Nickel/Briphos-Catalyzed Direct Transamidation of Unactivated Secondary Amides Using Trimethylsilyl Chloride

Article abstract of DOI:10.1021/acs.orglett.8b03304

Direct transamidation of secondary amides was developed via nickel catalysis. In the presence of trimethylsilyl chloride and manganese, Ni(diglyme)Cl₂ with a Briphos ligand efficiently promoted the transamidation of N-aryl benzamide derivatives with primary amines to afford the corresponding secondary amides in moderate to good yields. Primary amines bearing electron-donating groups gave higher yields of the transamidation products.

Full text of DOI:10.1021/acs.orglett.8b03304

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Nickel/Briphos-Catalyzed Direct Transamidation of Unactivated
Secondary Amides Using Trimethylsilyl Chloride
Subeen Yu,† Taeil Shin,‡ Maosheng Zhang,§ Yuanzhi Xia,§ Hyunwoo Kim,*,‡ and Sunwoo Lee*,†
†Department of Chemistry, Chonnam National University, Gwangju 61186, Republic of Korea
‡Department of Chemistry, KAIST, Daejeon 34141, Republic of Korea
§College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou, Zhejiang Province 325035, P. R. China
S
* Supporting Information
ABSTRACT: Direct transamidation of secondary amides was
developed via nickel catalysis. In the presence of trimethylsilyl
chloride and manganese, Ni(diglyme)Cl2 with a Briphos ligand
efficiently promoted the transamidation of N-aryl benzamide
derivatives with primary amines to afford the corresponding
secondary amides in moderate to good yields. Primary amines
bearing electron-donating groups gave higher yields of the
transamidation products.
Scheme 1. Transamidation of Secondary Amides
he amide functionality is one of the key structural motifs
Tfound in biological compounds such as peptides,
proteins, and alkaloids. It is also widely used to prepare
agrochemicals, pharmaceuticals, polymers, and materials.1
Therefore, a number of synthetic routes to amides have been
reported.2 The conventional methods are based on (1) acyl
substitution reactions with carboxylic acid derivatives and
amines and (2) coupling reactions with organo halides and
primary amides.3 However, these methods have limitations,
such as narrow substrate scope and the need for harsh reaction
conditions and activating reagents. Transamidation has
emerged as a topic of interest because it is an efficient,
green, and direct method for the synthesis of amides.4
However, direct transamidation is quite challenging because
of the higher resonance stability of the amide as compared to
that of other carbonyl compounds.5
A promising strategy to activate amides is transition-metal-
catalyzed C−N bond activation. In the past decade, a variety of
strategies for the conversion of amides to other amides, as well
as esters and ketones, have been developed.6 However, most of
the efficient methods in this regard have been developed using
tertiary amides, while the focus on secondary amides is limited.
When a secondary amide reacts with a primary amine, the
transamidation product is in equilibrium with the starting
amide. Accordingly, Stahl suggested that transamidation
reactions between tertiary amides and secondary amines are
better than those between secondary amides and primary
amines.7
developed, where the secondary amide was first converted to
an activated tertiary amide with tosyl or tert-butyloxycarbonyl
(Boc) groups using tosyl chloride or di-tert-butyl carbonate
(Boc2O), respectively. The N-functionalized amides were then
allowed to react with amines to provide the corresponding
secondary amides in good yields (Scheme 1, eq 2).9 Garg and
Szostak’s groups developed catalytic systems with nickel and
palladium, respectively. Hu’s group developed another method
to prepare N-Boc-activated amides by nickel-catalyzed
reductive transamidation, using nitroarenes as amine surro-
gates.10 Because two-step approaches still require a preparation
step for introducing the activating group, it is highly desirable
to develop a direct transamidation of secondary amides.
Herein, we report the direct nickel-catalyzed transamidation of
secondary amides in the presence of our π-acidic Briphos
ligand11 and trimethylsilyl chloride (TMSCl).12
Several modifications to the existing methods have been
made in order to realize the transamidation of secondary
amides (Scheme 1). While transamidation of secondary amides
was initially carried out with the assistance of Lewis acids such
as Al, Sc, Ti, and Zr, the reaction had a limited substrate scope
and afforded a mixture of the substrates and product amides
(Scheme 1, eq 1).8 Two-step approaches have recently been
The reaction of N-phenylbenzamide 1a with p-toluidine 2a
in the presence of TMSCl was adopted as the model reaction.
First, we tested a variety of nickel sources using 1,10-
Received: October 16, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03304
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
phenanthroline as a ligand, which was previously shown to be
compatible with nickel catalysis.10 All the tested nickel sources
afforded the transamidated product 3aa in moderate yields of
28% to 42% (Table 1, entries 1−6). Ni(glyme)Cl2 was found
gave the product 3aa in 60% and 58% yields, respectively
(Table 1, entries 13 and 14). When Briphos, which has been
used with rhodium and palladium catalysts,11 was employed,
the product was formed in 69% yield (Table 1, entry 15).
However, π-acidic phosphites such as P(OPh)3 and P(OEt)3
were found to be inefficient in this reaction (Table 1, entries
16 and 17).
Table 1. Optimal Conditions for Nickel-Catalyzed
Transamidation of N-Phenyl Benzamide in the Presence of
a
TMSCl
With Briphos as the ligand, we next investigated the solvent
effect. The reaction in DMF gave trace amounts of the product
(Table 1, entry 18). The reactions with diglyme, o-xylene, and
1,2-dichlorobenzene afforded the transamidation product in
61%, 45%, and 12% yields, respectively (Table 1, entries 19−
21). Thus, NMP was found to be the best among the solvents
tested. When the reaction temperature decreased to 140 and
100 °C, the yields were reduced to 42% and 9%, respectively
(Table 1, entries 22 and 23). When the reaction was carried
out in the absence of TMSCl or Mn, no product was formed
(Table 1, entries 24 and 25). However, when N-methyl-
benzamide was employed instead of 1a, no product was found
(Table 1, entry 26). Next, we evaluated other silane sources
such as TMSI, ClSiHMe2, TBSOTf, and PMHS, but they all
gave low yields or no products (see the Supporting
Information).13 Based on these observations, the optimized
reaction conditions were as follows: reaction of the secondary
amide and amine at 160 °C for 16 h in NMP using
Ni(glyme)Cl2/Briphos in the presence of Mn powder and
TMSCl.
With the optimized reaction conditions in hand, we then
evaluated the utility of this nickel-catalyzed transamidation
protocol (Scheme 2). First, a variety of amines were allowed to
react with N-phenyl benzamide under the optimal conditions.
p-Toluidine provided the desired product 3aa in 65% isolated
yield. 4-Ethyl-, 4-isopropyl-, and 4-tert-butyl anilines provided
the corresponding transamidated products 3ab, 3ac, and 3ad
in 66%, 75%, and 80% yields, respectively. However, 2-
methylaniline gave 3ae with a somewhat lower yield of 42%,
h
b
entry
catalyst
NiCl2
NiI2
Ni(OAc)2
Ni(PPh3)2Cl2
Ni(OTf)2
ligand
solvent
NMP
yield (%) 3aa
1
2
3
4
5
6
7
8
Phen
Phen
Phen
Phen
Phen
Phen
28
30
33
32
31
42
59
38
30
55
52
42
60
58
69
12
45
trace
61
45
12
42
9
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
DMF
Diglyme
o-Xylene
1,2-Cl2C6H4
NMP
NMP
NMP
NMP
NMP
Ni(glyme)Cl2
Ni(glyme)Cl2
Ni(glyme)Cl2
Ni(glyme)Cl2
Ni(glyme)Cl2
Ni(glyme)Cl2
Ni(glyme)Cl2
Ni(glyme)Cl2
Ni(glyme)Cl2
Ni(glyme)Cl2
Ni(glyme)Cl2
Ni(glyme)Cl2
Ni(glyme)Cl2
Ni(glyme)Cl2
Ni(glyme)Cl2
Ni(glyme)Cl2
Ni(glyme)Cl2
Ni(glyme)Cl2
Ni(glyme)Cl2
Ni(glyme)Cl2
Ni(glyme)Cl2
Me2Phen
Me4Phen
TMEDA
Xantphos
dppf
9
10
11
12
13
14
15
16
17
18
19
20
21
dppb
PPh3
PCy3
Briphos
P(OPh)3
P(OEt)3
Briphos
Briphos
Briphos
Briphos
Briphos
Briphos
Briphos
Briphos
Briphos
c
22
23
24
25
d
e
Scheme 2. Transamidation of N-Phenyl Benzamide with
0
0
0
a
f
Primary Amines
g
26
a
Reaction conditions: 1a (0.3 mmol), 2a (0.6 mmol), Ni (0.06
mmol), ligand (0.06 mmol), Mn (1.5 mmol), and TMSCl (0.6 mmol)
b
were reacted in the solvent (1.2 mL) at 160 °C for 16 h. Determined
by gas chromatography and 1H NMR with internal standard.
c
d
Reaction temperature = 140 °C. Reaction temperature = 100 °C.
e
f
g
No TMSCl. No Mn. N-Methyl benzanilide was used instead of 1a.
h
Ligand structure.
to be the best source, although only a moderate product yield
of 42% was observed (Table 1, entry 6). With the selected
nickel source, N,N-chelating ligands were tested. The use of
Me2Phen increased the product yield to 59% (Table 1, entry
7). When using Me4Phen and TMEDA, the product yields
were 38% and 30%, respectively (Table 1, entries 8 and 9).
P,P-Chelating phosphines such as Xantphos, dppf, and dppb
afforded 3aa in 55%, 52%, and 42% yields, respectively (Table
1, entries 10−12). Monophosphine ligands PPh3 and PCy3
a
Reaction conditions: 1a (2.0 mmol), 2 (4.0 mmol), Ni(glyme)Cl2
(0.4 mmol), Briphos (0.4 mmol), Mn (10.0 mmol), and TMSCl (4.0
mmol) were allowed to react in NMP at 160 °C for 16 h.
B
DOI: 10.1021/acs.orglett.8b03304
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Organic Letters
Letter
and 2,6-diisopropylaniline did not provide the desired product
due to the steric effect of the ortho-substituent. The reaction
with 4-methoxyaniline proceeded to completion to provide
3ag in 95% yield. 2,4-Dimethoxy aniline afforded 3ah in 62%
yield. 4-Methylthio- and 4-dimethylamino anilines furnished
3ai and 3aj in good yields, but 4-aminobenzonitrile provided
the transamidated 3ak in only 38% yield. 2-Aminonaphthalene,
2-aminopyridine, and 2-amino-4-methylpyridine participating
in the transamidation furnished the corresponding products in
48%, 72%, and 80% yields, respectively. Benzylamine and
benzhydrylamine provided 3ao and 3ap in 45% and 64%
yields, respectively. Alkylamines such as cyclohexylamine gave
good product yields in the transamidation, but tert-butylamine
did not give the transamidated product.
Scheme 4. Transamidation of N-Phenyl Benzamide with
Secondary Amines
a
a
Reaction conditions: 1a (2.0 mmol), 4 (4.0 mmol), Ni(glyme)Cl2
(0.4 mmol), Briphos (0.4 mmol), Mn (10.0 mmol) and TMSCl (4.0
mmol) were allowed to react in NMP at 160 °C for 16 h.
Next, we evaluated the substrate scope of N-phenyl
benzamide in the transformation. 4-Methoxy-, 4-fluoro, 2-
methyl, and 2-methoxyl-N-phenylbenzamides (1b, 1c, 1d, and
1e) were employed in the transamidation with primary amines.
In most cases, the desired products were obtained in good
yields (57%−84%), as summarized in Scheme 3. In particular,
a
Scheme 5. Transamidation of Alkyl Amide 6
a
Scheme 3. Transamidation of N-Aryl Benzamide Derivatives
with Aniline Derivatives
Reaction conditions: 6 (2.0 mmol), 2g (4.0 mmol), Ni(glyme)Cl2
a
(0.4 mmol), Briphos (0.4 mmol), Mn (10.0 mmol), and TMSCl (4.0
mmol) were allowed to react in NMP at 160 °C for 16 h.
only 3ad was formed in 54% yield (Scheme 6, eq 4). When 4-
methoxy- and 4-fluoro-N-phenylbenzamaide were allowed to
Scheme 6. Control Experiments
a
Reaction conditions: 1 (2.0 mmol), 2 (4.0 mmol), Ni(glyme)Cl2
(0.4 mmol), Briphos (0.4 mmol), Mn (10.0 mmol), and TMSCl (4.0
mmol) were allowed to react in NMP at 160 °C for 16 h.
the reactions with 4-tert-butylaniline gave more than 80%
product yields. In addition, 2-methyl- or 2-methoxy-substituted
N-phenylbenzamide was allowed to react with 4-methoxyani-
line to provide 3dg and 3eg in 76% and 64% yields,
respectively.
Our attempts to extend this methodology to transamination
with secondary amines was not successful (Scheme 4). The
reactions between N-phenylbenzamide and secondary amines
such as morpholine, piperidine, and pyrrolidine afforded the
transamidation products 5a, 5b, and 5c in only 24%, 21%, and
22% yields, respectively. However, when N-methylaniline was
employed, no product was formed.
Next, alkyl amides such as N-phenyl cyclohexane-
carboxamide 6 were also employed in this transamidation. As
shown in Scheme 5, alkyl amide 6 reacted with 2g to afford 7
in 85% yield.
react with 4-tert-butylaniline, 3cd was formed in higher yield
than 3bd (Scheme 6, eq 5). These results indicate that the
transamination was promoted by the electron-donating amine
and the electron-withdrawing benzamide. The role of TMSCl
was also investigated. 4-tert-Butyl-N,N-bis(trimethylsilyl)-
aniline 814 reacted with 1a to afford the product 3ad in 72%
yield, implying that TMSCl activates the primary amine to
generate 8 in situ in the optimized reaction conditions
(Scheme 6, eq 6). However, we were unable to detect any
activated amides (TMS-attached amides) (see Scheme S3 in
the Supporting Information).
Competition experiments were conducted to understand the
reactivity of the Ni-catalyzed transamination. When 4-tert-
butylaniline and 4-cyanoaniline were allowed to react with 1a,
C
DOI: 10.1021/acs.orglett.8b03304
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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The mechanism and the role of TMSCl are not clear at this
time. We propose that Ni(0) was generated by manganese and
added to the C−N bond of amide through oxidative addition
to give an acyl amino nickel(II) complex, followed by the
coordination of a primary amine to the nickel complex to
provide a transaminated nickel(II) complex. We suggest that
TMSCl might accelerate oxidative addition and/or trans-
amination steps. Finally, the reductive elimination provides the
transamidated secondary amide and Ni(0) catalyst.
In summary, we developed a direct transamidation of
secondary amides using a catalytic combination of nickel and a
Briphos ligand. Preactivation of the secondary amide is not
necessary because TMSCl activates the aniline derivatives via
the formation of the corresponding bis(trimethylsilyl)anilines.
The reaction of secondary amides and anilines proceeded
efficiently to afford the transamidation products in moderate to
good yields. Aniline derivatives having electron-donating
groups showed higher yields than those having electron-
withdrawing groups. Secondary amines participated in this
reaction, but the product yields were low. Further studies on
the reaction mechanism are underway in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03304.
Experimental procedures, NMR spectroscopic and MS
data for all new compounds (PDF)
(7) Hoerter, J. M.; Otte, K. M.; Gellman, S. H.; Cui, Q.; Stahl, S. S. J.
Am. Chem. Soc. 2008, 130, 647.
AUTHOR INFORMATION
Corresponding Authors
■
(8) (a) Bon, E.; Bigg, D. C. H.; Bertrand, G. J. J. Org. Chem. 1994,
59, 4035. (b) Eldred, S. E.; Stone, D. A.; Gellman, S. H.; Stahl, S. S. J.
Am. Chem. Soc. 2003, 125, 3422. (c) Hoerter, J. M.; Otte, K. M.;
Gellman, S. H.; Stahl, S. S. J. Am. Chem. Soc. 2006, 128, 5177.
(d) Stephenson, N. A.; Zhu, J.; Gellman, S. H.; Stahl, S. S. J. Am.
Chem. Soc. 2009, 131, 10003.
*E-mail: hwkim@kaist.edu (H.K.).
*E-mail: sunwoo@chonnam.ac.kr (S.L.).
ORCID
Yuanzhi Xia: 0000-0003-2459-3296
Hyunwoo Kim: 0000-0001-5030-9610
Sunwoo Lee: 0000-0001-5079-3860
(9) (a) Baker, E. L.; Yamano, M. M.; Zhou, Y.; Anthony, S. M.;
Garg, N. K. Nat. Commun. 2016, 7, 11554. (b) Hu, J.; Zhao, Y.; Liu,
J.; Zhang, Y.; Shi, Z. Angew. Chem., Int. Ed. 2016, 55, 8718.
(c) Dander, J. E.; Baker, E. L.; Garg, N. K. Chem. Sci. 2017, 8, 6433.
(d) Meng, G.; Lei, P.; Szostak, M. Org. Lett. 2017, 19, 2158. (e) Shi,
S.; Szostak, M. Chem. Commun. 2017, 53, 10584.
Notes
The authors declare no competing financial interest.
(10) Cheung, C. W.; Ploeger, M. L.; Hu, X. ACS Catal. 2017, 7,
7092.
ACKNOWLEDGMENTS
■
(11) (a) Lee, A.; Ahn, S.; Kang, K.; Seo, M.-S.; Kim, Y.; Kim, W. Y.;
Kim, H. Org. Lett. 2014, 16, 5490−5493. (b) Lee, A.; Kim, H. J. Am.
Chem. Soc. 2015, 137, 11250−11253. (c) Kang, K.; Kim, J.; Lee, A.;
Kim, W. Y.; Kim, H. Org. Lett. 2016, 18, 616−619. (d) Lee, A.; Kim,
H. J. Org. Chem. 2016, 81, 3520.
(12) Heinz, C.; Lutz, J. P.; Simmons, E. M.; Miller, M. M.; Ewing,
W. R.; Doyle, A. G. J. Am. Chem. Soc. 2018, 140, 2292.
(13) The effect of the amount of p-toluidine and TMSCl was studied
(see Scheme S2 in the Supporting Information).
(14) Lee, S.; Jorgensen, M.; Hartwig, J. F. Org. Lett. 2001, 3, 2729.
This research was supported by the National Research
Foundation of Korea (NRF) grant funded by the Korean
government (MSIP) (NRF-2015R1A4A1041036, NRF-
2017R1A2B4002650, and NRF-2017R1A2B2002929). The
spectral and HRMS data were obtained from the Korea
Basic Science Institute, Gwangju Center and Daegu Center.
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