Nickel-catalyzed transamidation of aliphatic amide derivatives

Article abstract of DOI:10.1039/c7sc01980g

Transamidation, or the conversion of one amide to another, is a long-standing challenge in organic synthesis. Although notable progress has been made in the transamidation of primary amides, the transamidation of secondary amides has remained underdeveloped, especially when considering aliphatic substrates. Herein, we report a two-step approach to achieve the transamidation of secondary aliphatic amides, which relies on non-precious metal catalysis. The method involves initial Boc-functionalization of secondary amide substrates to weaken the amide C-N bond. Subsequent treatment with a nickel catalyst, in the presence of an appropriate amine coupling partner, then delivers the net transamidated products. The transformation proceeds in synthetically useful yields across a range of substrates. A series of competition experiments delineate selectivity patterns that should influence future synthetic design. Moreover, the transamidation of Boc-activated secondary amide derivatives bearing epimerizable stereocenters underscores the mildness and synthetic utility of this methodology. This study provides the most general solution to the classic problem of secondary amide transamidation reported to date.

Full text of DOI:10.1039/c7sc01980g

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Nickel-Catalyzed Transamidation of Aliphatic Amide
Derivatives
Cite this: DOI: 10.1039/x0xx00000x
Jacob E. Dander,† Emma L. Baker,† and Neil. K. Garg*
Transamidation, or the conversion of one amide to another, has remained a long-standing challenge in
organic synthesis. Although notable progress has been made in the transamidation of primary amides,
the transamidation of secondary amides has remained underdeveloped, especially when considering
aliphatic substrates. Herein, we report a two-step approach to achieve the transamidation of secondary
aliphatic amides, which relies on non-precious metal catalysis. The method involves initial Boc-
functionalization of secondary amide substrates to weaken the amide C–N bond. Subsequent treatment
with a nickel catalyst, in the presence of an appropriate amine coupling partner, then delivers the net
transamidated products. The transformation proceeds in synthetically useful yields across a range of
substrates. A series of competition experiments delineate selectivity patterns that should influence
future synthetic design. Moreover, the scalable transamidation of a Boc-activated secondary amide
derivative bearing an epimerizable stereocenter underscores the mildness and synthetic utility of this
methodology. This study provides the most general solution to the classic problem of secondary amide
transamidation reported to date.
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
transamidation of secondary amide derivatives, each with a
focus on benzamide-derived substrates. The first uses Lewis
base catalysis,10 while the other utilizes Pd-NHC
Introduction
The ability to convert one amide to another, known as
the transamidation reaction, represents a long-standing
synthetic challenge.1,2 Although significant progress has
been made with regard to the transamidation of 1°
amides,3,4,5 the corresponding reaction involving secondary
complexes.11 Despite these discoveries, a general solution
to the transamidation of aliphatic 2° amides has remained
elusive.
In considering the challenges noted earlier, we sought
to develop an alternative strategy to achieve the
transamidation of secondary amides. As summarized in
Figure 1, it was envisioned that N-functionalization of
secondary amide substrates 1 could lead to weakening of
the acyl amide C–N bond,12 if the appropriate activating
group was utilized. Electron-withdrawing groups, such as
the Boc group, were viewed as ideal for this purpose,13
given the ease by which Boc groups can be introduced.
From the resulting Boc-activated secondary amide 5, it was
believed that oxidative addition with an appropriate nickel
catalyst could occur through a reasonable kinetic process.
In situ interception of this species with an amine
nucleophile 2 would furnish transamidated product 3. The
process would be driven thermodynamically by the
amides (1
+ 2 à 3 + 4) has remained largely
underdeveloped (Figure 1). Two factors are primarily
responsible for the difficulty of this transformation. First,
the kinetic barrier to break the amide C–N bond is
considered high because of well-known resonance effects.6
The second complication stems from thermodynamics, as
the energetics of starting materials and products in
transamidation reactions are often comparable, resulting in
thermoneutral rections.1a,7
Despite these challenges, several breakthroughs have
been reported with regard to secondary amide
transamidation. Gellman and Stahl utilized a dimeric
aluminum complex to affect secondary amide
transamidation, albeit with equilibrium mixtures resulting,
thus highlighting the difficulty regarding thermodynamics.8
Bertrand has reported a means to achieve secondary amide
transamidation of simple substrates using excess AlCl3.9 In
both of these cases, the transamidation is made possible by
Lewis acid activation of the amide carbonyl. Most recently,
Szostak reported two simple protocols for achieving the
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DOI: 10.1039/C7SC01980G
favorable release of carbamate 6.14
NaOtBu for in situ free-basing, afforded the desired amide
product 9 in quantitative yield (entry 3). We attribute the
improved competency of 12 (compared to 10) to its more
electron-rich nature, which ultimately renders oxidative
addition more facile.21,22 Of note, the reaction also took
place using lower amounts of catalyst, ligand, and base
(entry 4). Finally, we found that by increasing the
concentration, the equivalents of amine could be reduced
from 2.0 to 1.5, while also allowing for shorter reaction
times (entry 5). These conditions (entry 5) were found to be
sufficiently general and were used to explore the reaction
scope. Of note, in the absence of Ni(cod)2, no reaction
occurs, thus demonstrating that the conversion of 7 to 9 is
indeed catalyzed by nickel.23 Likewise, Lewis base-promoted
transamidation conditions were also deemed ineffective.24
Encouraged by the successful activation of amide C–N
bonds using transition metal catalysis, as demonstrated by
studies from Szostak, Shi, and our laboratory,15,16,17,18,19 we
explored the sequence described above. In 2016, we
validated this approach to achieve
a
two-step
transamidation of N-Bn,Boc benzamide derivatives.20
However, the corresponding reaction sequence using
substrates derived from aliphatic secondary amides was
unsuccessful. In this manuscript, we describe our efforts to
overcome this hurdle, which have led to the nickel-
catalyzed transamidation of aliphatic amide derivatives. The
methodology presented herein offers a robust solution to
the classic problem of secondary aliphatic amide
transamidation, and is expected to inform future efforts
toward natural product synthesis and derivatization.
Secondary amide transamidation
O
O
Ni(cod)2, ligand
NaOtBu
Bn
O
O
+
N
R'
R
N
H
R
HN
R"
R'
HN
H
H2N
+
+
toluene, time, 60 °C
Boc
N
H
N
R"
7
8
9
1
2
3
4
2° amide
2° or 3° amide
mol% of
Ni(cod)2
Ligand
(mol%)
Equivs of
8
mol% of
NaOtBu
Yield of
9a
Entry
Time
Conc.
Challenges
• High kinetic barrier
• Unfavorable thermodynamics/thermoneutrality
Solutions
• Activate amide C–N bond
• Perturb thermodynamics
10
(20 mol%)
—
1
10
2.0
1.0 M
24 h
15%
11
(20 mol%)
Two-step approach to the transamidation of secondary amides
—
2
3
10
10
2.0
2.0
1.0 M
1.0 M
24 h
24 h
0%
O
O
O
12
(20 mol%)
22
100%
Activation
Ni Catalysis
R
R
R'
N
N
H
N
Boc
R"
= alkyl
12
(10 mol%)
4
5
5
5
11
11
2.0
1.5
1.0 M
1.5 M
24 h
18 h
100%
90%
R'
R
1
3
5
HN
HN
Weakened
C–N bond
R"
Boc
12
(10 mol%)
2
6
Released
iPr
iPr
Fig. 1 Challenges associated with secondary amide transamidation and the
N
N
two step-approach to realize this challenging synthetic transformation.
Cl
Cy
N
N
N
N
N
iPr
iPr
Cy
SIPr (10)
terpyridine (11)
Benz-ICy•HCl (12)
Results and discussion
Table 1 Optimization of the reaction conditions. aYields determined by 1H
NMR analysis using 1,3,5-trimethoxybenzene as an internal standard.
Reaction discovery and optimization
To initiate our studies, we selected imide 7, obtained by
Boc-activation of the corresponding aliphatic amide, and
cyclohexylamine (8) as the reaction partners (Table 1). As
both coupling partners possess α-branching and are
sterically hindered, they were considered excellent
challenges for methodology development. We first tested
the amidation using 10 mol% Ni(cod)2 and 20 mol% SIPr
(10), to parallel the conditions we employed in our original
disclosure involving benzamide substrates (entry 1).20 As
anticipated, only a low yield of amide 9 was obtained. We
also tested terpyridine (11) as the ligand (entry 2), as this
was shown to be effective in promoting the Ni-catalyzed
esterification of aliphatic amide derivatives.16e To our
surprise, no reaction occurred, which prompted us to
evaluate additional NHC ligands. We were delighted to find
that use of ligand precursor 12, in combination with
Scope of methodology
Having arrived at suitable reaction conditions to achieve
the transamidation of aliphatic amide derivative 7, we
explored the generality of our methodology by first varying
the aliphatic amide partner (Figure 2).
cyclohexylamine (8), variety of amide derivatives
underwent the desired transamidation reaction. Beginning
with the parent example, the desired amide product 9 was
obtained in 82% isolated yield. Similarly, the corresponding
cyclopentyl substrate could be utilized in the
transamidation reaction to furnish 15 in excellent yield. As
a further test of the methodology, an indane substrate was
evaluated and found to undergo smooth coupling to give
amide 16. Additionally, two substrates bearing sterically
encumbered t-butyl groups were tested. When the t-butyl
Using
a
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group was positioned on the alpha carbon, neopentylic
amide 17 was obtained in 70% yield. Direct linkage of the t-
butyl group to the amide carbonyl carbon also did not
hinder the reaction, as judged by the formation of
pivalamide 18. Lastly, we evaluated two piperidine-
containing substrates, given the prevalence and importance
of piperidines in medicinal chemistry.25,26 In both cases, the
desired secondary amides were obtained in synthetically
useful yields, as shown by the formation of 19 and 20.
yield. p-Trifluoromethylbenzylamine was also utilized and
gave rise to amide 30 in 76% yield. This result showcases an
unbranched primary amine nucleophile, while also
incorporating the medicinally relevant –CF3 group.27 The
formation of 31a and 31b demonstrate that aniline and
aniline derivatives can be utilized in this methodology. It
should also be emphasized that secondary amines can be
employed in the transamidation reaction to give tertiary
amide products. The formation of 32–34, which relied on
the use of pyrrolidine, indoline, and morpholine,
respectively, are representative of this notion.
Ni(cod)2 (5 mol%)
12 (10 mol%)
NaOtBu (11 mol%)
O
O
Bn
+
H2N
(1.5 equiv)
R
N
R
N
H
Boc
13
toluene (1.5 M)
60 °C, 18 h
8
14
O
R'
Ni(cod)2 (10 mol%)
12 (20 mol%)
NaOtBu (22 mol%)
O
HN
R''
R'
Bn
+
N
O
O
N
O
Me Me
Me
R''
(1.5 equiv)
Boc
toluene (1.5 M)
60 °C, 18 h
N
H
N
H
N
H
7
2
25
n
O
O
Me
Me
O
Me
9 (n = 2); 82% yield
15 (n =1); 96% yield
16
80% yield
17
70% yield
N
H
N
H
N
H
O
O
O
Me
Me
26
94% yield
27
66% yield
28
85% yield
N
N
H
N
H
H
BocN
Me
N
Boc
R
O
18
75% yield
19
86% yield
20
77% yield
O
Me
O
Me
Me
N
H
N
H
N
H
Fig. 2 Variation of the amide substrate. Yields shown reflect the average of
two isolation experiments.
CF3
29
44% yield
30
76% yield
31a (R = H) 75% yield
31b (R = OMe) 61% yield
As shown in Figure 3, the scope of this methodology was not
limited to N-benzylamide derivatives. For example, N-n-Bu-
containing substrate 22 could be employed, thus demonstrating
that the aromatic benzyl substituent was not critical for success.
Additionally, α-branching was tolerated, as judged by the
successful coupling of the isopropylamine-derived substrate 23.
The methodology also displayed notable tolerance to sterics,
given that t-butylamine substrate 24 could be coupled with
cyclohexylamine (8) to furnish 9 in 59% yield.
O
O
O
N
N
N
O
32
93% yield
33
66% yielda
34
73% yield
Fig. 4 Scope of the amine nucleophile. Yields shown reflect the average of
two isolation experiments. a Yield determined by 1H NMR analysis using 1,3,5-
trimethoxybenzene as an internal standard.
O
Ni(cod)2 (10 mol%)
O
12 (20 mol%)
R
N
NaOtBu (22 mol%)
N
H
Amine competition studies
H2N
(1.5 equiv)
+
Boc
toluene (1.5 M)
60 °C, 18 h
With the aim of identifying selectivity patterns that may
aid in synthetic design, a series of competition experiments
were performed using substrate 7 and various amine
nucleophiles (Figure 5). First, we compared p-
trifluoromethylbenzylamine (35) and cyclohexylamine (8).
The major product obtained was benzylamide 30 in 82%
yield, with 9 being formed as the minor product. We
attribute this selectivity to steric factors. Next, we
21
8
9
O
O
Me
O
Me
Me
Me
N
Me
N
Me
N
Boc
Boc
Boc
22
23
24
91% yield of 9
82% yield of 9
59% yield of 9
Fig. 3 Scope of the amide substrate N-substituent. Yields shown reflect the
average of two isolation experiments.
compared
p-trifluoromethylbenzylamine
(35)
and
pyrrolidine (36). This reaction gave nearly a 1:1 ratio of
products 30 and 32, suggesting a fine balance between
steric and electronic factors about the nucleophilic N in this
case. In another comparison, pyrrolidine (36) and
cyclohexylamine (8) were treated with amide 7. Pyrrolidine-
derived tertiary amide 32 was formed as the major product,
rather than secondary amide 9, consistent with the relative
nucleophilicity of the amines being utilized.28 Lastly, we
The scope of this methodology with respect to the
amine nucleophile was also evaluated (Figure 4). Several α-
branched primary amines were tested, such as cyclopentyl
amine, iso-propylamine, and sec-phenethylamine. These
experiments led to the desired amides, 26–28, respectively,
in good to excellent yields. Even t-butyl amine, which bears
considerable steric hindrance, could be coupled as shown
by the formation of 29, albeit in somewhat diminished
performed
a
competition
experiment
between
cyclohexylamine (8) and t-butylamine (37), which led to the
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exclusive formation of cyclohexylamide 9, presumably as a
result of steric factors.
increased acidity of the substrate’s α-proton relative to 38.
As a workaround, we developed a modified protocol that
involves free-basing of ligand 12 in the presence of Ni(cod)2
in toluene to access the active catalyst in solution. Addition
of the catalyst solution and amine 8 to substrate 40
afforded amide 41 after 18 h at 60 °C. Amide 41 was
obtained in 60% yield and high optical purity. The mild and
scalable nature of the reaction conditions bodes well for
future synthetic applications.
Unbranched vs α-Branched Primary Amine
O
H2N
N
H
CF3
CF3
Ni(cod)2 (10 mol%)
12 (20 mol%)
NaOtBu (22 mol%)
30
35
(1.5 equiv)
O
82% yield
Bn
+
+
N
O
toluene (1.5 M)
60 °C, 24 h
Boc
7
N
H
Ni(cod)2 (3 mol%)
12 (6 mol%)
NaOtBu (6.6 mol%)
H2N
O
O
Bn
9
8
N
N
H
*
(1.5 equiv)
19% yield
+
*
H2N
(1.5 equiv)
Boc
toluene (1.5 M)
60 °C, 18 h
Unbranched Primary vs Secondary Amine
38
8
39
(78% yield)
O
H2N
Minimal erosion of stereochemistry
98% ee
90% ee
N
H
CF3
CF3
Ni(cod)2 (10 mol%)
12 (20 mol%)
NaOtBu (22 mol%)
O
Ni(cod)2 (10 mol%)
12 (20 mol%)
NaOtBu (22 mol%)
O
30
35
(1.5 equiv)
O
Bn
51% yield
N
*
Bn
N
H
+
+
+
N
*
H2N
N
Boc
toluene (1.5 M)
60 °C, 18 h
N
O
toluene (1.5 M)
60 °C, 24 h
Boc
Boc
(1.5 equiv)
Boc
41
HN
7
40
8
N
(60% yield)
Pre-generation of active catalyst
No erosion of stereochemistry
>99% ee
>99% ee
32
36
(1.5 equiv)
45% yield
Fig. 6 Transamidation of enantioenriched amide substrate 38 on gram-scale
and transamidation of enantioenriched N-Boc proline substrate 40 using a
modified protocol.
Secondary vs Primary α-Branched Amine
O
HN
N
Ni(cod)2 (10 mol%)
12 (20 mol%)
NaOtBu (22 mol%)
36
(1.5 equiv)
32
O
81% yield
Conclusions
Bn
+
+
N
toluene (1.5 M)
60 °C, 24 h
Boc
O
We have developed a facile approach to achieve the
transamidation of secondary aliphatic amides, an unmet
challenge in organic synthesis. Our strategy involves first
preparing Boc-activated secondary amide derivatives and
subsequently treating them with appropriate amine
coupling partners under Ni-mediated reaction conditions.
The methodology delivers secondary and tertiary amide
products in synthetically useful yields across a range of
7
N
H
H2N
8
9
(1.5 equiv)
19% yield
Cyclohexyl vs t-Butyl Amine
O
N
H
H2N
Ni(cod)2 (10 mol%)
12 (20 mol%)
NaOtBu (22 mol%)
8
9
O
substrates and amine nucleophiles.
A
variety of
(1.5 equiv)
98% yield
Bn
+
+
N
competition experiments were undertaken to reveal
selectivity patterns, the results of which are expected to
influence future synthetic design. Moreover, the scalable
transamidation of a N-functionalized secondary amide
derivative bearing an epimerizable stereocenter highlights
the mildness and synthetic utility of this transformation.
This study addresses the long-standing problem of
secondary amide transamidation through the use of a
general and mild nickel catalysis platform.
O
Me
toluene (1.5 M)
60 °C, 24 h
Boc
Me
Me
Me
Me
7
N
H
H2N
Me
29
0% yield
37
(1.5 equiv)
Fig. 5 A series of amine competition experiments. Yields determined by 1H
NMR analysis using hexamethylbenzene as an internal standard.
As a final test of our methodology, we evaluated two
substrates that each bear an epimerizable stereocenter
(Figure 6). Treatment of cyclohexenamide 38 with
cyclohexylamine (8) under typical reaction conditions,
notably using only 3 mol% Ni(cod)2, delivered amide 39 in
78% yield on gram-scale. Of note, product 39 was obtained
in 90% ee, indicative of minimal racemization occurring.
Attempts to couple proline-derived amide 40 using our
standard reaction protocol, on the other hand, led to
Acknowledgements
The authors are grateful to the NIH (T32-GM067555 and R01-
GM117016), the NSF (DGE-1144087 for E.L.B.), the Foote Family
(J.E.D. and E.L.B.), and the University of California, Los Angeles,
for financial support. These studies were supported by shared
instrumentation grants from the NSF (CHE-1048804) and the NIH
NCRR (S10RR025631).
substantial epimerization.
We attribute this to the
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Notes and references
15 For reviews on amide cross-couplings, see: (a) J. E. Dander
and N. K. Garg, ACS Catal., 2017, 7, 1413–1423; (b) G. Meng,
S. Shi, and M. Szostak, Synlett, 2016, 27, 2530–2540; (c) C.
Liu and M. Szostak, Chem. Eur. J., 2017, 23, 7157–7173.
16 For nickel-catalyzed amide C–N bond activations from our
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Baker, X. Hong, Y.-F. Yang, P. Liu, K. N. Houk, and N. K. Garg,
Nature, 2015, 524, 79−83; (b) N. A. Weires, E. L. Baker, and
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DOI: 10.1039/C7SC01980G
21 M. N. Hopkins, C. Richter, M. Schedler, and F. Glorius,
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22 The corresponding coupling of 7 and 8 under standard
reaction conditions (e.g., entry 5, Table 1 conditions) using
the related 1,3-dicyclohexylimidazolium (ICy) chloride ligand
salt gave 9 in 82% yield via 1H NMR analysis using
hexamethylbenzene as an external standard.
23 Control experiments using standard reaction conditions
absent Ni(cod)2, as well as experiments performed without
Ni(cod)2, 12, and NaOtBu led to minimal conversion to the
desired transamidated product. See Section B of the
supplementary information for details.
24 The Lewis base-promoted transamidation of an unbranched
N-Ph,Boc aliphatic amide derivative using benzylamine as
nucleophile was recently demonstrated (see reference 9).
Attempts to utilize these conditions for the transamidation
of less activated N-Bn,Boc aliphatic amide derivatives have
thus far been unsuccessful. See Section
H of the
supplementary information for details.
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28 According to “Mayr’s Database of Reactivity,” the
nucleophilicity parameter (N) of pyrrolidine is 17.21 and
12.00 for comparable i-PrNH2 in H2O (a nucleophilicity
parameter is not reported for cyclohexylamine (8)):
http://www.cup.lmu.de/oc/mayr/reaktionsdatenbank/fe/sho
wclass/41.
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DOI: 10.1039/C7SC01980G
TOC paragraph and graphic:
We report a two-step approach to achieve the transamidation of secondary aliphatic
amides using non-precious metal catalysis.