Metal-Free Transamidation of Secondary Amides by N-C Cleavage

Article abstract of DOI:10.1021/acs.joc.9b02013

Transamidation reactions represent a fundamental chemical process involving conversion of one amide functional group into another. Herein, we report a facile, highly chemoselective method for transamidation of N-tert-butoxycarbonylation (N-Boc) activated secondary amides that proceeds under exceedingly mild conditions in the absence of any additives. Because this reaction is performed in the absence of metals, oxidants, or reductants, the reaction tolerates a large number of useful functionalities. The reaction is compatible with diverse amides and nucleophilic amines, affording the transamidation products in excellent yields through direct nucleophilic addition to the amide bond. The utility of this methodology is highlighted in the synthesis of Tigan, a commercial antiemetic, directly from the amide bond. We expect that this new metal-free transamidation will have broad implications for the development of new transformations involving direct nucleophilic addition to the amide bond as a key step.

Full text of DOI:10.1021/acs.joc.9b02013

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Article
Metal-Free Transamidation of Secondary Amides by N–C Cleavage
Md. Mahbubur Rahman, Guangchen Li, and Michal Szostak
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02013 • Publication Date (Web): 20 Aug 2019
Downloaded from pubs.acs.org on August 21, 2019
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The Journal of Organic Chemistry
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Metal-Free Transamidation of Secondary Amides by N–
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†
†
,†
Md. Mahbubur Rahman, Guangchen Li, and Michal Szostak*
†Department of Chemistry, Rutgers University, 73 Warren Street, Newark, New Jersey 07102, United
States
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
Corresponding author
michal.szostak@rutgers.edu
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Abstract
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Transamidation reactions represent a fundamental chemical process involving conversion of one amide
functional group into another. Herein, we report a facile, highly chemoselective method for
transamidation of N-Boc activated secondary amides that proceeds under exceedingly mild conditions in
the absence of any additives. Because this reaction is performed in the absence of metals, oxidants or
reductants, the reaction tolerates a large number of useful functionalities. The reaction is compatible
with diverse amides and nucleophilic amines, affording the transamidation products in excellent yields
through direct nucleophilic addition to the amide bond. The utility of this methodology is highlighted in
the synthesis of Tigan, a commercial antiemetic directly from the amide bond. We expect that this new
metal-free transamidation will have broad implications for the development of new transformations
involving direct nucleophilic addition to the amide bond as a key step.
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The Journal of Organic Chemistry
1
. Introduction
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The amide bond is one of the most important functional groups in chemistry and nature.1–3 Because of
the prevalence of amides in organic synthesis, drug discovery and polymers, new methods for the
4
construction of amides have a major impact on the field. While one of the most attractive methods for
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*
the synthesis of amides involves transamidation, the high stability of amides resulting from n
N
→ C=O
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conjugation renders the amide N–C(O) bond very difficult to cleave. In particular, transamidation of
secondary amides poses a formidable challenge because of the thermoneutral character of the process
and the formation of undesired equilibrium mixtures.7
Recently, strategies for activation of amides by steric and electronic distortion of the N–C(O) amide
bond have gained a considerable momentum (Figure 1A).8–10 This broadly applicable amide activation
platform is of high interest to academic and industrial chemists because it enables to activate common
amides for an array of previously elusive transformations. In this context, a number of groups have
reported transamidations of sterically-distorted amides, including via metal-catalyzed and transition-
metal-free pathways.11–14 The direct activation of secondary amides by N-tert-butoxycarbonylation (N-
Boc) is particularly attractive15–17 because it allows one to engage common secondary amides in a
diverse set of N–C(O) cleavage reactions (RE, resonance energy, RE = 7.2 kcal/mol; Winkler-Dunitz
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distortion,  = 29.1°; 
N
= 8.4°; Ar = Ph, R = Ph). An ever-increasing drive to improve the utility,
1
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11–17
operational simplicity and environmental profile of reactions involving N–C cleavage
in common
amides led us to question whether it might be possible to increase the efficiency of transamidations of
secondary amides.
Herein, we report a highly chemoselective method for transamidation of N-Boc activated secondary
amides that proceeds under exceedingly mild conditions in the absence of any additives (Figure 1B).
The present method represents the first example of a general, metal-free method for transamidation of
synthetically-useful N-Boc amides. The reactivity of N-activated twisted amides hinges upon two
competing pathways: 1) nucleophilic addition, and 2) N-deprotection. The present study reports that the
combination of a polar aprotic solvent and external base-free conditions significantly improves the
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reactivity in transamidation. The method relies on facile preparation of N-Boc amides directly from
secondary amides, which makes the method synthetically-useful and is in sharp contrast to other
activated amides.
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Notable features of our study include: (1) The reaction is compatible with diverse amides and
nucleophilic amines, affording the transamidation products in excellent yields. (2) The method offers
major advantages in terms of operational-simplicity, decreased waste generation and improved atom
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economy, which is important from the environmental and sustainability standpoints. (3) The utility of
this methodology is highlighted in the synthesis of Tigan, a commercial antiemetic, directly from the
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amide bond. The strategy enabling simple secondary amides to serve broadly as electrophiles in metal-
free transamidation may have broad implications for the development of new transformations involving
direct nucleophilic addition to the amide bond as a key step.
Figure 1. (a) Activation of amides for N–C(O) cleavage. (b) Metal-free, highly selective transamidation
of N-Boc amides (this work).
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The Journal of Organic Chemistry
2
. Results and Discussion
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The site-selective N-tert-butoxycarbonylation of secondary amides proceeds in an average >80%
yield, including substrates containing Lewis basic sites,9,15,16 rendering secondary amides generic
electrophiles in synthetic reactions. The properties of the leaving amine, tert-butyl carbamate, make the
transamidation process thermodynamically favored. We proposed that stabilization of the tetrahedral
intermediate in a more polar transition state would lead to the increased efficiency of the transamidation
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process. The keyconsideration is the balance between the increased rate of nucleophilic addition to the
9c
N-Boc activated N–C(O) amide bond and the amide bond deprotection by N-Boc scission, which
effectively deactivates the amide bond from mild nucleophilic addition. The synthetic utility of
transamidation reactions under operationally-simple, metal-free conditions, in which the traditionally
inert amide bonds are employed as electrophiles in a direct nucleophilic addition mechanism, has served
as motivation for the current study.
The reaction between N-Boc activated amide (1a) and morpholine was selected as a model system
(Table 1). Notice that this reaction is unsuccessful under previous conditions promoted by Et N, which
3
leads to amide decomposition through N-deacylation pathway.14c Morpholine represents a nucleophilic
amine that is deactivated by the electron-negative oxygen atom. As such, morpholine has often been
used as an amine in transition-metal-catalyzed cross-coupling reactions of N-Boc amides, wherein the
background reaction in the absence of transition-metal was found to be non-existent.11,12 Clearly, a
strategy for the metal-free synthesis of valuable N-morpholinyl amides by transamidation of secondary
amides would be of considerable utility. Morpholinyl amides function as resonance stabilized Weinreb
amide equivalents in nucleophilic addition reactions via tetrahedral intermediates.9
In analogy to the classical nucleophilic addition reactions, the choice of solvent was found to have a
major impact on the yield. After extensive optimization we found that the use of morpholine (2.0 equiv)
in acetonitrile (1.0 M) in the absence of any other reagents led to highly efficient transamidation of
amide (1a) in quantitative yield at room temperature (Table 1, entry 1). Under these conditions, several
solvents could be utilized (Table 1, entries 2-10); however, acetonitrile was found to be optimal.
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Interestingly, changes in the reaction concentration led to a reduced yield (Table 1, entries 11-13), likely
as a result of slower addition and/or amide deprotection by N–Boc cleavage. Remarkably, the amount of
morpholine could be reduced to 1.5 equiv and even 1.0 equiv (Table 1, entries 14-15), consistent with
highly efficient transamidation. Under the optimized conditions cleavage of the alternative N–C bond
was not observed. The reactions were routinely stirred for 15 h (Table 1, entries 1-15). The reaction time
was not optimized; however, 30% conversion is observed after 1 h reaction time under standard
conditions (Table 1, entry 1). All reactions were set up under ambient conditions in the absence of
additional air, oxygen or inert gas. Further, the use of EtOH is not recommended as it leads to N-
decomposition (Table 1, entry 10).14g It is worthwhile to point out that 1) N-Ts amides cannot be easily
prepared from secondary amides as, typically, these reactions require a strong base and are plagued by
N-acylation; 2) N-Boc amides are significantly less reactive than N-Ts amides in metal-free
transamidation (i.e., no reaction is observed with less reactive amines, including morpholine).14c
Overall, this finding represents the first general method for a metal-free transamidation of synthetically
useful N-Boc amides.
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Table 1. Optimization of the Reaction Conditionsa
2
a
T
(°C)
yield
entry
solvent
CH CN
(%)b
(
equiv)
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2.0
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25
25
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>98
84
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92
88
94
83
2.0
THF
2.0
toluene
2.0
CH
Et
CHCl
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Cl
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2
O
2.0
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2.0
1,4-dioxane
DMF
2.0
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The Journal of Organic Chemistry
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2.0
2.0
2.0
2.0
2.0
1.5
1.0
DMSO
EtOH
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25
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25
82
60
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1c
2d
3e
CH
CH
CH
CH
CH
3
3
3
3
3
CN
CN
CN
CN
CN
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1
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93
97
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>98
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Conditions: amide (1.0 equiv), solvent (1.0 M), 25 °C, 15 h. GC/ H NMR yields. CH
(0.25 M). CH CN (0.50 M). CH CN (2.0 M).
3 3
3
CN
d
e
With optimized conditions in hand, the scope of this metal-free transamidation was surveyed
Schemes 1-2). As expected from the very mild, metal-free profile of this reaction, a variety of sensitive
(
functional groups is tolerated, providing the transamidation products in high to excellent yields. As
shown in Scheme1, electronic substitution of the amide at the conjugating para-position with electron-
neutral (3b), deactivating electron-donating (3c) and various electron-withdrawing groups (3d-3i) was
well-tolerated. Particularly noteworthy is functional group tolerance to electrophilic substituents such as
nitro (3e), bromo (3h) and ester (3i) that would be problematic in transition-metal-catalyzed
protocols11,12 or in the reactions promoted by strong metal bases.14a,b Moreover, the reaction provides
access to fluorinated amides (3f-3g) that constitute useful building blocks in pharmaceuticals.2a,b
Furthermore, we were pleased to find that electron-rich five-membered heterocycles substituted at the
conjugating position furnished the transamidation products in high yields (3j-3k). Notably, alkyl amides
were also found to be competent electrophiles in this reaction (3l). Finally, the synthesis of ,-
conjugated amide (3m) demonstrates the ability of this transformation to promote transamidation of
vinyl amides, albeit 60 °C is required in this case. Addition to the olefin was not observed under these
conditions, attesting to the mild conditions of the present transamidation method. Furthermore, we were
delighted that the scope of the amine component is also broad (Scheme 2). Primary amines with
different length chains (3n-3o) as well as those containing groups sensitive in transition-metal-catalysis
(
3p-3q) proved to be effective in this reaction. Acyclic (3r-3t) as well as cyclic (3u-3v) secondary
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amines afforded transamidation products in excellent yields. This includes N-Bn and N-allyl amines that
would be problematic in transition-metal-catalysis,11,12 clearly showing the advantage of this mild
protocol. Furthermore, -branched primary amines were tolerated (3w-3x). At present, the limit appears
to be reached with bulky amines; expectedly, tert-butylamine also reacted, albeit required elevated
temperature (120 °C) for transamidation (3y). It is worthwhile to point out that the method is compatible
with alkyl esters, halides and electrophilic functional groups that would be problematic in other
approaches.11–14 The method is not compatible with activated phenolic esters; it is well-established in
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the literature that activated esters are more reactive than amides. At the present stage of reaction
development iodo and cyano substituents have not been tested. The effect of ortho-substitution on steric
and electronic properties of N-activated acyclic twisted amides is currently ongoing in our laboratory.
Future studies will focus on expanding the scope of transamidation and related metal-free activation
methods of amide bonds.
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The Journal of Organic Chemistry
Scheme1. Additive-Free Transamidation of N-Boc Amidesa,b
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aAmide (1.0 equiv), 2a (2.0 equiv), CH
CN (1.0 M), 25 °C, 15 h. Isolated yields. 2a (1.2 equiv), 60 °C.
b
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Scheme2. Additive-Free Transamidation of N-Boc Amidesa,b
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aAmide (1.0 equiv), 2a (2.0 equiv), CH
CN (1.0 M), 25 °C, 15 h. Isolated yields. 120 °C.
b
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3
Importantly, N-alkyl amides are suitable substrates (Scheme 3, 1n-1o). In this instance, nucleophilic
amines react smoothly at room temperature, while the use of deactivated morpholine requires higher
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temperatures (120 °C), as expected from amidic resonance. Given thermal instability of tert-butyl
carbamates, this result highlights the fast nucleophilic addition of deactivated amines in this metal-free
transamidation manifold.
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Scheme3. Additive-Free Transamidation of N-Boc/N-Alkyl Amides
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To demonstrate the utility of this mild transamidation method, we accomplished the synthesis of
1
9
Tigan, a commercial antiemetic for treatment of nausea directly from the amide bond (Scheme 4). The
present synthetic route involves CDI-mediated amidation. Our method permits an alternative
disconnection utilizing amide as the starting material. The reaction using equimolar quantities of the
reagents (2n, 1.0 equiv) delivered Tigan in 84% yield. This reaction demonstrates the potential breadth
of applications of the present method in medicinal chemistry. The synthesis of Tigan represents, to the
best of our knowledge, the first example of a real-life application of any type in the burgeoning field of
N–C(O) bond activation.8,11–16 This example emphasizes the potential synthetic utility of the method.
Future studies will focus on the synthesis of analogues and application of N–C bond cleavage reactions
in medicinal chemistry.
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Scheme4. Synthesis of Tigan by Additive-Free Transamidation of N-Boc Amide
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To gain insight into the reaction mechanism, we performed intermolecular competition experiments
between differently substituted amides, which revealed electron-deficient amides to be more reactive
than their electron-rich or alkyl counterparts (Scheme 5). Furthermore, intermolecular competition
experiments between different amines established that the reaction is promoted by nucleophilic amines
(Scheme 6). These findings provide a strong support for the acyl substitution mechanism of the amide
20
21
bond, wherein selectivity is determined by amine nucleophilicity. There appears to be a scattered
correlation between nucleophilicities of amines and the reactivity. Because the reactivity is also
dependent on steric demand of the nucleophile, nucleophilicity provides an estimate of the reactivity in
this reaction manifold. Our findings in combination with other metal-free and transition-metal-free
methods permit to formulate a set of guidelines for using mild transamidation of N–Boc amides (vide
infra). The NHRBoc amine can be recovered from the reaction mixture, consistent with the proposed
mechanism.
Guidelines for Metal-Free and Transition-Metal-Free Transamidation Reactions. The present
method should be compared and contrasted with other known methods for transamidation reactions of
N-activated amides.11–14
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The Journal of Organic Chemistry
(
1) In principle, we recommend that metal-free transamidations described in the present study14c are
1
2
used for nucleophilic amines, such as aliphatic amines and strongly nucleophilic anilines. These
reactions appear to proceed through rate-limiting addition to the amide bond.
3
4
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(2) In contrast, transamidations with non-nucleophilic anilines are best performed using strong bases,
such as LiHMDS.14a,b Mechanistically, these reactions proceed via deprotonation of the amine and are
less suitable for nucleophilic aliphatic amines.
0
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(3) In cases when metal-free or transition-metal-free reactions fail to provide the desired level of
12
11
efficiency, we recommend the use of Pd- or Ni-catalyzed transamidations. An important practical
difference between the Pd- and Ni-catalytic systems described is the use of air-stable, well-defined
Pd(II)–NHC precatalysts that make the set up robust to air and moisture.8a
(4) Finally, since the present method represents the most reactive and operationally-straightforward
protocol for metal-free transamidation of N-activated amides, we recommend that this reaction is tested
in the first instance when developing new transamidation methods11–14 or expanding the scope of the
reported methods with other amide precursors.8,9
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Scheme5. Competition Experiments
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Scheme6. Competition Experiments
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The Journal of Organic Chemistry
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. Conclusions
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In summary, we have reported a facile method for metal-free transamidation of N-Boc activated
secondary amides. Notably, the reaction proceeds under exceedingly mild conditions in the absence of
any additives. This discovery provides a novel way for transamidation of the traditionally challenging
secondary amides. The method offers major advantages in terms of operational-simplicity, decreased
waste generation and improved atom economy, which are important factors in the search for more
benign strategies in organic synthesis. The utility of this methodology has been highlighted in the
synthesis of Tigan, a commercial antiemetic directly from the amide bond. In principle, a dominant
aspect of amide bond activation stems from the ability to predictably form tetrahedral intermediates
after selective N-activation. This advance should facilitate the development of general strategies for
deploying nucleophilic addition to amide bonds. Studies to expand the reaction scope and the
development of related reactions that utilize amide bond destabilization concept are underway.
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Experimental Section
General Methods. All starting materials reported in the manuscript have been previously described in
literature or prepared by the method reported previously. All tert-butyl benzoyl(phenyl)carbamate
derivatives were prepared according to standard methods.12a,14b,15a All products reported in the
manuscript have been previously described, unless stated otherwise. All experiments were performed
using standard Schlenk techniques under argon or nitrogen atmosphere unless stated otherwise. All
solvents were purchased at the highest commercial grade and used as received or after purification by
passing through activated alumina columns or distillation from sodium/benzophenone under nitrogen.
1
All other chemicals were purchased at the highest commercial grade and used as received. H NMR and
13C NMR spectra were recorded in CDCl
on Bruker spectrometers at 500 ( H NMR) and 125 MHz ( C
1
13
3
NMR). HRMS were recorded using Bruker FTMS equipped with a 7.0 T magnet, and an Apollo II Dual
ESI/MALDI source. For reactions that required heating, oil bath was used as the heat source (silicone
1
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oil). All other general methods have been published.16b 1H NMR and C NMR data are given for all
compounds in the Supporting Experimental for characterization purposes. H NMR, 13C NMR and
HRMS data are reported for all new compounds. All compounds have been fully characterized in
accordance with the established guidelines.
13
1
2
3
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9
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1
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General Procedure for the Synthesis of Starting Materials. All amides used in this study have
been prepared by established methods. 12a,14b,15a 1H NMR and C NMR data for all amides are given in
the section below for characterization purposes.
13
General Procedure for the Synthesis of N-Boc Amides from Secondary Amides. A previously
published procedure was followed.12a An oven-dried round-bottomed flask (100 mL) containing a stir
bar was charged with a secondary amide substrate (5.0 mmol, 1.0 equiv), 4-(dimethylamino)pyridine
(0.5 mmol, 0.10 equiv) and dichloromethane (typically, 0.20 M). Di-tert-butyl dicarbonate (5.0 mmol,
1
.0 equiv) was added in one portion and the reaction mixture was allowed to stir at room temperature
for 15 h. After the indicated time, the reaction mixture was quenched with NaHCO (aq., sat., 10 mL),
extracted with EtOAc (3× 20 mL), washed with H O (1 x 20 mL), brine (1 x 20 mL). The organic layers
3
2
were combined, dried, and concentrated under reduce pressure. Unless stated otherwise, purification by
flash chromatography (EtOAc/hexanes) afforded pure products. In our hands, N-Boc activation of
1
secondary amides typically proceeds in >80% yields. The isolated products were characterized by H
1
3
19
NMR, C NMR, F NMR (if required) and HRMS (new compounds).
General Procedure for Facile Transamidation Reactions. An oven-dried reaction flask containing
a stir bar was charged with an amide substrate (neat, 1.0 equiv) CH CN (typically, 1.0 M), and amine
3
(typically, 2.0 equiv) were added with vigorous stirring at room temperature, and the reaction mixture
was stirred at room temperature for an indicated time. After the indicated time, the reaction mixture was
diluted with EtOAc (15 mL), washed with HCl (aq., 1.0 N, 10 mL), the aqueous layer was extracted
with EtOAc (2 × 15 mL), the organic layers were combined, dried, filtered, and concentrated. A sample
1
was analyzed by H NMR (CDCl
3
, 500 MHz) and GC-MS to obtain conversion, yield and selectivity
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The Journal of Organic Chemistry
using internal standard and comparison with authentic samples. The crude product was purified by
chromatography (EtOAc/hexanes) to give analytically pure product. The isolated products were
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1
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1
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19
characterized by H NMR, C NMR, F NMR (if required) and HRMS (new compounds).
Representative Procedure for Facile Transamidation. 1.0 Mmol Scale. An oven-dried 25 mL
reaction flask containing a stir bar was charged with tert-butyl benzoyl(phenyl)carbamate (297.4 mg,
0
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3
4
5
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0
1
.0 mmol, 1.0 equiv), CH CN (1.0 mL, 1.0 M) and morpholine (174.2 mg, 2.0 mmol, 2.0 equiv), and
3
the reaction mixture was stirred at room temperature for 15 h. After the specified time, the reaction
mixture was diluted with EtOAc (30 mL), washed with HCl (aq., 1.0 N, 10 mL), the aqueous layer was
extracted with EtOAc (2 × 15 mL), the organic layers were combined, dried, filtered, and concentrated.
1
A sample was analyzed by H NMR (CDCl
3
, 500 MHz) and GC-MS to obtain conversion, yield and
selectivity using internal standard and comparison with authentic samples. Purification by
chromatography on silica gel (EtOAc/hexanes) afforded the title product. Yield 94% (180.1 mg). White
solid. Characterization data are included in the section below.
Characterization Data of Amide Starting Materials. All amides described in this manuscript were
prepared directly from secondary amides by established methods. Amides 1a,12a 1b,12a 1c,12a 1d,12a
1
g,12a 1i,12a 1j,12a 1l,12a 1n,12a 1o12a have been previously reported. Spectroscopic data match those
reported in the literature. Amides 1e, 1f, 1h, 1k, 1m, 1p are new compounds.
1
tert-Butyl benzoyl(phenyl)carbamate (1a). Yield 95% (1.41 g). White solid. H NMR (500 MHz,
CDCl ) δ 7.76 (d, J = 7.1 Hz, 2H), 7.55 (t, J = 7.4 Hz, 1H), 7.49-7.43 (m, 4H), 7.37 (t, J = 7.4 Hz, 1H),
.30 (d, J = 7.4 Hz, 2H), 1.26 (s, 9H). C{1H} NMR (125 MHz, CDCl
131.7, 129.2, 128.3, 128.1, 128.0, 127.8, 83.5, 27.5.
3
1
3
7
3
) δ 172.8, 153.3, 139.1, 137.0,
1
tert-Butyl (4-methylbenzoyl)(phenyl)carbamate (1b). Yield 91% (1.42 g). White solid. H NMR
(
500 MHz, CDCl ) δ 7.67 (d, J = 7.9 Hz, 2H), 7.44 (t, J = 7.7 Hz, 2H), 7.35 (t, J = 7.2 Hz, 1H), 7.30-
3
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1
3
7
1
.25 (m, 4H), 2.44 (s, 3H), 1.29 (s, 9H). C{1H} NMR (125 MHz, CDCl ) δ 172.7, 153.5, 142.5,
3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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3
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39.3, 133.9, 129.2, 128.9, 128.5, 127.9, 127.6, 83.3, 27.6, 21.6.
1
tert-Butyl (4-methoxybenzoyl)(phenyl)carbamate (1c). Yield 87% (1.42 g). White solid. H NMR
(500 MHz, CDCl
3
) δ 7.77 (d, J = 7.6 Hz, 2H), 7.43 (t, J = 7.2 Hz, 2H), 7.33 (t, J = 7.3 Hz, 1H), 7.28 (d,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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13
J = 7.9 Hz, 2H), 6.95 (d, J = 7.7 Hz, 2H), 3.88 (s, 3 H), 1.32 (s, 9H). C{1H} NMR (125 MHz, CDCl
3
)
δ 172.1, 162.8, 153.5, 139.5, 130.9, 129.1, 128.7, 127.8, 127.5, 113.6, 83.1, 55.5, 27.7.
1
tert-Butyl phenyl(4-(trifluoromethyl)benzoyl)carbamate (1d). Yield 78% (1.43 g). White solid. H
NMR (500 MHz, CDCl
3
) δ 7.81 (d, J = 8.1 Hz, 2H), 7.71 (d, J = 8.1 Hz, 2H), 7.45 (t, J = 7.6 Hz, 2H),
13
7
1
.37 (t, J = 7.4 Hz, 1H), 7.27 – 7.24 (m, 2H), 1.24 (s, 9H). C{1H} NMR (125 MHz, CDCl
3
) δ 171.7,
F
F
53.2, 140.7, 138.9, 133.4 (q, J = 32.7 Hz), 129.7, 128.5, 128.5, 128.3, 125.7 (q, J = 3.7 Hz), 124.0 (q,
F
19
J = 273.0 Hz), 84.5, 27.8. F NMR (471 MHz, CDCl ) δ -62.93.
3
tert-Butyl (4-nitrophenyl)carbamate (1e). New compound. Yield 75% (1.28 g). White solid. Mp =
1
1
02-103 °C. H NMR (500 MHz, CDCl
3
) δ 8.30 (d, J = 8.7 Hz, 2H), 7.83 (d, J = 8.8 Hz, 2H), 7.46 (t, J
1
3
=
7.6 Hz, 2H), 7.39 (d, J = 7.5 Hz, 1H), 7.27 – 7.23 (m, 2H), 1.27 (s, 9H). C{1H} NMR (125 MHz,
CDCl
3
) δ 170.9, 152.9, 149.4, 143.0, 138.5, 129.6, 128.9, 128.6, 128.3, 123.8, 84.7, 27.8. HRMS (ESI-
+
TOF) calcd for C18
H
18
N O
2 5
Na (M + Na) 365.1108 found 365.1125.
tert-Butyl (4-fluorobenzoyl)(phenyl)carbamate (1f). New compound. Yield 82% (1.29 g). White
1
solid. Mp = 87-88 °C. H NMR (500 MHz, CDCl
3
) δ 7.78 – 7.72 (m, 2H), 7.42 (t, J = 7.7 Hz, 2H),
1
3
7.34 (t, J = 7.4 Hz, 1H), 7.26 – 7.22 (m, 2H), 7.14 – 7.10 (m, 2H), 1.28 (s, 9H). C{1H} NMR (125
F
F
F
MHz, CDCl ) δ 171.8, 165.1 (d, J = 253.5 Hz), 153.5, 139.3, 133.2 (d, J = 3.2 Hz), 131.0 (d, J = 9.0
3
F
19
Hz), 129.5, 128.1 (d, J = 4.9 Hz), 115.8, 115.6, 83.9, 27.8. F NMR (471 MHz, CDCl
3
) δ -106.89.
+
HRMS (ESI-TOF) calcd for C36
H
36
F
2
N
2
O
6
Na (2M + Na) 653.2434 found 653.2435.
1
tert-Butyl phenyl(3,4-difluorobenzoyl)carbamate (1g). Yield 80% (1.33 g). White solid. H NMR
(
500 MHz, CDCl ) δ 7.56 (t, J = 8.8 Hz, 1H), 7.53 – 7.47 (m, 1H), 7.43 (t, J = 7.6 Hz, 2H), 7.35 (t, J =
3
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1
3
7
.4 Hz, 1H), 7.27 – 7.19 (m, 3H), 1.31 (s, 9H). C{1H} NMR (125 MHz, CDCl
3
) δ 170.7, 153.9 (dd,
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
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4
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4
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5
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5
5
5
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6
F
F
F
F
F
J = 255.65 Hz, J = 12.6 Hz), 153.4, 150.4 (dd, J = 150.9 Hz, J = 13.1 Hz), 139.1, 133.9 (dd, J = 5.1
F
F
F
F
Hz, J = 4.0 Hz), 129.6, 128.4, 128.2, 125.3 (dd, J = 7.1, J = 3.7 Hz), 118.2 (d, J = 19.2 Hz), 117.6
F
19
(
d, J = 18.0 Hz), 84.3, 27.9. F NMR (471 MHz, CDCl ) δ - 131.63, -136.54.
3
0
1
2
3
4
5
6
7
8
9
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1
2
3
4
5
6
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8
9
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tert-Butyl (4-bromobenzoyl)(phenyl)carbamate (1h). New compound. Yield 83% (1.57 g). White
1
solid. Mp = 85-86 °C. H NMR (500 MHz, CDCl
3
) δ 7.63 – 7.54 (m, 4H), 7.42 (t, J = 7.6 Hz, 2H),
1
3
7.35 (t, J = 7.4 Hz, 1H), 7.23 (d, J = 7.5 Hz, 2H), 1.28 (s, 9H). C{1H} NMR (125 MHz, CDCl
3
) δ
1
71.9, 153.3, 139.1, 135.9, 131.8, 130.0, 129.5, 128.2, 128.2, 126.6, 84.1, 27.8. HRMS (ESI-TOF)
+
calcd for C18
H
18BrNO K (M + K) 414.0102 found 414.0118.
3
tert-Butyl phenyl((4-(methoxycarbonyl)benzoyl)carbamate (1i). Yield 71% (1.26 g). White solid.
1H NMR (500 MHz, CDCl
) δ 8.14 (d, J = 8.1 Hz, 2H), 7.78 (d, J = 8.1 Hz, 2H), 7.46 (t, J = 7.6 Hz,
3
13
2
H), 7.38 (t, J = 7.3 Hz, 1H), 7.28 (d, J = 7.8 Hz, 2H), 3.97 (s, 3H), 1.26 (s, 9H). C{1H} NMR (125
MHz, CDCl
3
) δ 171.8, 166.2, 152.9, 141.0, 138.6, 132.5, 129.5, 129.3, 128.1, 128.0, 127.8, 84.0, 52.4,
27.5.
1
tert-Butyl (furan-2-carbonyl)(phenyl)carbamate (1j). Yield 81% (1.17 g). White solid. H NMR
(
500 MHz, CDCl ) δ 7.57-7.54 (m, 1H), 7.43 (t, J = 7.6 Hz, 2H), 7.35 (t, J = 7.4 Hz, 1H), 7.28 (d, J =
3
13
7
.2 Hz, 2H), 7.04 (d, J = 3.5 Hz, 1H), 6.53 (dd, J = 3.5, 1.7 Hz, 1H), 1.42 (s, 9H). C{1H} NMR (125
MHz, CDCl ) δ 161.2, 152.8, 148.5, 145.1, 138.6, 129.2, 128.0, 127.9, 118.1, 112.3, 83.3, 27.7.
3
tert-Butyl phenyl(thiophene-2-carbonyl)carbamate (1k). New compound. Yield 85% (1.29 g).
1
White solid. Mp = 86-87 °C. H NMR (500 MHz, CDCl
3
) δ 7.56 (dd, J = 4.9, 1.0 Hz, 1H), 7.48 (dd, J
=
3.8, 1.0 Hz, 1H), 7.40 (t, J = 7.6 Hz, 2H), 7.33 (t, J = 7.4 Hz, 1H), 7.28 – 7.26 (m, 2H), 7.03 (dd, J =
1
3
4.9, 3.9 Hz, 1H), 1.41 (s, 9H). C{1H} NMR (125 MHz, CDCl
3
) δ 165.3, 153.4, 139.4, 139.4, 133.4,
+
1
3
33.0, 129.4, 128.1, 128.1, 127.6, 83.6, 28.0. HRMS (ESI-TOF) calcd for C16
26.0821 found 326.0838.
H17NO
3
SNa (M + Na)
1
9
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1
tert-Butyl (1-decanoyl)(phenyl)carbamate (1l). Yield 88% (1.53 g). White solid. H NMR (500
MHz, CDCl ) δ 7.41 (t, J = 7.2 Hz, 2H), 7.34 (t, J = 7.3 Hz, 1H), 7.09 (d, J = 7.7 Hz, 2H), 2.92 (t, J =
7.4 Hz, 2H), 1.70 (p, J = 7.3, 6.8 Hz, 2H), 1.40 (s, 9H), 1.29 (s, 12H), 0.90 (t, J = 6.4 Hz, 3H). C{1H}
NMR (125 MHz, CDCl ) δ 176.0, 152.8, 139.2, 128.9, 128.2, 127.7, 82.9, 38.0, 31.9, 29.5, 29.3, 29.2,
7.8, 25.0, 22.7, 14.1.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
1
3
3
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
tert-Butyl cinnamoyl(phenyl)carbamate (1m). New compound. Yield 72% (1.16 g). White solid.
1
Mp = 117-118 °C. H NMR (500 MHz, CDCl
3
) δ 7.76 (d, J = 15.6 Hz, 1H), 7.57 – 7.54 (m, 2H), 7.44
13
–
7.34 (m, 7H), 7.17 (d, J = 7.4 Hz, 2H), 1.43 (s, 9H). C{1H} NMR (125 MHz, CDCl
3
) δ 168.5,
1
53.2, 144.6, 139.4, 135.3, 130.4, 129.3, 129.1, 128.6, 128.6, 128.1, 121.0, 83.6, 28.2. HRMS (ESI-
+
TOF) calcd for C40
H
42
N O
2 6
Na (2M + Na) 669.2935 found 669.2946.
1
tert-Butyl benzoyl(methyl)carbamate (1n). Yield 85% (1.01 g). Colorless oil. H NMR (500 MHz,
CDCl ) δ 7.53 (d, J = 7.2 Hz, 2H), 7.48 (t, J = 7.4 Hz, 1H), 7.40 (t, J = 7.5 Hz, 2H), 3.33 (s, 3 H), 1.17
3
1
3
(
s, 9H). C{1H} NMR (125 MHz, CDCl
3
) δ 173.6, 153.5, 137.9, 130.9, 128.0, 127.4, 83.0, 32.6, 27.4.
1
tert-Butyl benzoyl(benzyl)carbamate (1o). Yield 91% (1.42 g). White solid. H NMR (500 MHz,
CDCl
3
) δ 7.54 (d, J = 7.0 Hz, 2H), 7.47 (dd, J = 10.9, 7.4 Hz, 3H), 7.41 (d, J = 7.7 Hz, 2H), 7.37 (s,
13
2
1
H), 7.30 (s, 1H), 5.02 (s, 2H), 1.15 (s, 9H). C{1H} NMR (125 MHz, CDCl
3
) δ 173.1, 153.5, 137.9,
37.7, 131.0, 128.5, 128.2, 128.1, 127.5, 127.4, 83.2, 48.9, 27.4.
tert-Butyl phenyl(3,4,5-trimethoxybenzoyl)carbamate (1p). New compound. Yield 74% (1.43 g).
1
White solid. Mp = 95-96 °C. H NMR (500 MHz, CDCl
3
) δ 7.43 – 7.39 (m, 2H), 7.34 – 7.30 (m, 1H),
13
7
.25 – 7.21 (m, 2H), 6.98 (s, 2H), 3.89 (s, 3H), 3.86 (s, 6H), 1.31 (s, 9H). C{1H} NMR (125 MHz,
CDCl
3
) δ 172.4, 153.8, 153.3, 141.8, 139.6, 131.8, 129.5, 127.9, 127.9, 106.3, 83.7, 61.3, 56.6, 27.9.
+
HRMS (ESI-TOF) calcd for C42
H
50
N
2
O
12Na (2M + Na) 797.3256 found 797.3281.
2
2
22
22
24
24
23
24
Characterization Data of Transamidation Products. Amides 3a, 3b, 3c, 3d, 3e, 3f, 3h,
i, 3j, 3k, 3l, 3m, 3n, 3o,11c 3p,11c 3q, 3r, 3s,11c 3t, 3u, 3v, 3w, 3x, 3y, 4 have
25
24
24
26
27
11c
28
11c
28
28
28
11c
29
28 30
3
2
0
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The Journal of Organic Chemistry
been previously reported. Spectroscopic data match those reported in the literature. Amide 3g is a new
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
compound.
Morpholino(phenyl)methanone (3a). According to the general procedure, the reaction of tert-butyl
benzoyl(phenyl)carbamate (59.5 mg, 0.20 mmol, 1.0 equiv) with morpholine (34.8 mg, 0.40 mmol, 2.0
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
equiv) in CH
3
CN (1.0 M) at room temperature for 15 h, afforded after work-up and chromatography the
1
title compound in 92% yield (35.2 mg). White solid. H NMR (500 MHz, CDCl
3
) δ 7.45 – 7.35 (m,
) δ 170.6, 135.6,
1
3
5H), 3.76 (m, 4H), 3.64 (m, 2H), 3.45 (m, 2H). C{1H} NMR (125 MHz, CDCl
30.1, 128.7, 127.3, 67.2, 48.4, 42.7.
3
1
Morpholino(p-tolyl)methanone (3b). According to the general procedure, the reaction of tert-butyl
4-methylbenzoyl)(phenyl)carbamate (62.3 mg, 0.20 mmol, 1.0 equiv) with morpholine (34.8 mg, 0.40
(
mmol, 2.0 equiv) in CH
3
CN (1.0 M) at room temperature for 15 h, afforded after work-up and
1
chromatography the title compound in 89% yield (36.5 mg). White solid. H NMR (500 MHz, CDCl
3
)
1
3
δ 7.31 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 7.9 Hz, 2H), 3.69 – 3.49 (m, 8H), 2.38 (s, 3H). C{1H} NMR
(125 MHz, CDCl ) δ 170.9, 140.4, 132.7, 129.4, 127.5, 67.2, 48.7, 42.9, 21.7.
3
(4-Methoxyphenyl)(morpholino)methanone (3c). According to the general procedure, the reaction
of tert-butyl (4-methoxybenzoyl)(phenyl)carbamate (65.5 mg, 0.20 mmol, 1.0 equiv) with morpholine
(34.8 mg, 0.40 mmol, 2.0 equiv) in CH
3
CN (1.0 M) at room temperature for 15 h, afforded after work-
1
up and chromatography the title compound in 90% yield (39.8 mg). White solid. H NMR (500 MHz,
13
CDCl
3
) δ 7.41 – 7.35 (m, 2H), 6.94 – 6.89 (m, 2H), 3.83 (s, 3H), 3.69 – 3.63 (m, 8H). C{1H} NMR
(
125 MHz, CDCl ) δ 170.7, 161.2, 129.5, 127.6, 114.1, 67.2, 55.6, 48.1, 44.1.
3
Morpholino(4-(trifluoromethyl)phenyl)methanone (3d). According to the general procedure, the
reaction of tert-butyl phenyl(4-(trifluoromethyl)benzoyl)carbamate (73.1 mg, 0.20 mmol) with
morpholine (34.8 mg, 0.40 mmol, 2.0 equiv) in CH
3
CN (1.0 M) at room temperature for 15 h, afforded
1
after work-up and chromatography the title compound in 88% yield (45.6 mg). White solid. H NMR
2
1
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(
500 MHz, CDCl
3
) δ 7.69 (d, J = 8.2 Hz, 2H), 7.52 (d, J = 8.2 Hz, 2H), 3.79 (m, 4H), 3.62 (m, 2H),
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
13
F
3
.40 (m, 2H). C{1H} NMR (125 MHz, CDCl
3
) δ 169.3, 139.2, 132.2 (q, J = 32.76 Hz), 127.8, 126.0
F
F
19
(q, J = 3.74 Hz), 124.0 (q, J = 272.91 Hz), 67.1, 48.4, 42.9. F NMR (471 MHz, CDCl
3
) δ -62.94.
Morpholino(4-nitrophenyl)methanone (3e). According to the general procedure, the reaction of tert-
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
butyl (4-nitro-phenyl)carbamate (68.5 mg, 0.20 mmol, 1.0 equiv) with morpholine (34.8 mg, 0.40
mmol, 2.0 equiv) in CH
3
CN (1.0 M) at room temperature for 15 h, afforded after work-up and
1
chromatography the title compound in 87% yield (41.1 mg). Yellow solid. H NMR (500 MHz, CDCl
3
)
13
δ 8.32 – 8.25 (m, 2H), 7.61 – 7.54 (m, 2H), 3.80 (m, 4H), 3.63 (m, 2H), 3.38 (m, 2H). C{1H} NMR
(125 MHz, CDCl ) δ 168.4, 148.8, 141.8, 128.5, 124.3, 67.1, 48.4, 42.9.
3
(4-Fluorophenyl)(morpholino)methanone (3f). According to the general procedure, the reaction of
tert-butyl (4-fluorobenzoyl)(phenyl)carbamate (63.1 mg, 0.20 mmol, 1.0 equiv) with morpholine (34.8
mg, 0.40 mmol, 2.0 equiv) in CH
3
CN (1.0 M) at room temperature for 15 h, afforded after work-up and
1
chromatography the title compound in 89% yield (37.6 mg). Colorless oil. H NMR (500 MHz, CDCl
3
)
13
δ 7.45 – 7.38 (m, 2H), 7.13 – 7.06 (m, 2H), 3.69 – 3.48 (m, 8H). C{1H} NMR (125 MHz, CDCl
3
) δ
F
F
F
F
1
6
69.8, 163.8 (d, J = 250.8 Hz), 131.6 (d, J = 3.5 Hz), 129.7 (d, J = 8.5 Hz), 116.0 (d, J = 21.9 Hz),
1
9
7.1, 48.6, 43.0. F NMR (471 MHz, CDCl ) δ -109.91.
3
(3,4-Difluorophenyl)(morpholino)methanone (3g). According to the general procedure, the reaction
of tert-butyl phenyl(3,4-difluorobenzoyl)carbamate (66.7 mg, 0.20 mmol, 1.0 equiv) with morpholine
(34.8 mg, 0.40 mmol, 2.0 equiv) in CH
3
CN (1.0 M) at room temperature for 15 h, afforded after work-
1
up and chromatography the title compound in 81% yield (36.8 mg). New compound. Colorless oil. H
NMR (500 MHz, CDCl ) δ 7.29 – 7.24 (m, 1H), 7.24 – 7.18 (m, 1H), 7.18 – 7.13 (m, 1H), 3.69 – 3.49
3
1
3
F
F
(m, 8H). C{1H} NMR (125 MHz, CDCl ) δ 168.4, 151.6 (dd, J = 253.0 Hz, J = 12.6 Hz), 150.5
3
F
F
F
F
F
(dd, J = 251.5 Hz, J = 12.9 Hz), 132.4 (t, J = 4.7 Hz), 124.1 (dd, J = 6.8 Hz, J = 4.0 Hz), 118.0 (d,
F
F
19
J = 17.7 Hz), 117.3 (d, J = 18.1 Hz), 67.1, 48.4, 43.1. F NMR (471 MHz, CDCl ) δ -134.56, -
3
+
136.00. HRMS (ESI-TOF) calcd for C11
H
11
F
2
NO
2
Na (M + Na) 250.0650 found 250.0634.
2
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The Journal of Organic Chemistry
(
4-Bromophenyl)(morpholino)methanone (3h). According to the general procedure, the reaction of
1
2
tert-butyl (4-bromobenzoyl)(phenyl)carbamate (75.2 mg, 0.20 mmol, 1.0 equiv) with morpholine (34.8
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
mg, 0.40 mmol, 2.0 equiv) in CH
3
CN (1.0 M) at room temperature for 15 h, afforded after work-up and
1
chromatography the title compound in 85% yield (45.9 mg). White solid. H NMR (500 MHz, CDCl
3
)
1
3
δ 7.55 (d, J = 8.1 Hz, 2H), 7.29 (d, J = 8.2 Hz, 2H), 3.74 (m, 6H), 3.43 (m, 2H). C{1H} NMR (125
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
MHz, CDCl ) δ 169.7, 134.4, 132.1, 129.2, 124.6, 67.1, 48.6, 43.0.
3
Methyl 4-(morpholine-4-carbonyl)benzoate (3i). According to the general procedure, the reaction
of tert-butyl benzoyl(phenyl)carbamate (71.1 mg, 0.20 mmol, 1.0 equiv) with morpholine (34.8 mg,
0
.40 mmol, 2.0 equiv) in CH
3
CN (1.0 M) at room temperature for 15 h, afforded after work-up and
1
chromatography the title compound in 85% yield (42.4 mg). Yellow solid. H NMR (500 MHz, CDCl
3
)
δ 8.09 (d, J = 8.2 Hz, 2H), 7.47 (d, J = 8.2 Hz, 2H), 3.93 (s, 3H), 3.78 (m, 4H), 3.62 (m, 2H), 3.39 (m,
1
3
2
4
H). C{1H} NMR (125 MHz, CDCl ) δ 169.7, 166.6, 139.9, 131.7, 130.2, 127.4, 67.2, 52.7, 48.4,
3
2.9.
Furan-2-yl(morpholino)methanone (3j). According to the general procedure, the reaction of tert-
Butyl (furan-2-carbonyl)(phenyl)carbamate (57.5 mg, 0.20 mmol, 1.0 equiv) with morpholine (34.8 mg,
0
.40 mmol, 2.0 equiv) in CH
3
CN (1.0 M) at room temperature for 15 h, afforded after work-up and
1
chromatography the title compound in 85% yield (30.8 mg). White solid. H NMR (500 MHz, CDCl
3
)
δ 7.48 (dd, J = 1.6, 0.7 Hz, 1H), 7.03 (dd, J = 3.5, 0.6 Hz, 1H), 6.48 (dd, J = 3.5, 1.8 Hz, 1H), 3.82 (brs,
13
4
6
H), 3.76 – 3.72 (m, 4H). C{1H} NMR (125 MHz, CDCl
3
) δ 159.5, 148.162 144.1, 117.1, 111.7,
7.3.
Morpholino(thiophen-2-yl)methanone (3k). According to the general procedure, the reaction of
tert-butyl benzoyl(phenyl)carbamate (60.6 mg, 0.20 mmol, 1.0 equiv) with morpholine (34.8 mg, 0.40
mmol, 2.0 equiv) in CH
3
CN (1.0 M) at room temperature for 15 h, afforded after work-up and
1
chromatography the title compound in 80% yield (31.5 mg). Yellow solid. H NMR (500 MHz, CDCl
3
)
δ 7.46 (dd, J = 5.0, 0.9 Hz, 1H), 7.29 (dd, J = 3.6, 0.9 Hz, 1H), 7.05 (dd, J = 5.0, 3.7 Hz, 1H), 3.78 –
2
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1
3
3
1
.75 (m, 4H), 3.74 – 3.71 (m, 4H). C{1H} NMR (125 MHz, CDCl
3
) δ 163.9, 136.9, 129.2, 129.1,
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
27.0, 67.1, 45.9.
1
-Morpholinodecan-1-one (3l). According to the general procedure, the reaction of tert-butyl (1-
decanoyl)(phenyl)carbamate (69.5 mg, 0.20 mmol, 1.0 equiv) with morpholine (34.8 mg, 0.40 mmol,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
.0 equiv) in CH
3
CN (1.0 M) at room temperature for 15 h, afforded after work-up and chromatography
1
the title compound in 80% yield (24.1 mg). Colorless oil. H NMR (500 MHz, CDCl
3
) δ 3.69 – 3.63
(m, 4H), 3.60 – 3.62 (m, 2H), 3.49 – 3.42 (m, 2H), 2.33 – 2.26 (m, 2H), 1.65 – 1.58 (m, 2H), 1.34 – 1.23
13
(
m, 12H), 0.87 (t, J = 6.7 Hz, 3H). C{1H} NMR (125 MHz, CDCl
3
) δ 172.2, 67.3, 67.1, 46.4, 42.2,
3
3.5, 32.2, 29.8, 29.8, 29.8, 29.6, 25.6, 23.0, 14.4.
(E)-1-Morpholino-3-phenylprop-2-en-1-one (3m). According to the general procedure, the reaction
of tert-butyl cinnamoyl(phenyl)carbamate (64.7 mg, 0.20 mmol, 1.0 equiv) with morpholine (20.9 mg,
0
.24 mmol, 1.2 equiv) in CH
3
CN (1.0 M) at 60 °C for 15 h, afforded after work-up and chromatography
1
the title compound (3l) in 66% yield (28.7 mg). White solid. H NMR (500 MHz, CDCl
3
) δ 7.70 (d, J =
15.4 Hz, 1H), 7.54 – 7.49 (m, 2H), 7.40 – 7.33 (m, 3H), 6.84 (d, J = 15.4 Hz, 1H), 3.73 (m, 6H), 3.67
13
(
m, 2H). C{1H} NMR (125 MHz, CDCl
3
) δ 165.9, 143.5, 135.5, 130.1, 129.2, 128.1, 116.9, 67.2,
4
6.6, 42.8.
N-Butylbenzamide (3n). According to the general procedure, the reaction of tert-butyl
benzoyl(phenyl)carbamate (59.5 mg, 0.20 mmol, 1.0 equiv) with n-butylamine (29.3 mg, 0.40 mmol,
2
.0 equiv) in CH
3
CN (1.0 M) at room temperature for 15 h, afforded after work-up and chromatography
1
the title compound in 92% yield (32.6 mg). Colorless oil. H NMR (500 MHz, CDCl
3
) δ 7.78 – 7.73
(m, 2H), 7.48 (t, J = 7.3 Hz, 1H), 7.42 (t, J = 7.7 Hz, 2H), 6.17 (s, 1H), 3.45 (q, J = 6.6 Hz, 2H), 1.63 –
1
3
1
1
.56 (m, 2H), 1.45 – 1.37 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H). C{1H} NMR (125 MHz, CDCl ) δ 167.8,
3
35.2, 131.6, 128.9, 127.2, 40.1, 32.1, 20.5, 14.1.
2
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N-Dodecylbenzamide (3o). According to the general procedure, the reaction of tert-butyl
1
2
benzoyl(phenyl)carbamate (59.5 mg, 0.20 mmol, 1.0 equiv) with n-decylamine (74.1 mg, 0.40 mmol,
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2.0 equiv) in CH
3
CN (1.0 M) at room temperature for 15 h, afforded after work-up and chromatography
1
the title compound in 91% yield (52.7 mg). White solid. H NMR (500 MHz, CDCl
3
) δ 7.76 – 7.74 (m,
2
2
1
H), 7.53 – 7.46 (m, 1H), 7.46 – 7.39 (m, 2H), 6.10 (s, 1H), 3.45 (q, J = 6.7 Hz, 2H), 1.65 – 1.58 (m,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
H), 1.41 – 1.24 (m, 18H), 0.88 (t, J = 7.0 Hz, 3H). C{1H} NMR (125 MHz, CDCl ) δ 167.8, 135.3,
3
31.6, 128.9, 127.2, 40.5, 32.3, 30.1, 30.0, 30.0, 29.9, 29.9, 29.7, 27.4, 23.0, 14.5.
N-Benzylbenzamide (3p). According to the general procedure, the reaction of tert-butyl
benzoyl(phenyl)carbamate (59.5 mg, 0.20 mmol, 1.0 equiv) with benzylamine (42.9 mg, 0.40 mmol, 2.0
equiv) in CH
3
CN (1.0 M) at room temperature for 15 h, afforded after work-up and chromatography the
1
title compound in 91% yield (38.4 mg). White solid. H NMR (500 MHz, CDCl
3
) δ 7.80 – 7.78 (m,
2
H), 7.53 – 7.47 (m, 1H), 7.46 – 7.40 (m, 2H), 7.39 – 7.32 (m, 4H), 7.30 (m, 1H), 6.43 (s, 1H), 4.65 (d,
13
J = 5.7 Hz, 2H). C{1H} NMR (125 MHz, CDCl ) δ 167.7, 138.5, 134.8, 131.9, 129.2, 129.0, 128.3,
3
128.0, 127.3, 44.5.
N-Allylbenzamide (3q). According to the general procedure, the reaction of tert-butyl
benzoyl(phenyl)carbamate (59.5 mg, 0.20 mmol, 1.0 equiv) with allylamine (22.8 mg, 0.40 mmol, 2.0
equiv) in CH
3
CN (1.0 M) at room temperature for 15 h, afforded after work-up and chromatography the
1
title compound in 92% yield (29.7 mg). Colorless oil. H NMR (500 MHz, CDCl
3
) δ 7.79 – 7.77 (dd, J
=
5.2, 3.3 Hz, 2H), 7.53 – 7.48 (m, 1H), 7.46 – 7.41 (m, 2H), 6.19 (s, 1H), 5.99 – 5.90 (m, 1H), 5.30 –
13
5
.25 (m, 1H), 5.21 – 5.17 (m, 1H), 4.10 (tt, J = 5.7, 1.5 Hz, 2H). C{1H} NMR (125 MHz, CDCl
3
) δ
167.6, 134.9, 134.5, 131.9, 129.0, 127.2, 117.1, 42.8.
N,N-Diethylbenzamide (3r). According to the general procedure, the reaction of tert-butyl
benzoyl(phenyl)carbamate (59.5 mg, 0.20 mmol, 1.0 equiv) with diethylamine (29.3 mg, 0.40 mmol, 2.0
equiv) in CH
3
CN (1.0 M) at room temperature for 15 h, afforded after work-up and chromatography the
1
title compound in 78% yield (27.6 mg). White solid. H NMR (500 MHz, CDCl
3
) δ 7.41 – 7.33 (m,
2
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13
5
1
H), 3.55 (s, 2H), 3.25 (s, 2H), 1.25 (s, 3H), 1.11 (s, 3H). C{1H} NMR (125 MHz, CDCl ) δ 171.5,
3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
37.5, 129.3, 128.6, 126.5, 43.5, 39.5, 14.4, 13.1.
N-Benzyl-N-methylbenzamide (3s). According to the general procedure, the reaction of tert-butyl
benzoyl(phenyl)carbamate (59.5 mg, 0.20 mmol, 1.0 equiv) with N-benzylmethylamine (48.5 mg, 0.40
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
mmol, 2.0 equiv) in CH
3
CN (1.0 M) at room temperature for 15 h, afforded after work-up and
1
chromatography the title compound in 80% yield (36.0 mg). Colorless oil. H NMR (500 MHz, CDCl
3
)
δ 7.47 – 7.45 (m, 2H), 7.40 (brs, 2H), 7.36 (brs, 4H), 7.32 – 7.28 (m, 1H), 7.18 (brs, 1H), 4.77 (s, 1H),
13
4
1
.52 (s, 1H), 3.03 (s, 1H), 2.86 (s, 2H). C{1H} NMR (125 MHz, CDCl
3
) δ 173.6, 171.9, 137.6, 136.9,
36.5, 129.9, 129.1, 129.0, 128.7, 128.5, 127.8, 127.3, 127.2, 55.5, 51.2, 37.3, 33.5.
N,N-Diallylbenzamide (3t). According to the general procedure, the reaction of tert-butyl
benzoyl(phenyl)carbamate (59.5 mg, 0.20 mmol, 1.0 equiv) with diallylamine (38.9 mg, 0.40 mmol, 2.0
equiv) in CH
3
CN (1.0 M) at room temperature for 15 h, afforded after work-up and chromatography the
1
title compound in 81% yield (32.6 mg). Colorless oil. H NMR (500 MHz, CDCl
3
) δ 7.44 – 7.42 (m,
2H), 7.41 – 7.36 (m, 3H), 5.88 (s, 1H), 5.73 (s, 1H), 5.24 (q, J = 1.5 Hz, 1H), 5.22 (q, J = 1.25 Hz, 1H),
13
5
1
.21 (s, 1H), 5.18 (s, 1H), 4.14 (s, 2H), 3.83 (s, 2H). C{1H} NMR (125 MHz, CDCl
3
) δ 172.0, 136.6,
33.5, 133.1, 129.9, 128.6, 126.9, 117.9, 51.0, 47.2.
Phenyl(pyrrolidin-1-yl)methanone (3u). According to the general procedure, the reaction of tert-
butyl benzoyl(phenyl)carbamate (59.5 mg, 0.20 mmol, 1.0 equiv) with pyrrolidine (28.5 mg, 0.40 mmol,
2
.0 equiv) in CH
3
CN (1.0 M) at room temperature for 15 h, afforded after work-up and chromatography
1
the title compound in 92% yield (32.2 mg). Colorless oil. H NMR (500 MHz, CDCl
3
) δ 7.52 – 7.49
(m, 2H), 7.41 – 7.36 (m, 3H), 3.65 (t, J = 7.0 Hz, 2H), 3.42 (t, J = 6.6 Hz, 2H), 1.99 – 1.93 (m, 2H),
13
1
2
.90 – 1.84 (m, 2H). C{1H} NMR (125 MHz, CDCl ) δ 170.1, 137.6, 130.1, 128.6, 127.4, 49.9, 46.5,
3
6.7, 24.8.
2
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Phenyl(piperidin-1-yl)methanone (3v). According to the general procedure, the reaction of tert-
1
2
butyl benzoyl(phenyl)carbamate (59.5 mg, 0.20 mmol, 1.0 equiv) with piperidine (34.1 mg, 0.40 mmol,
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2.0 equiv) in CH
3
CN (1.0 M) at room temperature for 15 h, afforded after work-up and chromatography
1
the title compound in 88% yield (33.3 mg). Colorless oil. H NMR (500 MHz, CDCl
3
) δ 7.39 (m, 5H),
) δ 170.5, 136.7,
1
3
3
1
.71 (s, 2H), 3.34 (s, 2H), 1.68 (s, 4H), 1.51 (s, 2H). C{1H} NMR (125 MHz, CDCl
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
29.5, 128.6, 127.0, 48.9, 43.3, 26.7, 25.8, 24.8.
N-Isopropylbenzamide (3w). According to the general procedure, the reaction of tert-butyl
benzoyl(phenyl)carbamate (59.5 mg, 0.20 mmol, 1.0 equiv) with iso-propylamine (23.6 mg, 0.40 mmol,
2
.0 equiv) in CH
3
CN (1.0 M) at room temperature for 15 h, afforded after work-up and chromatography
1
the title compound in 87% yield (28.4 mg). White solid. H NMR (500 MHz, CDCl
3
) δ 7.75 – 7.73 (m,
2
6
H), 7.50 – 7.44 (m, 1H), 7.43 – 7.38 (m, 2H), 6.00 (s, 1H), 4.33 – 4.23 (m, 1H), 1.26 (d, J = 6.6 Hz,
1
3
H). C{1H} NMR (125 MHz, CDCl ) δ 167.0, 135.3, 131.6, 128.8, 127.1, 42.2, 23.2.
3
N-Cyclohexylbenzamide (3x). According to the general procedure, the reaction of tert-butyl
benzoyl(phenyl)carbamate (59.5 mg, 0.20 mmol, 1.0 equiv) with cyclohexylamine (39.7 mg, 0.40
mmol, 2.0 equiv) in CH
3
CN (1.0 M) at room temperature for 15 h, afforded after work-up and
1
chromatography the title compound in 90% yield (36.6 mg). White solid. H NMR (500 MHz, CDCl
3
)
δ 7.77 – 7.72 (m, 2H), 7.50 – 7.45 (m, 1H), 7.44 – 7.39 (m, 2H), 6.00 (s, 1H), 4.01 – 3.94 (m, 1H), 2.06
–
1.99 (m, 2H), 1.79 – 1.71 (m, 2H), 1.68 – 1.62 (m, 1H), 1.47 – 1.38 (m, 2H), 1.28 – 1.15 (m, 3H).
13C{1H} NMR (125 MHz, CDCl
) δ 166.9, 135.4, 131.5, 128.8, 127.2, 49.0, 33.5, 25.9, 25.2.
3
N-(tert-Butyl)benzamide (3y). According to the general procedure, the reaction of tert-butyl
benzoyl(phenyl)carbamate (59.5 mg, 0.20 mmol, 1.0 equiv) with tert-butylamine (29.3 mg, 0.40 mmol,
2
.0 equiv) in CH
3
CN (1.0 M) at 120 °C for 15 h, afforded after work-up and chromatography the title
1
compound in 81% yield (28.7 mg). White solid. H NMR (500 MHz, CDCl
3
) δ 7.74 – 7.69 (m, 2H),
1
3
7
.49 – 7.44 (m, 1H), 7.43 – 7.39 (m, 2H), 5.93 (s, 1H), 1.47 (s, 9H). C{1H} NMR (125 MHz, CDCl
3
)
δ 167.2, 136.3, 131.4, 128.8, 127.0, 51.9, 29.2.
2
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N-Butylbenzamide (3n), Transamidation of Amide (1n) with n-Butylamine. According to the
general procedure, the reaction of tert-butyl benzoyl(methyl)carbamate (47.0 mg, 0.20 mmol, 1.0 equiv)
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
with n-butylamine (29.3 mg, 0.40 mmol, 2.0 equiv) in CH CN (1.0 M) at room temperature for 15 h,
3
afforded after work-up and chromatography the title compound in 89% yield (31.5 mg). Colorless oil.
1H NMR (500 MHz, CDCl
3
) δ 7.78 – 7.73 (m, 2H), 7.48 (t, J = 7.3 Hz, 1H), 7.42 (t, J = 7.7 Hz, 2H),
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
6
.17 (s, 1H), 3.45 (q, J = 6.6 Hz, 2H), 1.63 – 1.56 (m, 2H), 1.45 – 1.37 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H).
13C{1H} NMR (125 MHz, CDCl
) δ 167.8, 135.2, 131.6, 128.9, 127.2, 40.1, 32.1, 20.5, 14.1.
3
Morpholino(phenyl)methanone (3a), Transamidation of Amide (1n) with Morpholine. According
to the general procedure, the reaction of tert-butyl benzoyl(methyl)carbamate (47.0 mg, 0.20 mmol, 1.0
equiv) with morpholine (34.8 mg, 0.40 mmol, 2.0 equiv) in CH
3
CN (1.0 M) at 120 °C for 15 h, afforded
1
after work-up and chromatography the title compound in 59% yield (22.6 mg). White solid. H NMR
1
3
(500 MHz, CDCl
3
) δ 7.45 – 7.35 (m, 5H), 3.76 (s, 4H), 3.64 (s, 2H), 3.45 (s, 2H). C{1H} NMR (125
MHz, CDCl ) δ 170.6, 135.6, 130.1, 128.7, 127.3, 67.1, 48.4, 42.7.
3
N-Butylbenzamide (3n), Transamidation of Amide (1o) with n-Butylamine. According to the
general procedure, the reaction of tert-butyl benzoyl(benzyl)carbamate (62.3 mg, 0.20 mmol, 1.0 equiv)
with n-butylamine (29.3 mg, 0.40 mmol, 2.0 equiv) in CH CN (1.0 M) at room temperature for 15 h,
3
afforded after work-up and chromatography the title compound in 89% yield (31.5 mg). Colorless oil.
1H NMR (500 MHz, CDCl
3
) δ 7.78 – 7.73 (m, 2H), 7.48 (t, J = 7.3 Hz, 1H), 7.42 (t, J = 7.7 Hz, 2H),
6
.17 (s, 1H), 3.45 (q, J = 6.6 Hz, 2H), 1.63 – 1.56 (m, 2H), 1.45 – 1.37 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H).
13C{1H} NMR (125 MHz, CDCl
) δ 167.8, 135.2, 131.6, 128.9, 127.2, 40.1, 32.1, 20.5, 14.1.
3
Morpholino(phenyl)methanone (3a), Transamidation of Amide (1o) with Morpholine. According
to the general procedure, the reaction of tert-butyl benzoyl(benzyl)carbamate (47.0 mg, 0.20 mmol, 1.0
equiv) with morpholine (34.8 mg, 0.40 mmol, 2.0 equiv) in CH
3
CN (1.0 M) at 120 °C for 15 h, afforded
1
after work-up and chromatography the title compound in 60% yield (22.9 mg). White solid. H NMR
2
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1
3
(500 MHz, CDCl
3
) δ 7.45 – 7.35 (m, 5H), 3.76 (s, 4H), 3.64 (s, 2H), 3.45 (s, 2H). C{1H} NMR (125
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
MHz, CDCl
3
) δ 170.6, 135.6, 130.1, 128.7, 127.3, 67.1, 48.4, 42.7.
Synthesis of Tigan (4). According to the general procedure, an oven-dried reaction flask containing a
stir bar was charged with amide (1p) (77.5 mg, 0.20 mmol, 1.0 equiv), amine (2n) (77.7 mg, 4.0 mmol,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
.0 equiv) and CH CN (1.0 M). The reaction mixture was stirred at room temperature for 15 hours.
3
After the indicated time, the solvent was removed under reduced pressure and the crude product was
1
purified directly by chromatography on silica gel to afford Tigan (4) (73.0 mg, 94 %). White solid. H
NMR (500 MHz, CDCl
3
) δ 7.29 – 7.26 (m, 2H), 7.00 (s, 2H), 6.93 – 6.88 (m, 2H), 6.29 (s, 1H), 4.56
(d, J = 5.6 Hz, 2H), 4.05 (t, J = 5.7 Hz, 2H), 3.88 (s, 6H), 3.87 (s, 3H), 2.72 (t, J = 5.7 Hz, 2H), 2.33 (s,
1
3
6H). C{1H} NMR (125 MHz, CDCl
3
) δ 167.3, 158.7, 153.5, 141.2, 130.7, 130.2, 129.6, 115.1, 104.7,
6
6.4, 61.2, 58.6, 56.6, 46.2, 44.0. Spectroscopic data matched those previously reported.30
Selectivity Studies – Amides. According to the general procedure, an oven-dried reaction flask
equipped with a stir was charged with two amide substrates (each 0.20 mmol, 1.0 equiv), CH CN (1.0
3
M) and amine (0.15 mmol, 0.75 equiv), and the reaction mixture was stirred at room temperature for 15
h. After the indicated time, the reaction mixture was diluted with EtOAc (15 mL), washed with HCl
(aq., 1.0 N, 10 mL), the aqueous layer was extracted with EtOAc (2 × 15 mL), the organic layers were
1
combined, dried, filtered, and concentrated. A sample was analyzed by H NMR (CDCl
3
, 500 MHz) and
GC-MS to obtain conversion, yield and selectivity using internal standard and comparison with
authentic samples. The observed selectivity is consistent with electrophilicity of the amide bond.
Selectivity Studies – Amines. According to the general procedure, an oven-dried reaction flask
equipped with a stir was charged with an amide substrate (0.10 mmol, 1.0 equiv), CH CN (1.0 M) and
3
two amine substrates (each 0.30 mmol, 3.0 equiv), and the reaction mixture was stirred at room
temperature for 15 h. After the indicated time, the reaction mixture was diluted with EtOAc (15 mL),
washed with HCl (aq., 1.0 N, 10 mL), the aqueous layer was extracted with EtOAc (2 × 15 mL), the
1
organic layers were combined, dried, filtered, and concentrated. A sample was analyzed by H NMR
2
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