Study on the propylphosphonic anhydride (T3P) mediated Ugi-type three-component reaction. Efficient synthesis of an α-amino amide library

Article abstract of DOI:10.1016/j.tet.2016.11.059

In the present work, a mild and simple synthesis of α-amino amides has been developed via the one-pot three-component ABC type Ugi reaction of a wide variety of aromatic aldehydes and primary aromatic amines, and two different aliphatic isocyanides. The reactions took place rapidly at room temperature in the presence of 1-propanephosphonic acid cyclic anhydride (T3P), rendering possible the highly efficient preparation of an α-amino amide library in medium to excellent yields. This study represents the first case in which T3Phas been used in the Ugi reaction.

Full text of DOI:10.1016/j.tet.2016.11.059

Accepted Manuscript
®
Study on the propylphosphonic anhydride (T3P ) mediated Ugi-type three-
component reaction. Efficient synthesis of an α-amino amide library
Mátyás Milen, András Dancsó, Tamás Földesi, Balázs Volk
PII:
S0040-4020(16)31224-8
10.1016/j.tet.2016.11.059
TET 28273
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 23 September 2016
Revised Date: 7 November 2016
Accepted Date: 21 November 2016
Please cite this article as: Milen M, Dancsó A, Földesi T, Volk B, Study on the propylphosphonic
®
anhydride (T3P ) mediated Ugi-type three-component reaction. Efficient synthesis of an α-amino amide
library, Tetrahedron (2016), doi: 10.1016/j.tet.2016.11.059.
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ACCEPTED MANUSCRIPT
Graphical abstract
Study on the propylphosphonic anhydride (T3P®) mediated Ugi-type three-
component reaction. Efficient synthesis of an -amino amide library
α
Mátyás Milen,* András Dancsó, Tamás Földesi, Balázs Volk
Egis Pharmaceuticals Plc., Directorate of Drug Substance Development, P. O. Box 100, H-1475
Budapest, Hungary
*To whom correspondence should be addressed. Phone: +36 1 8035874, e-mail:
milen.matyas@egis.hu
Abstract
In the present work, a mild and simple synthesis of α-amino amides has been developed via the
one-pot three-component ABC type Ugi reaction of a wide variety of aromatic aldehydes and
primary aromatic amines, and two different aliphatic isocyanides. The reactions took place
rapidly at room temperature in the presence of 1-propanephosphonic acid cyclic anhydride
(T3P®), rendering possible the highly efficient preparation of an α-amino amide library in
medium to excellent yields. This study represents the first case in which T3P® has been used in
the Ugi reaction.
Key words
Multicomponent reaction, Three-component Ugi reaction, α-Amino amides, T3P®, Mechanism

ACCEPTED MANUSCRIPT
INTRODUCTION
Multicomponent reactions (MCRs) play an important role in organic and medicinal chemistry as
a tool to generate small-molecule libraries.1 One of the most important MCRs is the Ugi four-
component reaction (Ugi-4CR) involving a carbonyl compound (1), an amine (2), an isocyanide
(3), and a carboxylic acid (4) to form an α-aminoacyl amides (5) and water as the only by-product
(Scheme 1).2–3 Hitherto, several modifications of the classical Ugi reaction have been discovered
and applied in the synthesis of amino acids, peptides, heterocycles, drug substances, natural
products and polymers.4–10
Scheme 1. Ugi four-component reaction
Moreover, various three-component Ugi reactions (Ugi-3CR) have been described in the
literature.11–14 The catalytic Ugi-3CR (ABC type, which means that one equivalent of each
reactant is used) of an aldehyde (1), a primary amine (2), and an isocyanide (3) resulting in α-
aminoamides 6 was first published by List and Pan in 2008 (Scheme 2).15 The condensation of
benzaldehyde, p-anisidine, and tert-butyl isocyanide was investigated in detail. It was found that
the reactions (toluene, 80 °C, 24 h) did not take place in the presence of p-toluenesulfonic acid
(pTsOH), diphenylphosphine oxide [Ph2P(O)H] or without catalysts. When using other acids,
such as phenylboronic acid [PhB(OH)2], diphenyl phosphate [(PhO)2P(O)(OH)], scandium
triflate [Sc(OTf)3], phenylphosphonic acid [PhP(O)(OH)2], and diphenylphosphinic acid
[Ph2P(O)(OH)], the appropriate α-amino amide (6, R1 = Ph; R2 = 4-MeO-C6H4; R3 = t-Bu) was
obtained only in poor yields (8–35%). However, an excellent result was achieved when applying
phenylphosphinic acid [PhP(O)(OH)H] as the catalyst. In this case, the corresponding α-amino
amide was prepared in 91% yield. This reaction was extended to various amines, aldehydes, and
isocyanides. The products were usually obtained in good yields (Method A, Scheme 2).
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Scheme 2. Catalytic three-component ABC type Ugi reaction
Shaabani et al. studied Lewis acid-catalyzed Ugi-3CR of aldehydes, 2-aminophenol derivatives,
and cyclohexyl isocyanide.16 According to their observation, the reaction proceeded smoothly in
the presence of ZnCl2 in methanol at room temperature. The desired products (6, R1 = Ph,
substituted phenyl, Bu; R2 = 2-HO-C6H4, 2-HO-4-Me-C6H3, 3-HO-pyrid-2-yl; R3 = c-Hex) were
obtained in good yields. However, the scope of the reaction was not studied extensively, only
seven representatives were synthesized (Method B, Scheme 2). The same research group applied
successfully cellulose sulphuric acid (CSA), a biodegradable biopolymer catalyst inter alia in the
synthesis of α-amino amides (6, R1 = Ph, substituted phenyl; R2 = Ph, Bn, allyl; R3 = c-Hex, t-Bu,
p-TsSO2CH2) via Ugi-3CR.17 Compounds 6 were prepared in good yields under mild conditions
in ethanol but this protocol required a prolonged (48 h) reaction time (Method C, Scheme 2).
In 2013, Kumar and his group described a green synthetic approach for the preparation of 2-
arylamino-2-phenylacetamide derivatives (6, R1 = phenyl, substituted phenyl; R2 = phenyl,
substituted phenyl; R3 = cyclohexyl or tert-butyl) using the reagents in aqueous medium. This
reaction was catalyzed by boric acid [B(OH)3] and the desired products were obtained in good to
excellent yields (Method D, Scheme 2).18 In the same year, Li and co-workers reported an Ugi-
3CR mediated by p-toluenesulfinic acid (pTSIA, Method E, Scheme 2).19 In this case α-amino
amidines (7, see Scheme 3) were also produced beside α-amino amides (6, R1 = Ph, substituted
phenyl, i-Bu, benzofuran-2-yl; R2 = substituted phenyl; R3 = alkyl, substituted phenyl).
Furthermore, when amines were used in excess (more than 1.5 equiv.), compounds 7 were
afforded as the main products. Synthesis of α-amino amidines (7) via AB2C type (B2 means that
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two equivalents of amine were used in this case) Ugi-3CR is known in the literature and it can
also be catalysed by ZnO-nanoparticles20 or molecular iodine21 (Scheme 3). It is also noteworthy
to mention that neutral hydrolysis of compounds 7 in the presence of I2 and sodium dodecyl
sulfate (SDS) led to α-amino amides (6, R1 = Ph, substituted phenyl, pyridine-4-yl; R2 = Ph,
substituted phenyl; R3 = t-Bu, c-Hex, p-Ts-CH2).20
Scheme 3. Synthesis of α-amino amidines (7) and α-amino amides (6) via catalytic three-
component AB2C type Ugi reaction
Recently, propylphosphonic anhydride (T3P®) has attracted tremendous attention in synthetic
organic chemistry. The T3P® reagent has several advantages including easy storability, low
toxicity, broad functional group tolerance and easy work-up procedures due the formation of
water-soluble by-products. A number of applications have been described using this reagent, for
example in organic functional group transformations, rearrangements, multicomponent reactions,
carbon-carbon bond formations, moreover in the synthesis of various heterocycles and natural
products.22–31
Herein, we would like to report the synthesis of α-amino amides (6) via T3P®-assisted Ugi-3CR
of aromatic aldehydes (1), primary aromatic amines (2), and aliphatic isocyanides (3) providing
the desired compounds (6) with good yields. To the best of our knowledge, this is the first case
that T3P® is used in an Ugi reaction.
RESULTS AND DISCUSSION
To optimize the T3P®-mediated Ugi-3CR, we extensively tested experimental parameters.
Initially, benzaldehyde (1a), 4-fluoroaniline (2a), and tert-butyl isocyanide (3a) (1 equiv. of
each) were chosen as starting materials (Table 1) and the reaction was investigated with various
amounts of T3P® reagent. When using 1.0 equiv. of T3P® in EtOAc at room temperature, the
desired α-amino amide 6a was obtained in 58% yield (Table 1, entry 1). When the amount of
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T3P® was increased to 1.5 or reduced to 0.2 equiv., compound 6a was afforded in similar yields
(60−61%) after 24 h (entries 2–4). A further decrease of T3P® amount to 0.02 equiv. proved to be
disadvantageous (entry 5). It is worth mentioning that under the same reaction conditions without
T3P®, no formation of expected product 6a occurred (entry 6). This result confirms previous
observations that Ugi-3CR does not take place in the absence of catalyst.15 Another investigation
was conducted aiming at the reaction time and temperature screen. It was found that the reaction
time could be decreased to 30 min at room temperature and the optimal amount of T3P® was 0.5
equiv. (entries 7–9). Higher temperature both in EtOAc and DMF solvents has not made a
positive effect on the reaction (entries 10, 11). A crude reaction mixture (entry 8) was analysed
by GC-MS/LC-MS, and the appropriate Schiff base (8–10%), α-amino amidine (3–4%) and other
unidentified by-products could be detected beside the main product 6a. Although the presence of
the Schiff base intermediate might indicate an incomplete conversion, a longer reaction time
(entry 3) or an increased amount of isocyanide 3a did not lead to higher yields of 6a.
Table 1. Screening of reaction conditions for the construction of α-amino amides
Entry
T3P® (equiv.) Temperature Reaction time (h) Yielda (%)
1
2
1.0
1.5
0.5
0.2
0.02
-
r. t.
r. t.
24
24
58
61
61
60
19
0
3
r. t.
24
4
r. t.
24
5
r. t.
24
6
r. t.
24
7
1.0
0.5
0.2
0.5
r. t.
0.5
0.5
0.5
0.5
58
58
24
46
8
r. t.
9
r. t.
10
reflux
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11b
0.5
80 °C
0.5
43
a Yield of the isolated product.
b The reaction was carried out in DMF and a DMF solution of T3P® reagent was used.
After establishing optimal reaction conditions, we surveyed the scope and limitations of the
T3P®-assisted Ugi-3CR (Scheme 4). Initially, the reaction of benzaldehyde (1a) with various
primary aromatic amines (2a–l) and tert-butyl isocyanide (3a) was examined (Table 2, entries 1–
12). The products from amines were usually obtained in good yields. However, when 2-
(methylthio)aniline (2c) and 2,4-dimethylaniline (2j) were used as the starting materials, the
appropriate α-amino amides (6c, j) were isolated only in 33 and 46% yields, respectively (entries
3, 10). Heteroaromatic 5-aminoquinoline (2l) can be employed in this synthesis with poor yield
(entry 12). Next, the reaction was investigated with a variety of aromatic aldehydes (1b–k),
aniline (2b), and tert-butyl isocyanide (3a) (entries 13–22). Both substituted benzaldehydes (1b–
f) and other aromatic ones, such as 2-naphthaldehyde (1g) and 9H-fluorene-2-carbaldehyde (1h)
were applied successfully affording the products in over 65% yield. The reaction also works with
heteroaromatic carbaldehydes (1i–k), the corresponding α-amino amides (6t–w) were obtained in
53–85% yields. Finally, the reaction was extended using 1-pentyl isocyanide (3b) instead of tert-
butyl isocyanide (3a) and four representatives (6y–ab) were prepared in variable yields (entries
25–28). Under these reaction conditions, use of non-aromatic amines, such as cyclopropylamine
and benzylamine (with benzaldehyde and tert-butyl isocyanide) or that of an aliphatic aldehyde,
butyraldehyde (with aniline and tert-butyl isocyanide) did not provide the desired products.
0.5 equiv. T3P®
O
C
H
N
R1 CHO
R3
+
R2 NH2
R3 NC
+
N
H
C
R2
EtOAc, r.t.
30 min
1a-k
R1
2a-l
3a,b
H
6a-ab
Scheme 4. T3P®-promoted three-component ABC type Ugi reaction
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Table 2. Yields of the reactions resulting in α-amino amides 6a−ab
Yield
(%)
Entry
R1
R2
R3
Product
1
2
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
4-FC6H4 (2a)
Ph (2b)
t-Bu (3a)
t-Bu (3a)
t-Bu (3a)
t-Bu (3a)
t-Bu (3a)
t-Bu (3a)
t-Bu (3a)
t-Bu (3a)
t-Bu (3a)
t-Bu (3a)
t-Bu (3a)
58
77
33
70
63
57
56
90
79
46
63
6a
6b
6c
6d
6e
6f
3
2-MeSC6H4 (2c)
3-ClC6H4 (2d)
3-F3CC6H4 (2e)
3-PhOC6H4 (2f)
4-F3CC6H4 (2g)
4-NCC6H4 (2h)
4-PhC6H4 (2i)
2,4-Me2C6H3 (2j)
2,3-dihydro-1H-
inden-5-yl (2k)
quinolin-5-yl (2l)
Ph (2b)
4
5
6
7
6g
6h
6i
8
9
10
11
6j
6k
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
Ph (1a)
3-FC6H4 (1b)
3-F3CC6H4 (1c)
3-PhOC6H4 (1d)
4-F3CC6H4 (1e)
4-PhC6H4 (1f)
naphthalen-2-yl (1g)
9H-fluoren-2-yl (1h)
furan-2-yl (1i)
pyridin-3-yl (1j)
quinolin-4-yl (1k)
4-F3CC6H4 (1e)
4-PhC6H4 (1f)
Ph (1a)
t-Bu (3a)
t-Bu (3a)
35
72
69
79
70
75
89
67
53
85
68
66
79
89
47
63
89
6l
6m
6n
6o
6p
6q
6r
Ph (2b)
t-Bu (3a)
Ph (2b)
t-Bu (3a)
Ph (2b)
t-Bu (3a)
Ph (2b)
t-Bu (3a)
Ph (2b)
t-Bu (3a)
Ph (2b)
t-Bu (3a)
6s
Ph (2b)
t-Bu (3a)
6t
Ph (2b)
t-Bu (3a)
6u
6v
6w
6x
6y
6z
Ph (2b)
t-Bu (3a)
4-PhC6H4 (2i)
4-NCC6H4 (2h)
Ph (2b)
t-Bu (3a)
t-Bu (3a)
n-pentyl (3b)
n-pentyl (3b)
n-pentyl (3b)
n-pentyl (3b)
Ph (1a)
4-FC6H4 (2a)
4-NCC6H4 (2h)
Ph (2b)
Ph (1a)
6aa
6ab
naphthalen-2-yl (1l)
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The structures of synthesized compounds (6a–ab) were characterized by IR, 1H NMR, 13C NMR
spectroscopy, and HRMS. Products 6b,18 6d,15 and 6g15 have been described previously, while
compounds 6a,c,e,f,h–ab are new.
A plausible mechanism for the formation of α-amino amides (6) via Ugi-3CR in the presence of
T3P® is outlined in Scheme 5. The first step is the T3P®-promoted condensation of the aldehyde
(1) and the amine (2) to form an imine (8) along with 1,5-dihydroxy-1,3,5-
tripropyltriphosphoxane 1,3,5-trioxide (QOH, 9). In the next step, Schiff base 8 is protonated by
QOH (9) and the iminium ion (10) obtained reacts with isocyanide 3 in a nucleophilic addition to
provide the nitrilium ion (11). Subsequently, another nucleophilic addition takes place at
intermediate 11 with the QO- anion to generate phosphonic acid ester 12. Finally, hydrolysis of
12 followed by tautomerization of imidic acid 13 leads to the final product, α-amino amide (6). In
order to exclude the possibility of the incomplete hydrolysis of 12 during work-up and
subsequent loss of yield, the relative rate of the hydrolysis has been determined based on the
following experiments using benzaldehyde (1a), 4-fluoroaniline (2a) and tert-butyl isocyanide
(3a). Two further batches of 6a were prepared using the optimal conditions determined
previously, but after the addition of 3a and a 30 min stirring at room temperature, 1.0 and 2.5
equivalents of water were added, and the reaction mixtures were stirred for further 24 h. After the
regular work-up procedure, we have not found significant differences among these yields and the
yield of the original experiment. Accordingly, the hydrolysis of 12a to 13a is sufficiently fast to
be completed during the usual work-up procedure.
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Scheme 5. Proposed mechanism for the T3P®-mediated three-component Ugi reaction
CONCLUSIONS
In conclusion, we have developed a simple and convenient method for the preparation of α-amino
amides using a T3P®-promoted three-component Ugi reaction starting from an aromatic
aldehyde, a primary aromatic amine and an aliphatic isocyanide. The advantages of this
procedure are the short reaction time, good yields, mild conditions, and high variability of the
reagents.
EXPERIMENTAL SECTION
General
All melting points were determined on a Büchi B-540 capillary melting point apparatus and are
uncorrected. IR spectra were obtained on a Bruker Vector 22 FT spectrometer in KBr pellets. 1H
13
NMR and C NMR spectra were recorded at 303 K on a Bruker Avance III HD (600 and 150
1
13
MHz for H and C NMR spectra, respectively) or a Bruker Avance III (400 and 100 MHz for
1H and 13C NMR spectra, respectively) spectrometer. CDCl3 was used as the solvent and
tetramethylsilane (TMS) as the internal standard. Chemical shifts (δ) and coupling constants (J)
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are given in ppm and in Hz, respectively. Mass spectra were recorded on a Bruker O-TOF
MAXIS Impact mass spectrometer coupled to a Dionex Ultimate 3000 RS HPLC system with a
diode array detector. The reactions were followed by analytical thin layer chromatography on
silica gel 60 F254 and LC–MS chromatography. Purifications by flash chromatography were
carried out using Merck 107736 silica gel 60 H using a hexane-ethyl acetate solvent system. All
reagents were purchased from commercial sources. Analytical samples of new compounds were
obtained by recrystallization from the solvents or solvent mixtures given below in parentheses.
General procedure for the synthesis of α-amino amides (6a–ab). The appropriate aromatic
aldehyde (1a−k, 1.0 mmol) and primary aromatic amine (2a−l, 1.0 mmol) were dissolved in
EtOAc (5 mL), and T3P® (Aldrich 50% solution in EtOAc, 0.3 mL, 0.5 mmol) was added. After
5 min, tert-butyl isocyanide (3a, 1.0 mmol) or 1-pentyl isocyanide (3b, 1.0 mmol) was added and
the mixture was stirred at room temperature for 30 min. Then the mixture was diluted with
EtOAc (10 mL) and washed with a 10% aqueous NaHCO3 solution (10 mL). The organic layer
was dried (Na2SO4), filtered and evaporated. The residue was purified by flash column
chromatography to afford products 6a‒ab.
N-tert-Butyl-2-[(4-fluorophenyl)amino]-2-phenylacetamide (6a). Yield: 174 mg (58%); white
crystals; mp 141–142 °C (hexane−EtOAc). Rf (hexane/EtOAc 4:1) 0.36. IR (KBr, cm–1): 3402,
1
3283, 1649, 1562, 1510, 1223, 818, 699. H NMR (600 MHz, CDCl3): δ 7.43–7.40 (m, 2H),
7.39–7.37 (m, 2H), 7.35–7.32 (m, 1H), 6.90–6.87 (m, 2H), 6.57–6.56 (m, 1H), 6.55–6.54 (m,
1H), 6.43 (br s, 1H), 4.54 (br d, J = 1.1 Hz, 1H), 4.47 (br s, 1H), 1.31 (s, 9H) ppm. 13C NMR (150
MHz, CDCl3): δ 170.0, 156.6 (d, J = 236.8 Hz), 143.0 (d, J = 2.0 Hz), 139.1, 129.2, 128.5, 127.2,
115.7 (d, J = 22.5 Hz), 114.7 (d, J = 7.6 Hz), 65.2, 51.2, 28.5 ppm. HRMS calcd. for C18H22FN2O
[M+H]+ 301.1716; found 301.1712.
N-tert-Butyl-2-phenyl-2-(phenylamino)acetamide (6b).18 Yield: 218 mg (77%); white crystals;
mp 132–133 °C (hexane−EtOAc). Rf (hexane/EtOAc 4:1) 0.37. IR (KBr, cm–1): 3409, 3280,
1
1650, 1602, 1558, 1509, 759. H NMR (400 MHz, CDCl3): δ 7.43–7.41 (m, 2H), 7.40–7.36 (m,
2H), 7.35–7.31 (m, 1H), 7.21–7.17 (m, 2H), 6.81–6.78 (m, 1H), 6.64–6.63 (m, 1H), 6.62–6.61
13
(m, 1H), 6.52 (br s, 1H), 4.60 (d, J = 2.2 Hz, 1H), 4.49 (br s, 1H). 1.32 (s, 9H) ppm. C NMR
(100 MHz, CDCl3): δ 170.2, 146.8, 139.3, 129.2 (two signals), 128.4, 127.3, 119.0, 113.9, 64.9,
51.2, 28.5 ppm. HRMS calcd. for C18H23N2O [M+H]+ 283.1810; found 283.1804.
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N-tert-Butyl-2-{[2-(methylsulfanyl)phenyl]amino}-2-phenylacetamide (6c). Yield: 109 mg
(33%); white crystals; mp 146–147 °C (hexane−EtOAc). Rf (hexane/EtOAc 4:1) 0.42. IR (KBr,
1
cm–1): 3320, 1651, 1559, 1493, 733. H NMR (400 MHz, CDCl3): δ 7.46–7.43 (m, 2H), 7.42–
7.41 (m, 1H), 7.40–7.38 (m, 2H), 7.36–7.34 (m, 1H), 7.17–7.13 (m, 1H), 6.78–6.74 (m, 1H), 6.55
(d, J = 8.0 Hz, 1H), 6.38 (br s, 1H), 5.75 (br d, J = 1.7 Hz, 1H), 4.64 (br d, J = 2.8 Hz, 1H), 2.35
13
(s, 3H), 1.31 (s, 9H) ppm. C NMR (100 MHz, CDCl3): δ 170.0, 146.7, 139.1, 133.3, 129.2,
129.1, 128.4, 127.1, 121.5, 118.9, 111.7, 64.7, 51.2, 28.5, 18.2 ppm. HRMS calcd. for
C19H25N2OS [M+H]+ 329.1688; found 329.1687.
N-tert-Butyl-2-[(3-chlorophenyl)amino]-2-phenylacetamide (6d).15 Yield: 233 mg (70%);
white crystals; mp 128–129 °C (hexane−EtOAc). Rf (hexane/EtOAc 4:1) 0.42. IR (KBr, cm–1):
1
3418, 3343, 1652, 1597, 1542, 1492, 1223, 989, 732. H NMR (400 MHz, CDCl3): δ 7.42–7.40
(m, 2H), 7.39–7.36 (m, 2H), 7.35–7.31 (m, 1H), 7.06 (t, J = 8.8 Hz, 1H), 6.74–6.71 (m, 1H),
5.59–6.58 (m, 1H), 6.49–6.46 (m, 1H), 6.17 (br s, 1H), 4.81 (br d, J = 2.6 Hz, 1H), 4.59 (br d, J =
2.9 Hz, 1H), 1.30 (s, 9H) ppm. 13C NMR (100 MHz, CDCl3): δ 169.5, 147.8, 138.9, 134.9, 130.2,
129.3, 128.6, 127.2, 118.7, 113.7, 112.0, 63.9, 51.4, 28.5 ppm. HRMS calcd. for C18H22ClN2O
[M+H]+ 317.1421; found 317.1417.
N-tert-Butyl-2-phenyl-2-{[3-(trifluoromethyl)phenyl)]amino]}acetamide (6e). Yield: 220 mg
(63%); white crystals; mp 137–138 °C (hexane−EtOAc). Rf (hexane/EtOAc 4:1) 0.40. IR (KBr,
1
cm–1): 3400, 3302, 1651, 1553, 1163, 1123, 696. H NMR (400 MHz, CDCl3): δ 7.44–7.41 (m,
2H), 7.40–7.37 (m, 2H), 7.36–7.32 (m, 1H), 7.24 (t, J = 7.0 Hz, 1H), 7.00–6.98 (m, 1H), 6.82–
6.81 (m, 1H), 6.75–6.72 (m, 1H), 6.11 (br s, 1H), 4.98 (br d, J = 2.2 Hz, 1H), 4.64 (d, J = 2.9 Hz,
13
1H), 1.30 (s, 9H) ppm. C NMR (100 MHz, CDCl3): δ 169.4, 146.8, 138.8, 131.5 (q, J = 32.1
Hz), 129.7, 129.4, 128.6, 127.2, 124.1 (q, J = 272.8 Hz), 116.6 (d, J = 1.3 Hz), 115.1 (q, J = 3.9
Hz), 110.2 (q, J = 3.8 Hz), 63.8, 51.5, 28.5 ppm. HRMS calcd. for C19H22F3N2O [M+H]+
351.1684; found 351.1683.
N-tert-Butyl-2-[(3-phenoxyphenyl)amino]-2-phenylacetamide (6f). Yield: 213 mg (57%);
white crystals; mp 96–98 °C (i-Pr2O). Rf (hexane/EtOAc 4:1) 0.43. IR (KBr, cm–1): 3290, 1650,
1
1489, 1222, 1152, 754, 691. H NMR (400 MHz, CDCl3): δ 7.38–7.36 (m, 3H), 7.34–7.31 (m,
2H), 7.30–7.28 (m, 2H), 7.12–7.10 (m, 1H), 7.08–7.06 (m, 1H), 6.99–6.98 (m, 1H), 6.97–6.96
(m, 1H), 6.40 (dd, J1 = 2.2 Hz, J2 = 7.9 Hz, 1H), 6.35 (dd, J1 = 1.9 Hz, J2 = 8.0 Hz, 1H), 6.24 (t, J
13
= 2.2 Hz, 1H), 6.20 (br s, 1H), 4.70 (br s, 1H), 4.57 (d, J = 2.2 Hz, 1H), 1.29 (s, 9H) ppm. C
11

ACCEPTED MANUSCRIPT
NMR (100 MHz, CDCl3): δ 169.8, 158.5, 156.9, 148.3, 139.2, 130.2, 129.6, 129.2, 128.4, 127.2,
123.2, 119.2, 109.0, 108.7, 104.2, 64.2, 51.3, 28.5 ppm. HRMS calcd. for C24H27N2O2 [M+H]+
375.2072; found 375.2068.
N-tert-Butyl-2-phenyl-2-{[4-(trifluoromethyl)phenyl)]amino]}acetamide (6g).15 Yield: 195
mg (56%); white crystals; mp 173–175 °C (hexane−EtOAc). Rf (hexane/EtOAc 4:1) 0.38. IR
(KBr, cm–1): 3407, 3309, 1650, 1617, 1320, 1112, 1066, 826, 700. 1H NMR (400 MHz, CDCl3):
δ 7.43–7.42 (m, 2H), 7.41–7.39 (m, 2H), 7.38–7.37 (m, 1H), 7.36–7.32 (m, 2H), 6.61–6.59 (m,
2H), 5.94 (br s, 1H), 5.23 (br d, J = 2.7 Hz, 1H), 4.67 (d, J = 3.2 Hz, 1H), 1.29 (s, 9H) ppm. 13C
NMR (100 MHz, CDCl3): δ 169.3, 149.0, 138.8, 129.4, 128.7, 127.1, 126.5 (q, J = 3.8 Hz), 124.7
(q, J = 270.4 Hz), 120.0 (q, J = 32.5 Hz), 113.0, 63.2, 51.6, 28.5 ppm. HRMS calcd. for
C19H22F3N2O [M+H]+ 351.1684; found 351.1683.
N-tert-Butyl-2-[(4-cyanophenyl)amino]-2-phenylacetamide (6h). Yield: 278 mg (90%); white
crystals; mp 198–199 °C (MeCN). Rf (CH2Cl2/MeOH 19:1) 0.60. IR (KBr, cm–1): 3364, 3323,
2209, 1678, 1605, 1528, 1174, 830. 1H NMR (400 MHz, CDCl3): δ 7.42–7.41 (m, 2H), 7.40–7.39
(m, 2H), 7.38–7.34 (m, 3H), 6.55–6.54 (m, 1H), 6.53–6.52 (m, 1H), 5.70–5.68 (m, 2H), 4.70 (d, J
13
= 3.8 Hz, 1H), 1.28 (s, 9H) ppm. C NMR (100 MHz, CDCl3): δ 168.7, 149.6, 138.4, 133.6,
129.5, 128.7, 126.9, 120.1, 113.3, 99.9, 62.1, 51.8, 28.5 ppm. HRMS calcd. for C19H22N3O
[M+H]+ 308.1763; found 308.1759.
2-({[1,1'-Biphenyl]-4-yl}amino)-N-tert-butyl-2-phenylacetamide (6i). Yield: 284 mg (79%);
white crystals; mp 140–141 °C (hexane−EtOAc). Rf (hexane/EtOAc 4:1) 0.34. IR (KBr, cm–1):
3412, 3327, 1654, 1611, 1525, 763. 1H NMR (400 MHz, CDCl3): δ 7.54–7.53 (m, 1H), 7.52–7.51
(m, 1H), 7.46–7.45 (m, 2H), 7.44–7.43 (m, 2H), 7.41–7.39 (m, 2H), 7.38–7.37 (m, 2H), 7.36–
7.32 (m, 1H), 7.28–7.24 (m, 1H), 6.71–6.70 (m, 1H), 6.69–6.68 (m, 1H), 6.45 (br s, 1H), 4.65 (br
s, 2H), 1.33 (s, 9H) ppm. 13C NMR (100 MHz, CDCl3): δ 170.1, 146.1, 140.9, 139.2, 131.9,
129.2, 128.7, 128.5, 127.9, 127.3, 126.4, 126.3, 114.2, 64.7, 51.3, 28.5 ppm. HRMS calcd. for
C24H27N2O [M+H]+ 359.2123; found 359.2125.
N-tert-Butyl-2-[(2,4-dimethylphenyl)amino]-2-phenylacetamide (6j). Yield: 144 mg (46%);
white crystals; mp 168–169 °C (hexane−EtOAc). Rf (hexane/EtOAc 4:1) 0.47. IR (KBr, cm–1):
1
3293, 1650, 1551, 1513, 807. H NMR (400 MHz, CDCl3): δ 7.45–7.44 (m, 1H), 7.43–7.42 (m,
1H), 7.39–7.35 (m, 2H), 7.34–7.31 (m, 1H), 6.91–6.88 (m, 2H), 6.50 (br s, 1H), 6.44 (d, J = 8.0
Hz, 1H), 4.60 (s, 1H), 4.30 (br s, 1H), 2.23 (s, 3H), 2.17 (s, 3H), 1.31 (s, 9H) ppm. 13C NMR (100
12

ACCEPTED MANUSCRIPT
MHz, CDCl3): δ 170.43, 142.6, 139.7, 131.0, 129.2, 128.3, 127.9, 127.4, 127.2, 123.0, 65.0, 51.1,
28.5, 20.3, 17.5 ppm. HRMS calcd. for C20H27N2O [M+H]+ 311.2123; found 311.2115.
N-tert-butyl-2-[(2,3-dihydro-1H-inden-5-yl)amino]-2-phenylacetamide (6k). Yield: 203 mg
(63%); white crystals; mp 142–143 °C (hexane−EtOAc). Rf (hexane/EtOAc 4:1) 0.42. IR (KBr,
1
cm–1): 3393, 3302, 2961, 1651, 1555, 1502, 699. H NMR (400 MHz, CDCl3): δ 7.42–7.39 (m,
2H), 7.38–7.35 (m, 2H), 7.34–7.30 (m, 1H), 7.04 (d, J = 8.0 Hz, 1H), 6.77 (br s, 1H), 6.55 (br d, J
= 1.8 Hz, 1H), 6.44 (dd, J1 = 2.3 Hz, J2 = 8.0 Hz, 1H), 4.55 (s, 1H), 4.24 (br s, 1H), 2.85–2.82 (m,
13
2H), 2.81–2.79 (m, 2H), 2.08–2.00 (m, 2H), 1.33 (s, 9H) ppm. C NMR (100 MHz, CDCl3): δ
170.6, 145.6, 145.5, 139.4, 135.0, 129.1, 128.3, 127.3, 124.7, 112.2, 110.1, 65.7, 51.0, 33.0, 31.9,
28.5, 25.6 ppm. HRMS calcd. for C21H27N2O [M+H]+ 323.2123; found 323.2122.
N-tert-Butyl-2-phenyl-2-[(quinolin-5-yl)amino]acetamide (6l). Yield: 118 mg (35%); pale
yellow crystals; mp 169–171 °C (MeCN). Rf (CH2Cl2/MeOH 19:1) 0.23. IR (KBr, cm–1): 3506,
3420, 1649, 1591, 1480, 1366, 785. 1H NMR (400 MHz, CDCl3): δ 8.80 (dd, J1 = 1.5 Hz, J2 = 4.2
Hz, 1H), 8.37–8.35 (m, 1H), 7.53–7.52 (m, 1H), 7.51–7.50 (m, 2H), 7.46–7.43 (m, 2H), 7.42–
7.38 (m, 2H), 7.37–7.34 (m, 1H), 6.47 (d, J = 7.4 Hz, 1H), 5.93 (br s, 1H), 5.83 (br d, J = 1.6 Hz,
13
1H), 4.81 (d, J = 2.4 Hz, 1H), 1.29 (s, 9H) ppm. C NMR (100 MHz, CDCl3): δ 169.6, 150.1,
149.0, 141.9, 139.0, 130.0, 129.4, 129.0, 128.7, 127.2, 119.6 (two signals), 118.8, 106.2, 63.4,
51.6, 28.5 ppm. HRMS calcd. for C21H23N3O [M+H]+ 334.1919; found 334.1924.
N-tert-Butyl-2-(3-fluorophenyl)-2-(phenylamino)acetamide (6m). Yield: 217 mg (72%); white
crystals; mp 93–94 °C (hexane−EtOAc). Rf (hexane/EtOAc 4:1) 0.38. IR (KBr, cm–1): 3434,
1
3315, 1648, 1603, 1549, 1505, 1320, 748. H NMR (400 MHz, CDCl3): δ 7.38–7.32 (m, 1H),
7.25–7.23 (m, 1H), 7.21–7.17 (m, 2H), 7.16–7.12 (m, 1H), 7.05–7.01 (m, 1H), 6.82–6.79 (m,
1H), 6.63–6.61 (m, 2H), 6.42 (br s, 1H), 4.61 (br d, J = 2.5 Hz, 1H), 4.54 (br s, 1H), 1.32 (s, 9H)
ppm. 13C NMR (100 MHz, CDCl3): δ 169.5, 163.2 (d, J =247.2 Hz), 146.4, 141.8 (d, J = 6.8 Hz),
130.7 (d, J = 8.1 Hz), 129.3, 123.1 (d, J = 2.9 Hz), 119.2, 115.4 (d, J = 21.3 Hz), 114.2 (d, J =
22.0 Hz), 113.9, 64.2 (d, J = 4.1 Hz), 51.3, 28.5 ppm. HRMS calcd. for C18H22FN2O [M+H]+
301.1716; found 301.1712.
N-tert-Butyl-2-(phenylamino)-2-[3-(trifluoromethyl)phenyl]acetamide (6n). Yield: 240 mg
(69%); white crystals; mp 105–106 °C (hexane). Rf (hexane/EtOAc 4:1) 0.43. IR (KBr, cm–1):
1
3321, 1643, 1332, 1122, 751. H NMR (400 MHz, CDCl3): δ 7.69 (s, 1H), 7.63–7.59 (m, 2H),
7.50 (t, J = 7.8 Hz, 1H), 7.22–7.18 (m, 2H), 6.85–6.81 (m, 1H), 6.65–6.62 (m, 2H), 6.54 (br s,
13

ACCEPTED MANUSCRIPT
1H), 4.68 (s, 1H), 4.46 (br s, 1H), 1.32 (s, 9H) ppm. 13C NMR (100 MHz, CDCl3): δ 169.4,
146.3, 140.2, 131.5 (q, J = 32.4 Hz), 130.8 (d, J = 1.4 Hz), 129.7, 129.4, 125.3 (q, J = 3.7 Hz),
124.1 (q, J = 3.8 Hz), 123.8 (q, J = 272.8 Hz), 119.5, 113.9, 64.4, 51.4, 28.5 ppm. HRMS calcd.
for C19H21F3N2O [M+H]+ 351.1684; found 351.1680.
N-tert-Butyl-2-(3-phenoxyphenyl)-2-(phenylamino)acetamide (6o). Yield: 297 mg (79%); pale
1
yellow oil. Rf (hexane/EtOAc 4:1) 0.43. IR (film, cm–1): 3320, 1672, 1600, 1497, 744, 693. H
NMR (400 MHz, CDCl3): δ 7.36–7.33 (m, 2H), 7.32–7.31 (m, 1H), 7.20–7.16 (m, 2H), 7.14–7.10
(m, 2H), 7.07–7.05 (m, 1H), 7.02–7.01 (m, 1H), 7.00–6.99 (m, 1H), 6.98–6.95 (m, 1H), 6.82–
6.78 (m, 1H), 6.62–6.60 (m, 2H), 6.47 (br s, 1H), 4.56 (d, J = 2.3 Hz, 1H), 4.46 (br d, J = 1.6 Hz,
1H), 1.29 (s, 9H) ppm. 13C NMR (100 MHz, CDCl3): δ 169.8, 158.0, 156.6, 146.6, 141.2, 130.5,
129.8, 129.2, 123.6, 122.1, 119.2, 119.1, 118.5, 117.1, 113.9, 64.6, 51.2, 28.5 ppm. HRMS calcd.
for C24H27N2O2 [M+H]+ 375.2072; found 375.2067.
N-tert-Butyl-2-(phenylamino)-2-[4-(trifluoromethyl)phenyl]acetamide (6p). Yield: 244 mg
(70%); white crystals; mp 140–141 °C (hexane−EtOAc). Rf (hexane/EtOAc 4:1) 0.30. IR (KBr,
1
cm–1): 3296, 1651, 1603, 1506, 1363, 1128, 748, 692. H NMR (400 MHz, CDCl3): δ 7.66–7.63
(m, 2H), 7.57–7.55 (m, 2H), 7.22–7.18 (m, 2H), 6.84–6.80 (m, 1H), 6.63–6.61 (m, 2H), 6.44 (br
13
s, 1H), 4.68 (s, 1H), 4.53 (br s, 1H), 1.32 (s, 9H) ppm. C NMR (100 MHz, CDCl3): δ 169.3,
146.3, 143.2, 130.4 (q, J = 33.0 Hz), 129.4, 127.7, 126.2 (q, J = 3.5 Hz), 123.9 (q, J = 272.2 Hz),
119.4, 113.9, 64.3, 51.4, 28.5 ppm. HRMS calcd. for C19H22F3N2O [M+H]+ 351.1684; found
351.1681.
2-{[1,1'-Biphenyl]-4-yl}-N-tert-butyl-2-(phenylamino)acetamide (6q). Yield: 268 mg (75%);
white crystals; mp 125–126 °C (hexane−EtOAc). Rf (hexane/EtOAc 4:1) 0.37. IR (KBr, cm–1):
1
3364, 2967, 1666, 1605, 1505, 755, 694. H NMR (400 MHz, CDCl3): δ 7.61–7.59 (m, 2H),
7.58–7.57 (m, 2H), 7.50–7.48 (m, 2H), 7.45–7.42 (m, 2H), 7.37–7.33 (m, 1H), 7.22–7.18 (m,
2H), 6.83–6.79 (m, 1H), 6.67–6.64 (m, 2H), 6.58 (br s, 1H), 4.65 (d, J = 2.3 Hz, 1H), 4.52 (br d, J
13
= 1.8 Hz, 1H), 1.34 (s, 9H) ppm. C NMR (100 MHz, CDCl3): δ 170.2, 146.8, 141.4, 140.5,
138.2, 129.3, 128.8, 127.9, 127.7, 127.5, 127.1, 119.1, 113.9, 64.6, 51.2, 28.6 ppm. HRMS calcd.
for C24H27N2O [M+H]+ 359.2123; found 359.2123.
N-tert-Butyl-2-(naphthalen-2-yl)-2-(phenylamino)acetamide (6r). Yield: 295 mg (89%); white
crystals; mp 148–149 °C (hexane−EtOAc). Rf (hexane/EtOAc 4:1) 0.37. IR (KBr, cm–1): 3367,
1
2931, 1668, 1607, 1508, 748. H NMR (400 MHz, CDCl3): δ 7.91–7.89 (m, 1H), 7.87–7.85 (m,
14

ACCEPTED MANUSCRIPT
2H), 7.83–7.81 (m, 1H), 7.53–7.48 (m, 3H), 7.20–7.16 (m, 2H), 6.80–6.77 (m, 1H), 6.67–6.65
13
(m, 2H), 6.44 (s, 1H), 4.78 (d, J = 2.3 Hz), 4.71 (s, 1H), 1.32 (s, 9H) ppm. C NMR (100 MHz,
CDCl3): δ 170.0, 146.8, 136.8, 133.4, 133.2, 129.3, 129.2, 128.0, 127.7, 126.6, 126.5, 126.3,
124.7, 119.0, 113.9, 64.7, 51.3, 28.6 ppm. HRMS calcd. for C22H25N2O [M+H]+ 333.1967; found
333.1963.
N-tert-Butyl-2-(9H-fluoren-2-yl)-2-(phenylamino)acetamide (6s). Yield: 249 mg (67%); white
crystals; mp 149.5–151.5 °C (hexane−EtOAc). Rf (hexane/EtOAc 4:1) 0.35. IR (KBr, cm–1):
3357, 1671, 1605, 1514, 750, 735, 692. 1H NMR (400 MHz, CDCl3): δ 7.79–7.76 (m, 2H), 7.61–
7.59 (m, 1H), 7.55–7.53 (m, 1H), 7.45–7.42 (m, 1H), 7.39–7.35 (m, 1H), 7.32–7.29 (m, 1H),
7.20–7.16 (m, 2H), 6.81–6.77 (m, 1H), 6.66–6.64 (m, 2H), 6.49 (s, 1H), 4.67 (d, J = 1.6 Hz, 1H),
4.62 (s, 1H), 3.90 (s, 2H), 1.32 (s, 9H) ppm. 13C NMR (100 MHz, CDCl3): δ 170.3, 146.9, 144.2,
143.4, 142.1, 141.1, 137.9, 129.2, 127.0, 126.8, 125.9, 125.1, 124.0, 120.4, 120.0, 119.0, 113.9,
64.9, 51.2, 36.9, 28.6 ppm. HRMS calcd. for C25H27N2O [M+H]+ 371.2123; found 371.2120.
N-tert-Butyl-2-(furan-2-yl)-2-(phenylamino)acetamide (6t). Yield: 143 mg (53%); white
crystals; mp 125–126 °C (i-Pr2O). Rf (hexane/EtOAc 4:1) 0.35. IR (KBr, cm–1): 3295, 1649,
1
1604, 1551, 1509, 748, 691. H NMR (400 MHz, CDCl3): δ 7.41–7.39 (m, 1H), 7.22–7.18 (m,
2H), 6.83–6.79 (m, 1H), 6.65–6.63 (m, 2H), 6.53 (br s, 1H), 6.37–6.35 (m, 1H), 4.76 (d, J = 3.0
Hz, 1H), 4.66 (br s, 1H), 1.33 (s, 9H) ppm. 13C NMR (100 MHz, CDCl3): δ 167.9, 151.2, 146.4,
142.5, 129.3, 119.2, 113.8, 110.8, 108.0, 58.5, 51.3, 28.5 ppm. HRMS calcd. for C16H21N2O2
[M+H]+ 273.1603; found 273.1601.
N-tert-butyl-2-(phenylamino)-2-(pyridin-3-yl)acetamide (6u). Yield: 240 mg (85%); white
crystals; mp 149.5–151.5 °C (hexane−EtOAc). Rf (CH2Cl2/MeOH 19:1) 0.19. IR (KBr, cm–1):
1
3330, 2967, 1659, 1603, 1485, 1248, 750, 691. H NMR (400 MHz, CDCl3): δ 8.69 (d, J = 2.1
Hz, 1H), 8.58 (dd, J1 = 1.5 Hz, J2 = 4.8 Hz, 1H), 7.76–7.72 (m, 1H), 7.32–7.29 (m, 1H), 7.22–
7.18 (m, 2H), 6.84–6.81 (m, 1H), 6.65–6.63 (m, 2H), 6.57 (br s, 1H), 4.66 (d, J = 3.0 Hz, 1H),
13
4.52 (br d, J = 2.6 Hz, 1H), 1.32 (s, 9H) ppm. C NMR (100 MHz, CDCl3): δ 169.3, 149.7,
148.9, 146.2, 135.0, 134.8, 129.4, 123.9, 119.4, 113.9, 62.4, 51.4, 28.5 ppm. HRMS calcd. for
C17H22N3O [M+H]+ 284.1763; found 284.1755.
N-tert-Butyl-2-(phenylamino)-2-(quinolin-4-yl)acetamide (6v). Yield: 228 mg (68%); white
crystals; mp 153–155 °C (hexane−EtOAc). Rf (CH2Cl2/MeOH 19:1) 0.40. IR (KBr, cm–1): 3352,
2969, 1674, 1652, 1604, 1510, 748. 1H NMR (400 MHz, CDCl3): δ 8.89–8.88 (m, 1H), 8.17–8.15
15

ACCEPTED MANUSCRIPT
(m, 1H), 8.02–8.00 (m, 1H), 7.76–7.72 (m, 1H), 7.59–7.55 (m, 1H), 7.45–7.44 (m, 1H), 7.25–
7.20 (m, 2H), 6.88–6.85 (m, 1H), 6.71–6.67 (m, 3H), 5.36 (d, J = 2.9 Hz, 1H), 4.59 (br d, J = 2.5
13
Hz, 1H), 1.35 (s, 9H) ppm. C NMR (100 MHz, CDCl3): δ 169.1, 150.4, 148.8, 146.5, 144.3,
130.7, 129.6, 129.5, 127.5, 126.5, 123.0, 119.7, 119.3, 113.9, 60.6, 51.6, 28.5 ppm. HRMS calcd.
for C21H24N3O [M+H]+ 334.1919; found 334.1916.
2-({[1,1'-Biphenyl]-4-yl}amino)-N-tert-butyl-2-[4-(trifluoromethyl)phenyl]acetamide (6w).
Yield: 280 mg (66%); white crystals; mp 167–168 °C (hexane−EtOAc). Rf (hexane/EtOAc 4:1)
1
0.40. IR (KBr, cm–1): 3406, 3336, 1651, 1612, 1490, 1328, 1120, 761. H NMR (400 MHz,
CDCl3): δ 7.67–7.65 (m, 2H), 7.59–7.57 (m, 2H), 7.53–7.51 (m, 2H),7.46–7.43 (m, 2H), 7.41–
7.37 (m, 2H), 7.29–7.25 (m, 1H), 6.70–6.67 (m, 2H), 6.39 (br s, 1H), 4.73 (br d, J = 2.7 Hz, 1H),
13
4.67 (br d, J = 2.4 Hz, 1H), 1.33 (s, 9H) ppm. C NMR (100 MHz, CDCl3): δ 169.2, 145.6,
143.2, 140.7, 132.3, 130.7 (q, J = 32.3 Hz), 128.7, 128.0, 127.7, 126.5, 126.4, 126.2 (q, J = 3.8
Hz), 123.9 (q, J = 272.2 Hz), 114.2, 64.1, 51.5, 28.5 ppm. HRMS calcd. for C25H26F3N2O
[M+H]+ 427.1997; found 427.1998.
2-{[1,1'-Biphenyl]-4-yl}-N-tert-butyl-2-[(4-cyanophenyl)amino]acetamide (6x). Yield: 302 mg
(79%); white crystals; mp 125–127 °C (hexane−EtOAc). Rf (hexane/EtOAc 4:1) 0.17. IR (KBr,
1
cm–1): 3338, 2966, 2213, 1678, 1606, 1523, 1175, 825, 758. H NMR (400 MHz, CDCl3): δ
7.67–7.65 (m, 2H), 7.59–7.57 (m, 2H), 7.53–7.51 (m, 2H), 7.46–7.43 (m, 2H), 7.41–7.37 (m,
2H), 7.29–7.25 (m, 1H), 6.70–6.67 (m, 2H), 5.72 (br s, 1H), 5.69 (br d, J = 2.7 Hz, 1H), 4.74 (br
d, J = 2.4 Hz, 1H), 1.30 (s, 9H) ppm. 13C NMR (100 MHz, CDCl3): δ 168.9, 149.6, 141.7, 140.1,
137.3, 133.8, 128.8, 128.1, 127.7, 127.3, 127.0, 120.1, 113.4, 100.1, 61.9, 51.9, 28.5 ppm. HRMS
calcd. for C25H26N3O [M+H]+ 384.2076; found 384.2073.
N-Pentyl-2-phenyl-2-(phenylamino)acetamide (6y). Yield: 263 mg (89%); colorless oil. Rf
1
(hexane/EtOAc 4:1) 0.30. IR (film, cm–1): 3311, 2931, 1652, 1602, 1504, 1315, 749, 649. H
NMR (400 MHz, CDCl3): δ 7.44–7.42 (m, 2H), 7.39–7.35 (m, 2H), 7.34–7.31 (m, 1H), 7.20–7.16
(m, 2H), 6.81–6.77 (m, 1H), 6.70 (br t, J = 6.4 Hz, 1H), 6.62 (d, J = 7.7 Hz, 2H), 4.72 (d, J = 2.2
Hz, 1H), 4.55 (br d, J = 1.3 Hz, 1H), 3.28–3.22 (m, 2H), 1.48–1.40 (m, 2H), 1.28–1.22 (m, 2H),
13
1.20–1.13 (m, 2H), 0.83 (t, J = 7.0 Hz, 3H) ppm. C NMR (100 MHz, CDCl3): δ 170.9, 146,7,
139.0, 129.3, 129.2, 128.5, 127.3, 119.0, 113.8, 64.2, 39.4, 29.1, 28.9, 22.2, 13.9 ppm. HRMS
calcd. for C19H25N2O [M+H]+ 297.1967; found 297.1960.
16

ACCEPTED MANUSCRIPT
2-[(4-Fluorophenyl)amino]-N-pentyl-2-phenylacetamide (6z). Yield: 148 mg (47%); colorless
1
oil. Rf (hexane/EtOAc 4:1) 0.27. IR (film, cm–1): 3308, 2932, 1652, 1510, 1222, 821, 698. H
NMR (400 MHz, CDCl3): δ 7.44–7.42 (m, 2H), 7.40–7.37 (m, 2H), 7.36–7.32 (m, 1H), 6.90–6.86
(m, 2H), 6.57–6.54 (m, 3H), 4.66 (br s, 1H), 4.53 (br s, 1H), 3.28–3.23 (m, 2H), 1.48–1.40 (m,
13
2H), 1.28–1.22 (m, 2H), 1.20–1.13 (m, 2H), 0.83 (t, J = 7.0 Hz, 3H) ppm. C NMR (100 MHz,
CDCl3): δ 170.8, 156.6 (d, J = 237.0 Hz), 143.0 (d, J = 2.0 Hz), 138.9, 129.3, 128.6, 127.3, 115.8
(d, J = 22.6 Hz), 114.7 (d, J = 7.6 Hz), 64.6, 39.5, 29.1, 28.9, 22.2, 13.9 ppm. HRMS calcd. for
C19H24FN2O [M+H]+ 315.1873; found 315.1869.
2-[(4-Cyanophenyl)amino]-N-pentyl-2-phenylacetamide (6aa). Yield: 201 mg (63%);
colorless oil. Rf (CH2Cl2/MeOH 19:1) 0.60. IR (film, cm–1): 3355, 2931, 2215, 1659, 1606, 1519,
1
1335, 1174, 826, 698, 545. H NMR (400 MHz, CDCl3): δ 7.43–7.41 (m, 2H), 7.40–7.38 (m,
2H), 7.37–7.32 (m, 3H), 6.56–6.53 (m, 2H), 5.89–5.86 (m, 1H), 5.72 (d, J = 3.4 Hz, 1H), 4.79 (d,
J = 3.7 Hz, 1H), 3.26–3.20 (m, 2H), 1.43–1.39 (m, 2H), 1.26–1.20 (m, 2H), 1.17–1.11 (m, 2H),
13
0.83 (t, J = 7.1 Hz, 3H) ppm. C NMR (100 MHz, CDCl3): δ 169.6, 149.6, 138.2, 133.6, 129.5,
128.9, 127.0, 120.0, 113.4, 100.0, 61.8, 39.9, 29.0, 28.7, 22.2, 13.9 ppm. HRMS calcd. for
C20H24N3O [M+H]+ 322.1919; found 322.1916.
2-(Naphthalen-2-yl)-N-pentyl-2-(phenylamino)acetamide (6ab). Yield: 310 mg (89%);
colorless oil. Rf (hexane/EtOAc 4:1) 0.42. IR (film, cm–1): 3312, 2932, 1660, 1504, 1316, 750,
1
478. H NMR (400 MHz, CDCl3): δ 7.91–7.90 (m, 1H), 7.86–7.83 (m, 2H), 7.82–7.81 (m, 1H),
7.52 (dd, J1 = 1.8 Hz, J2 = 10.2 Hz, 1H), 7.50–7.46 (m, 2H), 7.19–7.15 (m, 2H), 6.80–6.76 (m,
1H), 6.67–6.62 (m, 3H), 4.90 (d, J = 2.1 Hz, 1H), 4.75 (br d, J = 1.4 Hz, 1H), 3.31–3.20 (m, 2H),
13
1.47–1.39 (m, 2H), 1.26–1.20 (m, 2H), 1.19–1.13 (m, 2H), 0.81 (t, J = 6.9 Hz, 3H) ppm. C
NMR (100 MHz, CDCl3): δ 170.8, 146.7, 136.5, 133.4, 133.2, 129.3, 129.2, 127.9, 127.7, 126.6,
126.5, 126.4, 124.8, 119.0, 113.9, 64.1, 39.6, 29.1, 28.9, 22.2, 13.9 ppm. HRMS calcd. for
C23H27N2O [M+H]+ 347.2123; found 347.2122.
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