolyze the
acetanilide product to the aniline and acetic acid.6 Despite these
factors, the low cost, stability and convenience of the acetyl pro-
tecting group still make this a reaction of interest. As depicted in
Scheme 1, our initial investigation into this coupling indicated sev-
eral side products were forming in addition to our desired product.
While Imp1, Imp2, Imp3, and Imp4 all derive from undesired side
reactions, the aryl iodide (Ar–I) is thought to be a critical and pro-
ductive intermediate in this transformation as was shown by Buch-
wald and coworkers.7
Thus, we evaluated a large variety of ligands for the Cu-cata-
lyzed coupling of acetamide and 4-bromofluorobenzene to mini-
mize these side products. Through this study, summarized in
Table 1, we found that
a-aminoamides could serve as supporting
ligands in these reactions. This was somewhat surprising, though
a
-aminoamides have been used as ligands in other transition metal
catalyzed reactions,8 to the best of our knowledge they have not
been used as ligands in Cu-catalyzed coupling reactions.
Upon examination of Table 1, several themes begin to emerge.
First, it is immediately obvious that a surprisingly few number of
the ligands tested work for this seemingly simple transformation.
In fact, of the more popular ligands for Cu (1–3,9a,9b 4,9a 6, 11,9c
13,9d and 15–17), only 1 and 2 provide full conversion and high
yield and this is by far the best result. This is not surprising given
the high utility of these ligands demonstrated by Buchwald and
coworkers.10 It is noteworthy that the three phenanthroline deriv-
atives tested (1511a, 1611b, and 1711c), although great for other Cu-
catalyzed reactions,11 did not provide very active catalysts for this
transformation. Similarly, the diketones tested (5 and 6) did not
⇑
Corresponding author. Tel.: +1 317 276 2749; fax: +1 317 276 4507.
E-mail address: martinelli_joseph_r@lilly.com (J.R. Martinelli).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.09.099

A. W. Mitra et al. / Tetrahedron Letters 54 (2013) 6580–6583
6581
Table 1
General ligand screen for the coupling of acetamide and 4-bromofluorobenzenea
Ar–I <1
<1
24
10
47
(%)
Yield 17
(%)
30 mol% CuI
O
F
F
90 mol% Ligand
a
Reaction and conditions: 30 mol % Cul, 90 mol % ligand, 240 mg (1.36 mmol) 4-
+
H2N
Me
bromofluorobenzene, 4 equiv acetamide, 1 equiv KI, 3–4 equiv K3PO4 (4 equiv base
with oxalate salts, 3 equiv in all other cases) 7.5 vols (mL/g ArBr) DMF. Conversion,
Ar–I and yield were determined by HPLC, average of two runs.
Br
3-4 equiv. K3PO4
1 equiv KI
NH
Me
4 equiv.
O
DMF, 110oC, 18 h
provide very active catalysts despite their excellent utility for other
Cu-catalyzed transformations.12 Other ligands included in this
study were added to provide structural diversity. Although the
activities were not the highest of the ligands examined, the cata-
H
O
O
Me
N
H
N
N
Me
Me
N
H
HO
Me HO
Me(H)N
Ligand 1
(%)
Conv. >99
(%)
N(H)Me
2
3
4
lysts resulting from use of
a-aminoamides 18– and 21 provided
>99
<1
99
O
69
<1
11
97
<1
50
productive catalysts for this transformation. While 19 and 20 suf-
fered from significant side product formation, it is noteworthy that
18 and 21 both provided relatively good yields of product relative
to the conversion of the starting material to either product or the
intermediate aryl iodide (Scheme 1, Ar–I).7
Ar–I
(%)
0
Yield 95
(%)
O
O
O
Me2N
We wanted to further understand the use of a-aminoamides in
NMe2
N
Me
Me
tBu
tBu
Cu-catalyzed C–N bond forming reactions so we explored the
importance of substitution. The importance of having the appropri-
ate substitution pattern has been previously demonstrated for
other ligands.4a In this case, we also wanted to understand if N–
Hs were beneficial. Thus, several derivatives of an easily tunable
OH
Ligand 5
(%)
Conv. 47
(%)
Ar–I <1
(%)
6
7
8
65
<1
43
39
0
49
<1
1
a-aminoamide that provided moderate results (18) were used in
our test reaction to determine the effect of different methyl group
substitution patterns. As shown in Table 2, replacing either one (22
and 23), or both (24), of the N–H groups with a methyl group se-
verely hampers the reactivity of the catalyst system. In these cases,
the conversion is reduced from 98% to ꢀ10% and the yield of the
product drops correspondingly. In fact, the reactivity of either
mono-methyl derivative or the per-methylated derivative is about
the same as the background reaction with no ligand present (Ta-
ble 2, entries 2–4 vs entry 6). Since several ligands are used as their
oxalate salts, the background reactivity of oxalic acid was also
tested and found to be inadequate for this transformation (Table 2,
entry 5).
Yield
(%)
9
1
O
O
N
OH
HN
NH
N
H
N
N
O
OH
Ligand 9
(%)
Conv. 38
(%)
Ar–I <1
(%)
Yield <1
(%)
10
62
<1
12
11
43
<1
3
12
75
<1
18
O
O
Once it was clear that both the amide and amine needed to be
secondary vs. tertiary, several derivatives of 18 and 21 were syn-
thesized and these derivatives were tested in the coupling of acet-
amide and 4-bromofluorobenzene. As shown in Table 3, several
interesting reactivity trends were observed in this screen. The poor
reactivity of tertiary amides was conserved in the proline scaffold,
as illustrated by the use of 29. It was observed that secondary pro-
line amides were generally very reactive but their use resulted in
the formation of high amounts of reduced product or ligand cou-
pling (Scheme 1, imp1 and imp2). In an effort to minimize the for-
mation of these byproducts, more hindered derivatives were
synthesized. The m-xylyl derivative 30 did not provide any
improvement in reaction profile. The i-propyl derivative 21, how-
ever, did provide a much more selective reaction (Table 3), albeit
at a reduced reaction rate. Ligand 28 was synthesized from o-
methoxybenzylamine in the hope that a slightly more electron rich
and potentially chelating amide group might help corral the side
product formation, however it did not provide any major selectiv-
ity improvements. Perhaps not surprisingly, making the i-propyl or
t-butyl amide analogs of 18 (Table 3, ligands 26 and 27) resulted in
drastically reduced reaction rates. Thus, given the balance achieved
between selectivity and reaction rate, we decided to explore the
substrate scope of the catalyst derived from the use of 21.
A small group of substrates were tested to gain some initial in-
sight into the scope of this catalyst system.13 As previously stated,
the use of acetamide was one of our initial goals so we evaluated
NEt2
N
N
OH
N
N
Ligand 13
(%)
Conv. 46
(%)
Ar–I <1
(%)
14
45
0
15
89
<1
<1
Yield
(%)
2
7
Me
Me MeO
Me
OMe
O
H
N
Bn
N
Bn
Me
H
N
N
N
N
Ligand 16
(%)
Conv. 33
(%)
Ar–I <14
(%)
Yield 17
(%)
17
61
<1
27
18 (oxalate)
64
7
38
O
H
O
Me
H
N
H
N
N
Me
Me
Me
20
84
N
H
N
H
Me
N
O
H
Ligand 19 (HCl)
21 (oxalate)
(%)
Conv. 97
(%)
64

6582
A. W. Mitra et al. / Tetrahedron Letters 54 (2013) 6580–6583
Table 2
Examining the importance
Conv.
(%)
Ar–I
(%)
Yield
(%)
64
10
47
10
<1
<1
6
1
2
a
-aminoamide substitutiona
30 mol% CuI
O
F
F
90 mol% Ligand
+
H2N
Me
Br
NH
Me
4-3 equiv. K3PO4
1 equiv KI
OMe
O
Me
O
H
N
H
N
O
4 equiv.
H
N
O
N
N
H
DMF, 130oC, 18 h
N
H
Me
Ligand
(%)
Conv.
(%)
Ar–I
(%)
Yield
(%)
28 (HCl)
100
29 (oxalate)
30 (HCl)
Entry
1
Ligand
Conv.b (%)
Yieldb (%)
74
7
93
O
H
N
<1
<1
3
10
97
6
N
H
18 (oxalate)
39
26
O
H
a
N
Reaction and conditions: 30 mol % Cul, 90 mol % ligand, 240 mg (1.36 mmol) 4-
N
2
3
4
3
8
2
bromofluorobenzene, 4 equiv acetamide, 1 equiv KI, 3–4 equiv K3PO4 (4 equiv base
with oxalate salts, 3 equiv. in all other cases), 7.5 vols (mL/g ArBr) DMF. Conversion,
Ar–I and yield were determined by HPLC, average of two runs.
Me
22 (oxalate)
O
Me
N
12
5
N
H
and we found that the reaction proceeded to completion within
5 h using this ligand. Presumably, the steric demands of 18 are
too great for use with secondary amides but the increased reactiv-
ity of 25 enables a productive coupling reaction. One limitation
23 (oxalate)
O
Me
N
N
Me
Table 4
24 (oxalate)
Substrate scope for Goldberg couplings utilizing
a
-aminoamide ligandsa
5
6
Oxalic acid
No ligand
5
10
3
3
a
MeO
Reaction and conditions: 30 mol % Cul, 90 mol % ligand, 240 mg (1.36 mmol) 4-
O
H
N
bromofluorobenze, 4 equiv acetamide, 1 equiv KI, 3–4 equiv K3PO4 (4 equiv base
with oxalate salts, 3 equiv in all other cases), 7.5 vols (mL/g ArBr) DMF.
30 mol% CuI
O
N
N
H
R2
60 mol% Ligand
b
Conversion and yields are determined by HPLC, average of two runs.
Br
R
R1
25 (HCl)
Me
4 equiv amide
3-4 equiv. K3PO4
1 equiv KI
R
the use of acetamide with various p-substituted aryl bromides.
These initial reactions illustrated that electron poor and rich
substrates are tolerated (Table 4, entries 1, 3 and 5). Two examples
of a very simple secondary amide, 2-pyrrolidinone, were also eval-
uated in this cross-coupling. We were surprised to learn the use of
18 with this as the secondary amide was very sluggish, <25% con-
version after 48 h. These substrates were then tested with 25,
which generally provided very rapid conversion of aryl bromide,
O
H
N
DMF (7.5 vols)
130oC
Me
N
H
5 h (for L1) or
18 h (for L2)
21 (oxalate)
Entry Ar–
Br
Amide
Product
Ligand Conv.b
(%)
Yieldc
(%)
F
O
O
Me
Table 3
Me
NH2
Screening a
-aminoamides for the coupling of acetamide and 4-bromofluorobenzenea
F
N
1
21
25
21
21
25
>99
>99
>99
>99
>99
75
61
63
83
70
H
Br
F
30 mol% CuI
O
F
F
O
O
90 mol% Ligand
+
H2N
Me
NH
F
N
Br
3-4 equiv. K3PO4
1 equiv KI
NH
Me
2
4 equiv.
O
DMF, 110oC, 18 h
Br
CF3
O
O
O
N
Me
Me
Me
NH2
NH2
F3C
3
4
5
H
O
O
H
MeO
H
O
Me
N
Bn
N
H
N
Br
OMe
N
H
N
H
Bn
N
H
O
Me
Ligand
Conv.
(%)
19 (HCl)
97
18 (oxalate)
64
25 (HCl)
100
MeO
MeO
N
H
Br
OMe
Ar–I
(%)
Yield
(%)
<1
26
Me
7
<1
42
O
O
38
NH
N
O
O
H
Me
O
Me
Me
Br
H
N
H
N
Me
Me Bn
N
Me
N
H
Bn
N
H
N
H
a
Reaction and conditions: 30 mol % Cul, 60 mol % ligand, 1g Ar–Br, 4 equiv
amide, 1 equiv KI, 3–4 equiv K3PO4 (4 equiv base with oxalate salts, 3 equiv in all
other cases), 7.5 vols (mL/g ArBr) DMF.
Ligand
(%)
21 (oxalate)
26 (oxalate)
27 (oxalate)
b
Determined by HPLC, average of two runs.
Isolated yield, average of two runs.
c

A. W. Mitra et al. / Tetrahedron Letters 54 (2013) 6580–6583
6583
Chem. 2002, 219, 131–209; c Jiang, L.; Buchwald, S. L. Palladium-Catalyzed
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2004; pp 699–760; (d) Buchwald, S. L.; Mauger, C.; Mignani, G.; Scholz, U. Adv.
Syn. Cat. 2006, 348, 23–39; (e) Surry, D.; Buchwald, S. L. Angew. Chem., Int. Ed.
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2067; (h) Hartwig, J. F. Acc. Chem. Res. 2008, 41, 1534–1544; Applications in
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44, 4442–4489; (j) Fischer, C.; Koenig, B. Beilstein. J. Org. Chem. 2011, 7, 59–74.
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3. Goldberg, I. Ber. Dtsch. Chem. Ges. 1906, 39, 1691.
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worth noting is that a few o-substituted aryl bromides (2-bromo-
benzotrifluoride, 2-bromotoluene and 2-bromofluorobenzene)
were tested using 18 or 25, and these reactions were very poor
with either acetamide or 2-pyrrolidinone.
In conclusion, we have shown that
as ligands in Goldberg amidations. Our initial findings have shown
that the substitution of the -aminoamides is critical for maintain-
ing a good level of reactivity. The catalysts based on -aminoa-
a-aminoamides can be used
a
a
mides are not the most active for these reactions, however their
use as ligands is Goldberg reactions is unusual and expands the
scope of available ligand motifs. In particular,
a-aminoamide li-
gand 18 was shown to be superior to most common ligands (with
the exceptions of diamines 1 and 2) used for the coupling of acet-
amide and 4-bromofluorobenzene. The initial substrate scope for
these catalysts includes primary and secondary amide coupling
partners and electronically activated and deactivated aryl bro-
mides, however o-substituted aryl bromides appear to be
problematic.
Acknowledgments
Robert A. Forbes is gratefully acknowledged for help with quan-
titative HPLC calculations. Amy C. DeBaillie, Jeffrey A. Ward, Craig
Ruble and Ryan Linder are acknowledged for helpful discussions.
Shanghai PharmExplorer is acknowledged for the preparation of
some ligands used for these studies. The reviewers are acknowl-
edged for helpful suggestions.
10. For an excellent review detailing the development of catalysts based on the use
of ligands 1 and 2 see:(a) (a) Surry, D. S.; Buchwald, S. L. Chem. Sci. 2010, 1, 13–
31; For additional examples of the use of catalysts based on 1 and 2 see: (b)
Zhao, G.; Wu, J.; Dai, W.-M. Synlett 2012, 23, 2845–2849; (c) Shetty, R. S.; Lee,
Y.; Liu, B.; Husain, A.; Joseph, R. W.; Lu, Y.; Nelson, D.; Mihelcic, J.; Chao, W.;
Moffett, K. K.; Schumacher, A.; Flubacher, D.; Stojanovic, A.; Bukhtiyarova, M.;
Williams, K.; Lee, K.-J.; Ochman, A. R.; Saporito, M. S.; Moore, W. R.; Flynn, G.
A.; Dorsey, B. D.; Springman, E. B.; Fujimoto, T.; Kelly, M. J. J. Med. Chem. 2011,
54, 179–200; (d) Dandapani, S.; Lan, P.; Beeler, A. B.; Beischel, S.; Abbas, A.;
Roth, B. L.; Porco, J. A.; Panek, J. S. J. Org. Chem. 2006, 71, 8934–8945; (e)
Tehrani, L. R.; Smith, N. D.; Huang, D.; Poon, S. F.; Roope, J. R.; Seiders, T. J.;
Chapman, D. F.; Chung, J.; Cramer, M.; Cosford, N. D. P. Bioorg. Med. Chem. Lett.
2005, 15, 5061–5064.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
09.099.
11. (a) Kiyomori, A.; Marcoux, J.-F.; Buchwald, S. L. Tetrahedron Lett. 1999, 40,
2657; (b) Nordmann, G.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125,
4978–4979; (c) Altman, R. A.; Buchwald, S. L. Org. Lett. 2006, 8, 2779–
2782.
References and notes
12. Shafir, A.; Buchwald, S. L. J. Am. Chem. Soc. 2006, 128, 8742–8743.
13. No attempt was made to optimize the catalyst loading for these studies. In
general, it appeared that loadings of 10 mol% or lower provided inconsistent
results so loadings of 30 mol% were used to eliminate variability.
1. Reviews from Buchwald: (a) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald,
S. L. Acc. Chem. Res. 1998, 31, 805–818; (b) Muci, A. R.; Buchwald, S. L. Top. Curr.