NHC-Catalyzed Aza-Benzoin Condensation of N, N′-Dipyridin-2-yl Aminals with Aldehydes

Article abstract of DOI:10.1021/acs.joc.1c00973

α-Amino ketones are useful compounds because of their synthetic utility and bioactivities. After observing the ability of N,N′-dipyridin-2-yl aminals to form imines in situ, the synthesis of α-amino ketones using N,N′-dipyridin-2-yl aminals was proposed.

Full text of DOI:10.1021/acs.joc.1c00973

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Article
NHC-Catalyzed Aza-Benzoin Condensation of N,N′‑Dipyridin-2-yl
Aminals with Aldehydes
Justin S. Lamb, Ryo Takashima, and Yumiko Suzuki*
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ABSTRACT: α-Amino ketones are useful compounds because of
their synthetic utility and bioactivities. After observing the ability of
N,N′-dipyridin-2-yl aminals to form imines in situ, the synthesis of
α-amino ketones using N,N′-dipyridin-2-yl aminals was proposed.
Through the NHC-catalyzed aza-benzoin reaction between
aromatic/aliphatic aldehydes and N,N′-dipyridin-2-yl aminals, α-
amino ketones, including aromatic, heterocyclic, and aliphatic
versions, were synthesized with yields up to 99%. A direct route
toward N-Boc-protected α-amino ketones from N,N,N′-tris-Boc aminals was also discovered, yielding the desired N-Boc-protected
α-amino ketones in yields up to 73%.
aminals attractive precursors to imines, which also make them
ideal starting materials for the NHC-catalyzed synthesis of α-
amino ketones.
INTRODUCTION
■
α-Amino ketones1 have been fundamental substrates in the
syntheses of nitrogen-containing heterocyclic compounds2−6
such as indoles,2 indolines,3 and pyrroles.4 Furthermore, the α-
amino ketone framework is an important motif in biologically
active molecules. For instance, it is found in the antidepressant
bupropion7a,b and the vasoconstrictor adrenalone.7c α-Amino
ketones can be accessed from various substrates,1,8−12
including α-amino acids,8a,b alkenes,9 and ketones.10a−e Imines
provide another synthetic starting point toward α-amino
ketones.13a−f The NHC-catalyzed aza-benzoin condensation
reaction between aldehydes and imines is a convenient
synthetic method for α-amino ketones.14−18 However, since
imines may be unstable, it is common to form them in situ
(Scheme 1).16−18
To the best of our knowledge, only two previous reports on
the NHC-catalyzed synthesis of α-amino ketones from aminal-
derived intermediates exist. Both reports used benzotriazole-
based aminals (Scheme 2).17,18 Over the course of previous
research, we found N,N′-dipyridin-2-yl aminals to be bench-
stable in the solid form but to quickly form imines in solution
at room temperature. We believed that the ability of these
aminals to form imines efficiently and previous reports of the
removal of pyridin-2-yl groups19 make these compounds
attractive starting materials. Thus, we attempted the
application of N,N′-dipyridin-2-yl aminals in the aza-benzoin
condensation reaction. Herein, we report the synthesis of α-
amino ketones by the use of N,N′-dipyridin-2-yl aminals as
imine precursors in the NHC-catalyzed aza-benzoin reaction.
The in situ formation of imines can be achieved using α-
aminosulfones16 or aminals (Scheme 1).17,18 Aminals can be
easily prepared and are bench-stable. These properties make
RESULTS AND DISCUSSION
■
Initial studies were conducted using 4-chlorobenzaldehyde and
aminal 2a in ethanol (Table 1, see Table S1 in the Supporting
Information for a full list of screening conditions). The
reaction using commercially available thiazolium salt A as the
catalyst precursor with Et3N as the base provided the desired
α-amino ketone 3a in 71% yield (entry 1). Mesityl-substituted
thiazolium perchlorate salt B afforded the desired product in
Scheme 1. In Situ Formation of Imines
Received: April 26, 2021
Published: July 22, 2021
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82% yield (entry 2). Despite these promising results, further
experiments using ethanol revealed the yields to be
inconsistent, and the formation of varying amounts of ethyl
4-chlorobenzoate originating from 1a and ethanol was
observed. As a result, an alternative solvent was desired. A
solvent screening revealed tetrahydrofuran (THF) and chloro-
form as effective solvents for this reaction (entries 3−8). The
reaction using catalyst precursor B in chloroform at reflux
temperature with 1.5 equiv of aldehyde afforded 3a in 78%
yield (entry 7). The reaction in THF at reflux temperature
with 1.2 equiv of aldehyde gave 3a in 77% yield (entry 8).
Chloroform was not considered for further reactions due to its
potential toxicity. As a result, THF was chosen as the solvent
for all further reactions. To test whether catalyst precursor B
was the optimal salt for this reaction, a catalyst screening was
conducted. Thiazolium salt A proved to be poorly soluble in
THF and yielded the desired product in only 46% yield (entry
9). No product was detected with the use of triazolium salt C
(entry 10). Benzimidazolium salt D and imidazo[1,5-a]-
pyridinium salt E led to the yields lower than salt B (58 and
15%, entries 11 and 12, respectively). The reaction conditions
were then examined using thiazolium salt B. Reduction of the
reaction time to 6 h dramatically decreased the yield to only
Scheme 2. Previous Work and This Work
b
Table 1. Catalyst and Condition Screening
entry
pre-cat.
X equiv
solvent
temp (°C)
time (h)
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
A
B
B
B
B
B
B
B
A
C
D
E
B
B
B
B
1.2
1.2
2
EtOH
EtOH
CH2Cl2
DMSO
iPr2O
MeCN
CHCl3
THF
THF
THF
THF
THF
70
70
reflux
70
reflux
70
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
r.t.
48
48
48
48
24
48
24
48
48
48
48
48
6
71
82
68
34
45
4
78
77
46
n.d.
58
15
38
88
90
41
1.0
1.2
1.0
1.5
1.2
1.2
1.2
1.2
1.2
1.2
2
a
a
a
THF
THF
THF
THF
48
24
24
1.5
2
a
b
DBU (20 mol %) was used as the base. n.d. = not detected.
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a
Scheme 3. Aldehyde Substrate Screening
a
b
2 equiv of aldehyde. n.d. = not detected.
38% (entry 13). Further adjustments to the aldehyde loading
revealed that a larger excess of aldehyde could significantly
improve the yield. Compound 3a was obtained in 88% yield
after 48 h at reflux temperature using 2 equiv of aldehyde in
comparison to 77% when 1.2 equiv was used (entries 14 and 8,
respectively). Further adjustments of the aldehyde loading
revealed 1.5 equiv to be appropriate as 3a was afforded in 90%
yield with a reaction time of only 24 h (entry 15). Reducing
the reaction temperature to room temperature negatively
impacted the yield with the reaction affording the desired
compound in only 41% yield, even with an increased aldehyde
loading of 2 equiv (entry 16). The results of these screening
reactions revealed the conditions shown in entry 15 to be
optimal.
With the optimal conditions investigated, the substrate
screening began with aromatic aldehydes. The reaction with
both benzaldehyde and 3-chlorobenzaldehyde proceeded
smoothly, yielding the desired products 3b and 3c in
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a
Scheme 4. Substrate Scope Expansion
a
n.d. = not detected.
g h
,
Table 2. Reactions with N,N,N′-Tris-Boc Aminals
entry
ab
aminal
pre-cat.
solvent
temp (°C)
time (h)
yield (%)
,
1
2
3
4
5
6
7
2g
2g
2g
2h
2h
2h
2h
A
A
B
A
B
A
B
EtOH
EtOH
EtOH
EtOH
EtOH
THF
70
70
70
70
70
reflux
reflux
48
48
48
48
48
24
24
73
cd
,
n.d.
n.d.
10
5
n.d.
cd
,
ce
,
ce
,
f
f
THF
n.d.
a
b
c
d
e
Pre-catalyst (40 mol %), Et3N (40 mol %), and 1a (3.3 equiv). 0.12 mmol scale. 3 Å molecular sieves were added. 0.22 mmol scale. 1 mmol
f
g
h
scale. 0.24 mmol scale. n.d. = not detected. Standard reaction conditions: 1a (1.5 equiv), 2g or 2h (1 equiv), pre-catalyst (20 mol %), and Et3N
(20 mol %).
quantitative yields (Scheme 3). 2-Chlorobenzaldehyde proved
to be a poor substrate for this reaction, with only a trace
amount of 3d being obtained. 4-Bromobenzaldehyde and 4-
fluorobenzaldehyde afforded the corresponding products 3e
and 3f in 94 and 73% yields, respectively. 4-Methoxybenzalde-
hyde provided α-amino ketone 3g in 73% yield. 3-
Methoxybenzaldehyde was also a good substrate for this
reaction, affording 3h in 68% yield. Heterocyclic aldehydes
proved to be suitable substrates for this reaction. The use of 2-
pyridinecarboxaldehyde and 3-pyridinecarboxaldehyde yielded
products 3i and 3j with yields of 60 and 24%, respectively.
Furfural and 2-thiophenecarboxaldehyde afforded the corre-
sponding products 3k and 3l in 68 and 93% yields,
respectively. 2-Napthaldehyde also proved to be a suitable
substrate in this reaction, providing 3m in 86% yield. Linear
aliphatic aldehydes afforded the desired products 3n−3q in
moderate to good yields (57−80%). More sterically demand-
ing aliphatic aldehydes such as cyclohexanecarboxaldehyde and
pivalaldehyde did not yield the desired products 3r and 3s,
respectively.
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Figure 1. Key mechanistic stepconversion of aminal 2a into imine 2a′.
Figure 2. Compound 2a in DMSO-d6 and CDCl3. Comparison of aminal 2a dissolved in DMSO-d6 (top) and CDCl3 (bottom) is shown. When
aminal 2a is dissolved in DMSO-d6, the equilibrium is shifted heavily toward aminal 2a, allowing for the observation of aminal 2a. When aminal 2a
is dissolved in CDCl3, the equilibrium is shifted heavily toward imine 2a′ and 2-aminopyridine, allowing for the clear observation of both imine 2a′
(blue triangles) and 2-aminopyridine (red circles).
Expansion of the substrate scope began with derivatives of
piperonal and 3,4-dimethoxybenzaldehyde (Scheme 4).
Benzodioxole aminal 2b gave product 4a in quantitative yield
when reacted with 4-chlorobenzaldehyde. Compound 4b was
obtained in 72% yield by the reaction of 2b with
butyraldehyde. The reaction between the dimethoxyphenyl-
substituted aminal 2c and 4-chlorobenzaldehyde afforded 4c in
87% yield. The use of 2c with butyraldehyde provided the
corresponding product 4d in 58% yield. To compare the
reactivity of N,N′-dipyridin-2-yl aminals with other N,N′-
substituted aminals, N,N′-bis(2-thiazolyl) and N,N′-bis-Boc-
substituted aminals were tested. N,N′-Bis(2-thiazolyl) aminal
2d provided no desired product 4e. N,N′-Bis-Boc aminal 2e
failed to afford the desired amino ketone 4f. N,N′-bis-Boc
aminals have previously been shown to be unreactive under
basic conditions by Kano and co-workers.20 The conversion20
of the corresponding N,N′-bis-Boc aminal 2f into N,N,N′-tris-
Boc aminal 2g allowed for the synthesis of amino ketone 4g in
73% yield (Table 2, entry 1). However, further experiments
revealed the reaction in ethanol to be poorly reproducible
(entries 2 and 3), similar to what was found with N,N′-
dipyridin-2-yl aminals. The formation of significant amounts of
ethyl 4-chlorobenzoate was observed in these reactions. Strict
exclusion of oxygen is likely necessary for reproducible high
yields when ethanol is used as the solvent. Reactions using
phenyl-substituted N,N,N′-tris-Boc aminal 2h gave the desired
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918 system equipped with JAIGEL-1HR and JAIGEL-2HR columns
using chloroform as the solvent. Merck thin-layer chromatography
(TLC) plates (silica gel 60G F254 0.25 mm) were used. TLC plates
were visualized by fluorescence under a UV lamp (254 or 365 nm).
1H NMR was recorded on a JEOL JNM-ECX (500 MHz) or a Bruker
Ascend 400 (400 MHz) spectrometer. Chemical shifts were recorded
in parts per million (ppm, δ), relative to tetramethylsilane (δ 0.00).
1H NMR splitting patterns are reported as singlet (s), doublet (d),
triplet (t), dd (doublet of doublets), dt (doublet of triplets), m
(multiplet), etc. 13C NMR spectra were recorded on a JEOL JNM-
ECX (125 MHz) spectrometer or a Bruker Ascend 400 (100 MHz)
spectrometer. Mass spectra were recorded using a TOF (ESI)
analyzer or a magnetic sector (FAB) analyzer. Melting points were
measured using an ATM-02, AS ONE melting point apparatus and
were uncorrected.
General Procedure for the Synthesis of N,N′-Dipyridin-2-yl
Aminals (General Procedure A). 2-Aminopyridine was added to a
dried flask containing activated 4 Å molecular sieves and a magnetic
stirring bar. The flask was then purged with argon. Aldehyde (1 equiv)
and dehydrated toluene (20 mL for the 10 mmol scale; 10 mL for the
6 mmol scale) were added, and the reaction mixture was stirred under
argon for 24 h at 70 °C in an EYELA ChemiStation Personal
Synthesizer PPS-CTRL1 machine. The mixture was then filtered and
washed with hot toluene. The filtrate was concentrated under reduced
pressure, yielding either an off-white powder or a yellow oil. The
powder was washed with cool ether and dried in vacuo. The oil was
allowed to crystallize overnight. The crystals were then filtered,
washed with cool ether, and dried in vacuo. Oils which did not
crystallize overnight where purified by silica gel medium-pressure
liquid chromatography (5% ethyl acetate in n-hexane).
product 4h in 10% yield when pre-catalyst A was used and 5%
yield when pre-catalyst B was used (entries 4 and 5,
respectively). When N,N,N′-tris-Boc aminal 2h was used
with the optimized conditions previously found, the desired α-
amino ketone 4h was not observed (entries 6 and 7).
The reaction most likely proceeds through an aza-benzoin
condensation mechanism. The prerequisite step for this
transformation using aminals is the conversion of the aminal
into the imine. With N,N′-dipyridin-2-yl aminals, hydrogen
bonding between the amine hydrogen atom and the pyridine’s
nitrogen atom likely promotes the leaving group ability of the
aminopyridine moiety (Figure 1). The increased leaving group
ability of the aminopyridine moiety allows for the conversion
of the starting aminal into the imine. Reaction between the
intermediate imine and the Breslow intermediate leads to the
formation of the desired α-amino ketone.16
Conversion of aminal 2a into imine 2a′ and 2-aminopyridine
1
at room temperature can be observed by H NMR. When
aminal 2a was dissolved in DMSO-d6, only a trace amount of
imine 2a′ can be observed (Figure 2, top). However, when
aminal 2a was dissolved in CDCl3, imine 2a′ and 2-
aminopyridine were clearly observed. A characteristic imine
singlet from imine 2a′ was observed at 9.14 ppm, and the
amine protons from 2-aminopyridine were observed as a broad
singlet at 4.40 ppm when 2a was dissolved in CDCl3 (Figure 2,
bottom). These data help confirm both the synthesis of aminal
2a and the proposed mechanistic step of the in situ formation
of the desired, reactive imine 2a′ from aminal 2a.
1-Phenyl-N,N′-di-2-pyridinylmethanediamine (2a).21,22 The
compound was prepared from benzaldehyde (1.02 mL, 10 mmol)
and 2-aminopyridine (1.88 g, 20 mmol) following general procedure
A. White solid; 2.48 g, 90% yield; 1H NMR (500 MHz, DMSO-d6): δ
7.93−7.88 (m, 2H), 7.44 (d, J = 7.7 Hz, 2H), 7.37−7.19 (m, 5H),
7.00 (d, J = 7.8 Hz, 2H), 6.86 (t, J = 7.7 Hz, 1H), 6.55 (d, J = 8.8 Hz,
2H), 6.47 (t, J = 6.5 Hz, 2H). 13C NMR (125 MHz, DMSO-d6): δ
158.2, 148.0, 143.1, 137.2, 128.6, 127.7, 127.3, 112.8, 109.1, 61.6.
1-(1,3-Benzodioxol-5-yl)-N,N′-di-2-pyridinylmethane-diamine
(2b).22 The compound was prepared from 1,3-benzodioxole-5-
carbaldehyde (900 mg, 6 mmol) and 2-aminopyridine (1.13 g, 12
mmol) following general procedure A. Off-white solid; 1.42 g, 74%
yield; 1H NMR (400 MHz, DMSO-d6): δ 8.00−7.93 (m, 2H), 7.43−
7.34 (m, 2H), 7.04 (d, J = 1.7 Hz, 1H), 7.01−6.94 (m, 3H), 6.87 (d, J
= 8.0 Hz, 1H), 6.78 (t, J = 7.6 Hz, 1H), 6.61−6.55 (m, 2H), 6.55−
6.49 (m, 2H), 5.99 (s, 2H). 13C NMR (100 MHz, DMSO-d6): δ
158.0, 148.0, 147.6, 146.8, 137.2, 137.1, 120.4, 112.8, 108.9, 108.3,
107.6, 101.3, 61.5.
1-(3,4-Dimethoxyphenyl)-N,N′-di-2-pyridinylmethane-diamine
(2c).22 The compound was prepared from 3,4-dimethoxybenzalde-
hyde (895 μL, 6 mmol) and 2-aminopyridine (1.13 g, 12 mmol)
following general procedure A. Off-white solid; 1.80 g, 89% yield; 1H
NMR (400 MHz, DMSO-d6): δ 8.00−7.93 (m, 2H), 7.43−7.34 (m,
2H), 7.13 (s, 1H), 7.05−6.98 (m, 1H), 6.98−6.87 (m, 3H), 6.79 (t, J
= 7.6 Hz, 1H), 6.59 (d, J = 8.3 Hz, 2H), 6.55−6.48 (m, 2H), 3.74 (d,
J = 4.2 Hz, 6H). 13C NMR (100 MHz, DMSO-d6): δ 158.2, 149.1,
148.6, 148.0, 137.2, 135.4, 119.2, 112.8, 112.0, 111.2, 108.8, 61.7,
56.1, 56.0.
CONCLUSIONS
■
In conclusion, α-amino ketones have been synthesized from
N,N′-dipyridin-2-yl aminals via the NHC-catalyzed aza-
benzoin condensation reaction. The aminals provide stable,
easily synthesized, and easily handled imine precursors. The
reaction using mesityl-substituted thiazolium salt B showed
good tolerance to both aromatic and aliphatic aldehydes. Yields
were typically good to excellent when aromatic aldehydes were
used. Yields were moderate when linear aliphatic aldehydes
were used. The reaction was applied to a variety of different
N,N′-dipyridin-2-yl aminals, obtaining up to quantitative yields
of the corresponding N-pyridin-2-yl α-amino ketones. Previous
reports show that N-pyridin-2-yl groups can be removed with
high yields using multiple methods.19 Additionally, we have
uncovered evidence that N-Boc-protected α-amino ketones
can be directly synthesized from N,N,N′-tris-Boc aminals using
the aza-benzoin condensation reaction. Further investigation of
the reaction conditions necessary to realize an effective,
reproducible transformation of N,N,N′-tris-Boc aminals to α-
amino ketones is currently underway in our laboratory.
EXPERIMENTAL SECTION
■
General Information. Reagents and solvents were purchased
from commercial sources. Solid aldehydes were used without further
purification. Liquid aldehydes were purified by distillation before use.
All other reagents were used without further purification. All solvents
were of the dehydrated or super dehydrated form. All reactions were
performed under argon and stirring unless otherwise noted. Column
chromatography was performed using spherical silica gel (63−219
μm) (Kanto Chemicals). Medium-pressure liquid chromatography
was performed using a Yamazen EPC LC W-Prep 2XY system
equipped with a Yamazen Ultra Pack B silica column or a Yamazen
Hi-Flash silica column. Recycling size-exclusion chromatography was
conducted using a Japan Analytical Industry (JAI) recycling
preparative high-performance liquid chromatography (HPLC) LC-
1-Phenyl-N,N′-bis(2-thiazolyl)methanediamine (2d).23 2-Amino-
thiazole (1.00 g, 10 mmol, 2 equiv) was added to a flask containing 3
Å molecular sieves. The flask was then purged with argon. Distilled
benzaldehyde (510 μL, 5 mmol, 1 equiv) and dehydrated toluene (5
mL) were subsequently added by syringe. The mixture was stirred for
16 h at 70 °C. The reaction mixture was then filtered (washed with
hot toluene), and the solvent was removed under reduced pressure.
The title product was obtained as a yellow solid and was recrystallized
1
from n-hexane/ethyl acetate (350 mg, 25% yield). H NMR (400
MHz, DMSO-d6): δ 8.36 (d, J = 7.3 Hz, 2H), 7.54−7.48 (m, 2H),
7.42−7.30 (m, 3H), 7.03 (d, J = 3.6 Hz, 2H), 6.67 (d, J = 3.6 Hz,
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2H), 6.49 (t, J = 7.2 Hz, 1H). HRMS (ESI) m/z: [M + Na]+ calcd for
C13H12N4S2Na, 311.0401; found, 311.0399.
resulting mixture was purified by silica gel medium-pressure liquid
chromatography (9:1 n-hexane/ethyl acetate). Further purification
was conducted, as necessary, by a second run of silica gel medium-
pressure liquid chromatography (9:1 n-hexane/ethyl acetate),
followed by, for oils, recycling size-exclusion HPLC (JAIGEL-1HR
and JAIGEL-2HR columns, with chloroform as the solvent) or, for
solids, recrystallization.
1-(4-Chlorophenyl)-2-(2-pyridinylamino)-2-phenylethanone
(3a). The title compound was prepared following general procedure B
with 4-chlorobenzaldehyde (105 mg, 0.75 mmol). Purified by silica
gel medium-pressure liquid chromatography (9:1 n-hexane/ethyl
acetate). Recrystallized from EtOH. White solid; 145.8 mg, 90% yield;
Rf ca. 0.15 (9:1 n-hexane/ethyl acetate); mp: 122−123 °C; 1H NMR
(500 MHz, CDCl3): δ 8.05−8.02 (m, 1H), 8.00−7.94 (m, 2H),
7.47−7.43 (m, 2H), 7.41−7.34 (m, 3H), 7.33−7.28 (m, 2H), 7.26−
7.22 (m, 2H), 6.63 (d, J = 7.3 Hz, 1H), 6.58−6.54 (m, 1H), 6.49 (d, J
= 8.4 Hz, 1H), 5.68 (d, J = 7.3 Hz, 1H). 13C NMR (125 MHz,
CDCl3): δ 196.8, 156.9, 147.9, 139.9, 137.7, 137.3, 133.7, 130.5,
129.3, 129.1, 128.5, 128.4, 113.8, 109.2, 60.4. HRMS (FAB) m/z: [M
+ H]+ calcd for C19H16ClN2O, 323.0946; found, 323.0962.
Di-tert-butyl (Phenylmethylene)dicarbamate (2e).24,25 tert-Butyl
carbamate (1.3 g, 11 mmol) was added to a flask which was then
purged with argon. Benzaldehyde (670 μL, 6.6 mmol) was added by
syringe, followed by acetic anhydride (1.5 mL). Trifluoroacetic acid
(41 μL, 0.55 mmol) was then added. The mixture was stirred at room
temperature for 18 h. The aminal precipitated from the solution as a
white solid. The solid was filtered off and washed with n-hexane (880
mg, 49% yield). 1H NMR (500 MHz, CDCl3): δ 7.44−7.27 (m, 5H),
6.10 (t, J = 7.9 Hz, 1H), 5.43 (br s, 2H), 1.44 (s, 18H).
Di-tert-butyl (4-Methoxyphenylmethylene)dicarbamate (2f).24
tert-Butyl carbamate (640 mg, 5.5 mmol) was added to a flask
which was then purged with argon. p-Anisaldehyde (400 μL, 3.3
mmol) was added by syringe, followed by acetic anhydride (750 μL).
Trifluoroacetic acid (21 μL, 0.27 mmol) was then added. The mixture
was stirred at room temperature for 24 h. The aminal precipitated
from the solution as a white solid. The solid was filtered off and
washed with n-hexane (454 mg, 47%). 1H NMR (400 MHz, CDCl3):
δ 7.35−7.28 (m, 2H), 6.92−6.84 (m, 2H), 6.05 (t, J = 7.8 Hz, 1H),
5.36 (br s, 2H), 3.80 (s, 3H), 1.44 (s, 18H).
1,2-Diphenyl-2-(2-pyridinylamino)ethanone (3b). 3-Mesityl-4,5-
dimethylthiazol-3-ium perchlorate (332 mg, 1.0 mmol) was added to
a dried two-necked flask. The flask was then purged with argon.
Triethylamine (140 μL, 1.0 mmol) and super dehydrated THF (5
mL) were then added. The mixture was stirred under argon for 5 min
at room temperature. Aminal 2a (1.45 g, 5 mmol) and benzaldehyde
(770 μL, 1.5 equiv, 7.5 mmol) were then added. The flask was flushed
with argon, and the reaction mixture was stirred under an argon
atmosphere at reflux for 24 h in an EYELA ChemiStation Personal
Synthesizer PPS-CTRL1 machine. The solvent was removed under
reduced pressure, and the resulting mixture was purified by silica gel
medium pressure liquid chromatography (9:1 n-hexane/ethyl acetate)
to afford the title compound as a yellow-white solid. The solid was
recrystallized from ethanol, yielding a white solid (1.45 g, 95% yield).
The reaction at the 0.5 mmol scale with 1.5 equiv of benzaldehyde
(76 μL) afforded the title compound in 96% yield (138 mg). The
reaction at the 0.5 mmol scale with 2 equiv of benzaldehyde (102 μL)
afforded the title compound in 99% yield (143 mg). Rf ca. 0.19 (9:1 n-
hexane/ethyl acetate); mp: 108−109 °C; 1H NMR (500 MHz,
CDCl3): δ 8.07−8.01 (m, 3H), 7.54−7.45 (m, 3H), 7.44−7.38 (m,
2H), 7.38−7.33 (m, 1H), 7.32−7.26 (m, 2H), 7.24−7.19 (m, 1H),
6.68 (d, J = 7.3 Hz, 1H), 6.58−6.52 (m, 1H), 6.49 (d, J = 8.1 Hz,
1H), 5.80 (d, J = 7.4 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ 197.8,
157.0, 148.0, 138.1, 137.2, 135.3, 133.5, 129.1, 128.7, 128.5, 128.2,
113.6, 109.1, 60.3. HRMS (ESI) m/z: [M + H]+ calcd for
C19H17N2O, 289.1336; found, 289.1341.
N,N,N′-Tris(tert-butoxycarbonyl)-1,1-diamino-1-(4-methoxy-
phenyl)methane (2g). The procedure is based on the work of Kano
and co-workers.20 Aminal 2f (454 mg, 1 mmol) was added to a dried
flask containing 4-(dimethylamino)pyridine (16 mg, 0.13 mmol). The
flask was then purged with argon. Dry THF (6 mL) was added, and
the flask was then cooled to 0 °C. Freshly distilled di-tert-butyl
dicarbonate (450 μL, 2.2 mmol) was then added. The reaction
mixture was stirred at 0 °C for 48 h. Aqueous NH4Cl solution (10
mL) was added, and the mixture was extracted with CH2Cl2 twice.
The organic layers were combined, washed with brine, and dried with
Na2SO4. The mixture was filtered, and the solvent was removed under
reduced pressure. The resulting oil was purified by silica gel medium-
pressure liquid chromatography (9:1 n-hexane/ethyl acetate). The
title compound was obtained as a colorless oil. 303 mg; 52% yield; Rf
ca. 0.38 (9:1 n-hexane/ethyl acetate). 1H NMR (500 MHz, CDCl3): δ
7.23 (d, J = 8.4 Hz, 2H), 7.04 (d, J = 10.6 Hz, 1H), 6.84 (d, J = 8.8
Hz, 2H), 5.97 (d, J = 10.7 Hz, 1H), 3.76 (s, 3H), 1.46 (s, 9H), 1.39
(s, 18H). 13C NMR (125 MHz, CDCl3): δ 159.1, 154.8, 152.2, 131.4,
126.6, 113.8, 83.2, 80.1, 64.9, 55.4, 28.4, 28.0. HRMS (ESI) m/z: [M
+ Na]+ calcd for C23H36N2O7Na, 475.2421; found, 475.2415.
N,N,N′-Tris(tert-butoxycarbonyl)-1,1-diamino-1-phenylmethane
(2h). The synthesis of this compound has been reported by Kano and
co-workers.20 Aminal 2e (2.04 g, 6.3 mmol) was added to a dried flask
containing 4-(dimethylamino)pyridine (230 mg, 1.88 mmol). The
flask was then purged with argon. Dry THF (20 mL) was added, and
the flask was then cooled to 0 °C. Freshly distilled di-tert-butyl
dicarbonate (2.18 mL, 9.47 mmol) was then added. The reaction
mixture was stirred at 0 °C for 48 h. Aqueous NH4Cl solution (30
mL) was added, and the mixture was extracted with CH2Cl2 twice.
The organic layers were combined, washed with brine, and dried with
Na2SO4. The mixture was filtered, and the solvent was removed under
reduced pressure. The resulting oil was purified by silica gel medium-
pressure liquid chromatography (9:1 n-hexane/ethyl acetate). The
title compound was obtained as a colorless oil which crystallized
overnight in a freezer into a white solid (1.45 g, 54% yield). 1H NMR
(500 MHz, CDCl3): δ 7.30 (d, J = 4.6 Hz, 4H), 7.26−7.18 (m, 1H),
7.11 (d, J = 10.6 Hz, 1H), 5.96 (d, J = 10.6 Hz, 1H), 1.46 (s, 9H),
1.36 (s, 18H).
1-(3-Chlorophenyl)-2-(2-pyridinylamino)-2-phenylethan-one
(3c). The title compound was prepared following general procedure B
with 3-chlorobenzaldehyde (105 mg, 0.75 mmol). Purified by silica
gel medium-pressure liquid chromatography (9:1 n-hexane/ethyl
acetate). Yellow oil; 160 mg, 99% yield; Rf ca. 0.12 (9:1 n-hexane/
1
ethyl acetate); H NMR (500 MHz, CDCl3): δ 8.06−8.02 (m, 1H),
8.02−7.98 (m, 1H), 7.93−7.88 (m, 1H), 7.50−7.43 (m, 3H), 7.40−
7.28 (m, 4H), 7.28−7.20 (m, 1H), 6.63 (d, J = 7.1 Hz, 1H), 6.57 (dd,
J = 7.3, 5.1 Hz, 1H), 6.50 (d, J = 8.4 Hz, 1H), 5.69 (d, J = 7.1 Hz,
1H). 13C NMR (125 MHz, CDCl3): δ 196.9, 156.9, 147.8, 137.4,
137.3, 137.0, 135.0, 133.3, 130.0, 129.3, 129.1, 128.5, 128.5, 127.2,
113.8, 109.2, 60.6. HRMS (FAB) m/z: [M + H]+ calcd for
C19H16ClN2O, 323.0946; found, 323.0936.
General Procedure for the Synthesis of α-Amino Ketones
(General Procedure B). 3-Mesityl-4,5-dimethylthiazol-3-ium per-
chlorate (thiazolium salt B; 33 mg, 0.1 mmol) was added to a dried
two-necked flask. The flask was then purged with argon. Triethyl-
amine (14 μL, 0.1 mmol) and super dehydrated THF (3 mL) were
then added. The mixture was stirred under argon for 5 min at room
temperature. Aminal 2a (138 mg, 0.5 mmol) and aldehyde (0.75 or 1
mmol) were then added. The flask was flushed with argon, and the
reaction mixture was stirred under an argon atmosphere at reflux for
24 h in an EYELA ChemiStation Personal Synthesizer PPS-CTRL1
machine. The solvent was removed under reduced pressure, and the
1-(4-Bromophenyl)-2-(2-pyridinylamino)-2-phenyl-ethanone
(3e). The title compound was prepared following general procedure B
with 4-bromobenzaldehyde (139 mg, 0.75 mmol). Purified by silica
gel medium-pressure liquid chromatography (9:1 n-hexane/ethyl
acetate). Recrystallized from EtOH. White solid; 173 mg, 94% yield;
Rf ca. 0.17 (9:1 n-hexane/ethyl acetate); mp: 136−137 °C; 1H NMR
(500 MHz, CDCl3): δ 8.06−8.01 (m, 1H), 7.92−7.86 (m, 2H),
7.57−7.51 (m, 2H), 7.48−7.42 (m, 2H), 7.39−7.33 (m, 1H), 7.33−
7.27 (m, 2H), 7.27−7.21 (m, 1H), 6.62 (d, J = 7.2 Hz, 1H), 6.59−
6.53 (m, 1H), 6.49 (d, J = 8.3 Hz, 1H), 5.67 (d, J = 7.3 Hz, 1H). 13C
NMR (125 MHz, CDCl3): δ 197.0, 156.9, 147.9, 137.7, 137.3, 134.1,
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132.0, 130.6, 129.3, 128.7, 128.5, 128.4, 113.8, 109.2, 60.4. HRMS
(ESI) m/z: [M + H]+ calcd for C19H16BrN2O, 367.0441; found,
367.0444.
1H), 7.25−7.29 (m, 1H), 7.30−7.41 (m, 4H), 7.46−7.50 (m, 2H),
8.04 (dd, J = 5.2, 1.1 Hz, 1H), 8.27 (dt, J = 7.8, 1.9 Hz, 1H), 8.71 (dd,
J = 5.2, 1.7 Hz, 1H), 9.25 (d, J = 1.7 Hz, 1H). 13C NMR (125 MHz,
CDCl3): δ 197.2, 156.8, 153.6, 150.3, 147.8, 137.3, 137.0, 136.3,
131.1, 129.4, 128.6, 123.7, 113.9, 109.2, 61.1. HRMS (ESI) m/z: [M
+ H]+ calcd for C18H16N3O, 290.1288; found, 290.1299.
1-(4-Fluorophenyl)-2-(2-pyridinylamino)-2-phenylethan-one
(3f). The title compound was prepared following general procedure B
with 4-fluorobenzaldehyde (80.5 μL, 0.75 mmol). Purified by silica gel
medium-pressure liquid chromatography (9:1 n-hexane/ethyl ac-
etate). Recrystallized twice from n-hexane/ethyl acetate. White solid;
111 mg, 73% yield; Rf ca. 0.18 (9:1 n-hexane/ethyl acetate); mp:
1-(2-Furanyl)-2-(2-pyridinylamino)-2-phenylethanone (3k). 3-
Mesityl-4,5-dimethylthiazol-3-ium perchlorate (132.7 mg, 0.4 mmol)
was added to a dried two-necked flask containing a magnetic stirring
bar. The flask was then purged with argon. Triethylamine (60 μL, 0.4
mmol) and super dehydrated THF (5 mL) were then added. The
mixture was stirred under argon for 5 min at room temperature.
Aminal 2a (552.7 mg, 2 mmol) and furfural (250 μL, 1.5 equiv, 3
mmol) were then added. The flask was flushed with argon, and the
reaction mixture was stirred under an argon atmosphere at reflux for
24 h in an EYELA ChemiStation Personal Synthesizer PPS-CTRL1
machine. The solvent was removed under reduced pressure, and the
resulting mixture was purified by silica gel medium-pressure liquid
chromatography (9:1 n-hexane/ethyl acetate) to afford the title
compound as a yellow-white solid. The solid was recrystallized from
an n-hexane/ethyl acetate mixture, yielding a white solid. 379 mg,
68% yield; Rf ca. 0.23 (4:1 n-hexane/ethyl acetate); mp: 106−108 °C;
1H NMR (500 MHz, CDCl3): δ 8.06−8.02 (m, 1H), 7.59−7.56 (m,
1H), 7.55−7.50 (m, 2H), 7.38−7.28 (m, 4H), 7.28−7.21 (m, 1H),
6.57−6.53 (m, 1H), 6.52−6.48 (m, 1H), 6.47 (d, J = 8.1 Hz, 1H),
6.39 (d, J = 6.9 Hz, 1H), 5.75 (d, J = 7.4 Hz, 1H). 13C NMR (125
MHz, CDCl3): δ 186.2, 156.9, 151.2, 148.1, 147.0, 137.8, 137.3,
129.0, 128.4, 128.3, 119.1, 113.7, 112.6, 108.8, 60.6. HRMS (ESI) m/
z: [M + H]+ calcd for C17H15N2O2, 279.1128; found, 279.1146.
1-(2-Thienyl)-2-(2-pyridinylamino)-2-phenylethanone (3l). The
title compound was prepared following general procedure B with
thiophene-2-carbaldehyde (70 μL; 0.75 mmol). Purified by silica gel
medium-pressure liquid chromatography (9:1 n-hexane/ethyl ac-
etate). Yellow oil; 137 mg, 93% yield; Rf ca. 0.19 (4:1 n-hexane/ethyl
acetate); 1H NMR (500 MHz, CDCl3): δ 8.07−8.01 (m, 1H), 7.88−
7.82 (m, 1H), 7.64−7.57 (m, 1H), 7.55−7.47 (m, 2H), 7.39−7.28
(m, 3H), 7.28−7.23 (m, 1H), 7.11−7.03 (m, 1H), 6.59−6.52 (m,
1H), 6.51−6.42 (m, 2H), 5.70 (d, J = 7.6 Hz, 1H). 13C NMR (125
MHz, CDCl3): δ 190.4, 156.9, 148.0, 141.8, 138.3, 137.3, 134.4,
133.5, 129.1, 128.4, 128.3, 128.3, 113.8, 109.0, 61.5. HRMS (FAB)
m/z: [M + H]+ calcd for C17H15N2OS, 295.0900; found, 295.0893.
1-(2-Naphthyl)-2-(2-pyridinylamino)-2-phenylethan-one (3m).
The title compound was prepared following general procedure B
with 2-naphthaldehyde (117 mg, 0.75 mmol). Purified by silica gel
medium-pressure liquid chromatography (9:1 n-hexane/ethyl ac-
etate). Yellow oil; 146 mg, 86% yield; Rf ca. 0.13 (9:1 n-hexane/ethyl
1
105−106 °C; H NMR (500 MHz, CDCl3): δ 8.11−8.02 (m, 3H),
7.50−7.43 (m, 2H), 7.39−7.33 (m, 1H), 7.33−7.27 (m, 2H), 7.27−
7.20 (m, 1H), 7.11−7.03 (m, 2H), 6.67 (d, J = 7.4 Hz, 1H), 6.58−
6.53 (m, 1H), 6.49 (d, J = 8.2 Hz, 1H), 5.76 (d, J = 7.3 Hz, 1H). 13C
NMR (125 MHz, CDCl3): δ 196.4, 165.9 (d, J = 257.2 Hz), 157.0,
147.9, 138.0, 137.2, 131.78 (d, J = 9.6 Hz), 131.76 (d, J = 3.6 Hz),
129.2, 128.5, 128.3, 115.9 (d, J = 22.2 Hz), 113.7, 109.2, 60.3. HRMS
(ESI) m/z: [M + H]+ calcd for C19H16FN2O, 307.1241; found,
307.1234.
1-(4-Methoxyphenyl)-2-(2-pyridinylamino)-2-phenyl-ethanone
(3g). The title compound was prepared following general procedure B
with p-anisaldehyde (91 μL, 0.75 mmol). Purified by silica gel
medium-pressure liquid chromatography (9:1 n-hexane/ethyl ac-
etate). Note: elution of the title compound during column
chromatography is slow using a mixture of 9:1 n-hexane/ethyl
acetate. However, 9:1 n-hexane/ethyl acetate provided good
separation compared to other ratios. Colorless oil; 116 mg, 73%
1
yield; Rf ca. 0.07 (9:1 n-hexane/ethyl acetate); H NMR (500 MHz,
CDCl3): δ 8.07−8.00 (m, 3H), 7.51−7.45 (m, 2H), 7.37−7.32 (m,
1H), 7.31−7.26 (m, 2H), 7.23−7.18 (m, 1H), 6.90−6.86 (m, 2H),
6.63 (d, J = 7.2 Hz, 1H), 6.56−6.52 (m, 1H), 6.48 (d, J = 8.5 Hz,
1H), 5.85 (d, J = 7.4 Hz, 1H), 3.82 (s, 3H). 13C NMR (125 MHz,
CDCl3): δ 197.8, 157.0, 148.0, 138.1, 137.2, 135.3, 133.5, 129.1,
128.7, 128.5, 128.2, 113.6, 109.1, 60.3. HRMS (ESI) m/z: [M + H]+
calcd for C20H19N2O2, 319.1441; found, 319.1459.
1-(3-Methoxyphenyl)-2-(2-pyridinylamino)-2-phenyl-ethanone
(3h). The title compound was prepared following general procedure B
with m-anisaldehyde (91 μL, 0.75 mmol). Purified by silica gel
medium-pressure liquid chromatography (9:1 n-hexane/ethyl ac-
etate). Recrystallized from n-hexane/ethyl acetate. White solid; 108
mg, 68% yield; Rf ca. 0.08 (9:1 n-hexane/ethyl acetate); mp: 107−108
°C; 1H NMR (500 MHz, CDCl3): δ 8.07−8.02 (m, 1H), 7.64 (d, J =
8.1 Hz, 1H), 7.55−7.50 (m, 1H), 7.49−7.45 (m, 2H), 7.39−7.19 (m,
5H), 7.05 (dd, J = 8.2, 2.6 Hz, 1H), 6.64 (d, J = 7.3 Hz, 1H), 6.58−
6.52 (m, 1H), 6.49 (d, J = 8.6 Hz, 1H), 5.79 (d, J = 7.4 Hz, 1H), 3.80
(s, 3H). 13C NMR (125 MHz, CDCl3): δ 197.6, 159.8, 157.0, 148.0,
138.1, 137.2, 136.6, 129.7, 129.1, 128.5, 128.2, 121.7, 120.1, 113.6,
113.2, 109.1, 60.4, 55.5. HRMS (ESI) m/z: [M + H]+ calcd for
C20H19N2O2, 319.1441; found, 319.1453.
1
acetate); H NMR (500 MHz, CDCl3): δ 8.62 (s, 1H), 8.10−8.03
(m, 2H), 7.94 (d, J = 8.2 Hz, 1H), 7.84 (t, J = 8.9 Hz, 2H), 7.60−7.50
(m, 4H), 7.40−7.35 (m, 1H), 7.28 (t, J = 7.7 Hz, 2H), 7.23−7.17 (m,
1H), 6.85 (d, J = 7.3 Hz, 1H), 6.60−6.55 (m, 1H), 6.53 (d, J = 8.2
Hz, 1H), 5.87 (d, J = 7.4 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ
197.7, 157.1, 148.0, 138.2, 137.3, 135.8, 132.6, 132.5, 131.1, 129.8,
129.1, 128.8, 128.6, 128.5, 128.2, 127.8, 126.9, 124.6, 113.6, 109.2,
60.3. HRMS (FAB) m/z: [M + H]+ calcd for C23H19N2O, 339.1492;
found, 339.1510.
1-(2-Pyridinyl)-2-(2-pyridinylamino)-2-phenylethan-one (3i).
The title compound was prepared following general procedure B
with 2-pyridinecarboxaldehyde (71 μL, 0.75 mmol). Purified by silica
gel medium-pressure liquid chromatography (9:1 n-hexane/ethyl
acetate). Yellow solid; 86.7 mg, 60% yield; Rf ca. 0.11 (4:1 n-hexane/
1
ethyl acetate); mp: 122−123 °C; H NMR (500 MHz, CDCl3): δ
8.71 (d, J = 4.5 Hz, 1H), 8.05 (d, J = 4.9 Hz, 1H), 8.00 (d, J = 7.8 Hz,
1H), 7.80−7.73 (m, 1H), 7.59 (d, J = 7.4 Hz, 2H), 7.45−7.38 (m,
1H), 7.38−7.31 (m, 1H), 7.25 (t, J = 7.6 Hz, 2H), 7.18 (t, J = 7.3 Hz,
1H), 7.11 (d, J = 7.3 Hz, 1H), 6.57−6.51 (m, 1H), 6.47 (d, J = 8.4
Hz, 1H), 5.98 (d, J = 7.4 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ
197.8, 157.2, 151.8, 149.0, 148.3, 137.6, 137.4, 137.0, 128.7, 127.9,
127.5, 123.4, 113.5, 107.9, 59.3. HRMS (ESI) m/z: [M + H]+ calcd
for C18H16N3O, 290.1288; found, 290.1290.
1-Phenyl-1-(2-pyridinylamino)-2-pentanone (3n). 3-Mesityl-4,5-
dimethylthiazol-3-ium perchlorate (33 mg, 0.1 mmol) was added to a
dried two-necked flask containing a magnetic stirring bar. The flask
was then purged with argon. Triethylamine (14 μL, 0.1 mmol) and
super dehydrated THF (3 mL) were then added. The mixture was
stirred under argon for 5 min at room temperature. Aminal 2a (138
mg, 0.5 mmol) and butyraldehyde (90 μL, 2 equiv, 1 mmol) were
then added. The flask was flushed with argon, and the reaction
mixture was stirred under an argon atmosphere at reflux for 24 h in an
EYELA ChemiStation Personal Synthesizer PPS-CTRL1 machine.
The solvent was removed under reduced pressure, and the resulting
mixture was purified by two runs of silica gel medium-pressure liquid
chromatography (9:1 n-hexane/ethyl acetate) to afford the title
compound as a white solid (102 mg, 80% yield). Note: the title
compound usually appears as a yellow oil after the initial column.
1-(3-Pyridinyl)-2-(2-pyridinylamino)-2-phenylethan-one (3j).
The title compound was prepared following general procedure B
with 3-pyridinecarboxaldehyde (70 μL; 0.75 mmol). Purified by silica
gel medium-pressure liquid chromatography (9:1 n-hexane/ethyl
acetate). Recrystallized from n-hexane/ethyl acetate. White solid, 34.8
mg, 24% yield; Rf ca. 0.03 (4:1 n-hexane/ethyl acetate); mp: 160−162
°C; 1H NMR (500 MHz, CDCl3): δ 5.62 (d, J = 6.9 Hz, 1H), 6.52 (d,
J = 8.0 Hz, 1H), 6.58 (td, J = 6.0, 1.7 Hz, 1H), 6.62 (d, J = 7.4 Hz,
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Further purification [e.g., a second run of silica gel medium-pressure
liquid chromatography (9:1 n-hexane/ethyl acetate)] is sometimes
needed to yield the white solid form. Rf ca. 0.14 (9:1 n-hexane/ethyl
acetate); mp: 64−65 °C; 1H NMR (500 MHz, CDCl3): δ 8.05−8.00
(m, 1H), 7.46−7.40 (m, 2H), 7.39−7.27 (m, 4H), 6.56−6.50 (m,
1H), 6.37 (dt, J = 8.4, 1.0 Hz, 1H), 5.86 (d, J = 5.7 Hz, 1H), 5.50 (d, J
= 5.7 Hz, 1H), 2.53−2.34 (m, 2H), 1.64−1.44 (m, 2H), 0.78 (t, J =
7.4 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 207.0, 157.0, 148.1,
137.8, 137.2, 129.1, 128.4, 128.2, 113.5, 108.4, 65.3, 41.5, 17.3, 13.6.
HRMS (ESI) m/z: [M + H]+ calcd for C16H19N2O, 255.1492; found,
255.1500.
122.1, 113.7, 109.1, 108.8, 108.6, 101.2, 59.8. HRMS (ESI) m/z: [M
+ H]+ calcd for C20H16ClN2O3, 367.0844; found, 367.0861.
1-(1,3-Benzodioxol-5-yl)-1-(2-pyridinylamino)-2-pentanone
(4b). 3-Mesityl-4,5-dimethylthiazol-3-ium perchlorate (66.4 mg, 0.2
mmol) was added to a dried two-necked flask containing a magnetic
stirring bar. The flask was then purged with argon. Triethylamine (28
μL, 0.2 mmol) and super dehydrated THF (3 mL) were then added.
The mixture was stirred under argon for 5 min at room temperature.
Aminal 2b (320.4 mg, 1 mmol) and butyraldehyde (135 μL, 1.5
equiv, 1.5 mmol) were then added. The flask was flushed with argon,
and the reaction mixture was stirred under an argon atmosphere at
reflux for 24 h in an EYELA ChemiStation Personal Synthesizer PPS-
CTRL1 machine. The solvent was removed under reduced pressure,
and the resulting mixture was purified by silica gel medium-pressure
liquid chromatography (9:1 n-hexane/ethyl acetate). Recrystallization
from n-hexane/ethyl acetate afforded the title compound as a white
solid (216 mg, 72% yield). Rf ca. 0.23 (4:1 n-hexane/ethyl acetate);
mp: 66−67 °C; 1H NMR (400 MHz, CDCl3): δ 8.07−8.00 (m, 1H),
7.37−7.29 (m, 1H), 6.93 (dd, J = 8.0, 1.8 Hz, 1H), 6.88 (d, J = 1.8
Hz, 1H), 6.78 (d, J = 7.9 Hz, 1H), 6.58−6.50 (m, 1H), 6.38 (dt, J =
8.4, 1.0 Hz, 1H), 5.94 (q, J = 1.4 Hz, 2H), 5.87 (d, J = 5.7 Hz, 1H),
5.41 (d, J = 5.6 Hz, 1H), 2.53−2.34 (m, 2H), 1.68−1.44 (m, 2H),
0.82 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 206.8,
156.9, 148.2, 148.0, 147.6, 137.2, 131.5, 121.8, 113.5, 108.6, 108.3,
108.2, 101.3, 64.7, 41.4, 17.3, 13.6. HRMS (FAB) m/z: [M + H]+
calcd for C17H19N2O3, 299.1390; found, 299.1390.
1-(4-Chlorophenyl)-2-(2-pyridinylamino)-2-(3,4-dimethoxy-
phenyl)ethanone (4c). 3-Mesityl-4,5-dimethylthiazol-3-ium perchlo-
rate (66 mg, 0.2 mmol) was added to a dried two-necked flask
containing a magnetic stirring bar. The flask was then purged with
argon. Triethylamine (28 μL, 0.2 mmol) and super dehydrated THF
(3 mL) were then added. The mixture was stirred under argon for 5
min at room temperature. Aminal 2c (336.4 mg, 1 mmol) and 4-
chlorobenzaldehyde (210.9 mg, 1.5 equiv, 1.5 mmol) were then
added. The flask was flushed with argon, and the reaction mixture was
stirred under an argon atmosphere at reflux for 24 h in an EYELA
ChemiStation Personal Synthesizer PPS-CTRL1 machine. The
solvent was removed under reduced pressure, and the resulting
mixture was purified by silica gel medium pressure liquid
chromatography (9:1 n-hexane/ethyl acetate) to afford the title
compound as a white solid (332 mg, 87% yield). Rf ca. 0.12 (4:1 n-
hexane/ethyl acetate); mp: 150−151 °C; 1H NMR (500 MHz,
CDCl3): δ 8.06−8.01 (m, 1H), 8.00−7.93 (m, 2H), 7.41−7.33 (m,
3H), 7.01−6.94 (m, 2H), 6.78 (d, J = 8.0 Hz, 1H), 6.59−6.53 (m,
2H), 6.50 (dt, J = 8.4, 1.0 Hz, 1H), 5.62 (d, J = 7.2 Hz, 1H), 3.82 (d, J
= 12.6 Hz, 6H). 13C NMR (125 MHz, CDCl3): δ 196.9, 157.0, 149.6,
149.1, 147.9, 139.8, 137.3, 133.8, 130.4, 129.9, 129.0, 121.1, 113.8,
111.4, 111.1, 109.2, 60.2, 56.0, 55.9. HRMS (ESI) m/z: [M + Na]+
calcd for C21H19ClN2O3Na, 405.0982; found, 405.0971.
1-Phenyl-1-(2-pyridinylamino)-2-heptanone (3o). The title com-
pound was prepared following general procedure B with hexanal (92
μL, 0.75 mmol). Purified by silica gel medium-pressure liquid
chromatography (9:1 n-hexane/ethyl acetate). Yellow oil; 88.4 mg,
1
62% yield; Rf ca. 0.26 (4:1 n-hexane/ethyl acetate); H NMR (400
MHz, CDCl3): δ 8.05−7.97 (m, 1H), 7.47−7.38 (m, 2H), 7.36−7.20
(m, 4H), 6.54−6.44 (m, 1H), 6.35 (d, J = 8.4 Hz, 1H), 5.98 (d, J =
5.8 Hz, 1H), 5.52 (d, J = 5.7 Hz, 1H), 2.54−2.32 (m, 2H), 1.62−1.39
(m, 2H), 1.25−1.04 (m, 4H), 0.80 (t, J = 7.1 Hz, 3H). 13C NMR
(100 MHz, CDCl3): δ 207.0, 157.0, 147.9, 137.8, 137.1, 129.0, 128.2,
128.1, 113.4, 108.4, 65.2, 39.5, 31.1, 23.4, 22.3, 13.9. HRMS (ESI) m/
z: [M + H]+ calcd for C18H23N2O, 283.1805; found, 283.1798.
1-Phenyl-1-(2-pyridinylamino)-2-nonanone (3p). The title com-
pound was prepared following general procedure B with octanal (117
μL, 0.75 mmol). Purified by silica gel medium-pressure liquid
chromatography (9:1 n-hexane/ethyl acetate). Yellow oil; 88.5 mg,
1
57% yield; Rf ca. 0.14 (9:1 n-hexane/ethyl acetate); H NMR (500
MHz, CDCl3): δ 8.04−7.99 (m, 1H), 7.45−7.40 (m, 2H), 7.35−7.22
(m, 4H), 6.52−6.46 (m, 1H), 6.35 (d, J = 8.2 Hz, 1H), 5.97 (d, J =
5.7 Hz, 1H), 5.52 (d, J = 5.7 Hz, 1H), 2.52−2.36 (m, 2H), 1.60−1.40
(m, 2H), 1.26−1.07 (m, 8H), 0.83 (t, J = 7.1 Hz, 3H). 13C NMR
(125 MHz, CDCl3): δ 207.2, 157.1, 148.0, 137.9, 137.2, 129.1, 128.3,
128.2, 113.5, 108.5, 65.3, 39.6, 31.7, 29.0, 23.8, 22.6, 14.2. HRMS
(ESI) m/z: [M + H]+ calcd for C20H27N2O, 311.2118; found,
311.2136.
1-Phenyl-1-(2-pyridinylamino)-2-undecanone (3q). The title
compound was prepared following general procedure B with decanal
(141 μL, 0.75 mmol). Purified by silica gel medium-pressure liquid
chromatography (9:1 n-hexane/ethyl acetate). Yellow oil; 116 mg,
1
68% yield; Rf ca. 0.09 (9:1 n-hexane/ethyl acetate); H NMR (500
MHz, CDCl3): δ 8.04−8.00 (m, 1H), 7.45−7.40 (m, 2H), 7.36−7.24
(m, 4H), 6.54−6.48 (m, 1H), 6.36 (dt, J = 8.3, 1.0 Hz, 1H), 6.01 (d, J
= 5.8 Hz, 1H), 5.50 (d, J = 4.6 Hz, 1H), 2.53−2.33 (m, 2H), 1.61−
1.39 (m, 2H), 1.32−1.08 (m, 12H), 0.86 (t, J = 7.1 Hz, 3H). 13C
NMR (125 MHz, CDCl3): δ 207.1, 157.0, 147.9, 137.8, 137.3, 129.1,
128.4, 128.2, 113.5, 108.4, 65.3, 39.6, 31.9, 29.4, 29.32, 29.30, 29.0,
23.8, 22.7, 14.2. HRMS (ESI) m/z: [M + H]+ calcd for C22H31N2O,
339.2431; found, 339.2427.
1-(3,4-Dimethoxyphenyl)-1-(2-pyridinylamino)-2-pentanone
(4d). 3-Mesityl-4,5-dimethylthiazol-3-ium perchlorate (66.4 mg, 0.2
mmol) was added to a dried two-necked flask containing a magnetic
stirring bar. The flask was then purged with argon. Triethylamine (28
μL, 0.2 mmol) and super dehydrated THF (3 mL) were then added.
The mixture was stirred under argon for 5 min at room temperature.
Aminal 2c (336.4 mg, 1 mmol) and butyraldehyde (135 μL, 1.5 equiv,
1.5 mmol) were then added. The flask was flushed with argon, and the
reaction mixture was stirred under an argon atmosphere at reflux for
24 h in an EYELA ChemiStation Personal Synthesizer PPS-CTRL1
machine. The solvent was removed under reduced pressure, and the
resulting mixture was purified by silica gel medium-pressure liquid
chromatography (9:1 n-hexane/ethyl acetate) to afford the title
compound as a yellow oil (183.5 mg, 58% yield). Rf ca. 0.08 (4:1 n-
1-(4-Chlorophenyl)-2-(2-pyridinylamino)-2-(1,3-benzo-dioxol-5-
yl)ethanone (4a). 3-Mesityl-4,5-dimethylthiazol-3-ium perchlorate
(66.4 mg, 0.2 mmol) was added to a dried two-necked flask
containing a magnetic stirring bar. The flask was then purged with
argon. Triethylamine (28 μL, 0.2 mmol) and super dehydrated THF
(3 mL) were then added. The mixture was stirred under argon for 5
min at room temperature. Aminal 2b (320.4 mg, 1 mmol) and 4-
chlorobenzaldehyde (210.9 mg, 1.5 equiv, 1.5 mmol) were then
added. The flask was flushed with argon, and the reaction mixture was
stirred under an argon atmosphere at reflux for 24 h in an EYELA
ChemiStation Personal Synthesizer PPS-CTRL1 machine. The
solvent was removed under reduced pressure, and the resulting
mixture was purified by silica gel medium-pressure liquid chromatog-
raphy (9:1 n-hexane/ethyl acetate) to afford the title compound as a
white solid (364 mg, 99% yield). Rf ca. 0.07 (9:1 n-hexane/ethyl
1
hexane/ethyl acetate); H NMR (400 MHz, CDCl3): δ 8.07−8.01
(m, 1H), 7.37−7.28 (m, 1H), 7.02 (dd, J = 8.2, 2.1 Hz, 1H), 6.89 (d,
J = 2.1 Hz, 1H), 6.85 (d, J = 8.2 Hz, 1H), 6.58−6.50 (m, 1H), 6.38
(dt, J = 8.5, 1.0 Hz, 1H), 5.86 (d, J = 5.7 Hz, 1H), 5.44 (d, J = 5.6 Hz,
1H), 3.86 (d, J = 3.0 Hz, 6H), 2.54−2.33 (m, 2H), 1.68−1.44 (m,
2H), 0.81 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 207.1,
157.0, 149.5, 149.0, 147.9, 137.2, 130.0, 120.8, 113.4, 111.3, 110.6,
1
acetate); mp: 118−119 °C; H NMR (400 MHz, CDCl3): δ 8.08−
8.02 (m, 1H), 7.99−7.93 (m, 2H), 7.44−7.33 (m, 3H), 6.96−6.89
(m, 2H), 6.72 (d, J = 7.9 Hz, 1H), 6.62−6.45 (m, 3H), 5.93−5.88 (m,
2H), 5.67 (d, J = 7.2 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 196.5,
156.8, 148.2, 147.8, 147.6, 139.8, 137.1, 133.6, 131.4, 130.4, 129.0,
10232
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J. Org. Chem. 2021, 86, 10224−10234

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
108.3, 64.8, 55.9, 55.9, 41.3, 17.3, 13.6. HRMS (FAB) m/z: [M + H]+
calcd for C18H23N2O3, 315.1703; found, 315.1705.
Ryo Takashima − Department of Materials and Life Sciences,
Faculty of Science and Technology, Sophia University, Tokyo
102-8554, Japan
tert-Butyl-(2-(4-chlorophenyl)-1-(4-methoxyphenyl)-2-oxoethyl)-
carbamate26 (4g). 3-Benzyl-5-(2-hydroxyethyl)-4-methylthiazolium
chloride (10 mg, 0.037 mmol) was added to a dried two-necked flask
containing a magnetic stirring bar. The flask was then purged with
argon. Triethylamine (5.2 μL, 0.037 mmol) and dehydrated EtOH (3
mL) were then added. The mixture was stirred under argon for 5 min
at room temperature. Tris-Boc aminal 2g (54.6 mg, 0.12 mmol) and
4-chlorobenzaldehyde (56 mg, 3.3 equiv, 0.4 mmol) were then added.
The flask was flushed with argon, and the reaction mixture was stirred
under an argon atmosphere at 70 °C for 48 h in an EYELA
ChemiStation Personal Synthesizer PPS-CTRL1 machine. The
solvent was removed under reduced pressure, and the resulting
mixture was purified by silica gel medium pressure liquid
chromatography (9:1 n-hexane/ethyl acetate) to afford the title
compound as a yellow-white solid (32.9 mg, 73% yield). This
compound has been previously reported.26 1H NMR (500 MHz,
CDCl3): δ 7.89−7.82 (m, 2H), 7.36−7.29 (m, 2H), 7.27−7.21 (m,
2H), 6.83−6.77 (m, 2H), 6.15 (d, J = 7.5 Hz, 1H), 5.94 (d, J = 7.5
Hz, 1H), 3.71 (s, 3H), 1.41 (s, 9H). 13C NMR (125 MHz, CDCl3): δ
195.2, 159.7, 155.1, 140.0, 133.0, 130.5, 129.5, 129.2, 129.1, 114.7,
80.0, 59.4, 55.3, 28.4.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00973
Author Contributions
All authors have given approval to the final version of the
manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge Sophia University for financial
support. We also thank Ms. Emiko Okano of the Faculty of
Science and Technology, Sophia University, for mass
spectrometry measurements.
REFERENCES
tert-Butyl-(2-(4-chlorophenyl)-2-oxo-1-phenylethyl)carbamate26
(4h). 3-Mesityl-4,5-dimethylthiazol-3-ium perchlorate (66.4 mg, 0.2
mmol) or 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride
(54.0 mg, 0.2 mmol) and 3 Å molecular sieves were added to a dried
two-necked flask containing a magnetic stirring bar. The flask was
then purged with argon. Et3N (28 μL, 0.2 mmol) and dehydrated and
degassed (freeze−pump−thaw method, 4 cycles) ethanol were added.
The mixture was stirred under argon for 5 min at room temperature.
Aminal 2h (422.5 mg, 1 equiv, 1 mmol) and 4-chlorobenzaldehyde
(210.8 mg, 1.5 equiv, 1.5 mmol) were then added. The flask was
flushed with argon, and the flask was stirred under an argon
atmosphere at 70 °C for 48 h in an EYELA ChemiStation Personal
Synthesizer PPS-CTRL1 machine. The solvent was removed under
reduced pressure, and the resulting mixture was purified by silica gel
medium-pressure liquid chromatography (9:1 n-hexane/ethyl acetate)
to afford the title compound as a colorless oil which crystallized into a
white solid (17.4 mg, 5% yield when-mesityl-4,5-dimethylthiazol-3-
ium perchlorate was used as the pre-catalyst; 36 mg, 10% yield when
3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride was used as
the pre-catalyst). This compound has been previously reported.26 1H
NMR (500 MHz, CDCl3): δ 7.88 (d, J = 8.6 Hz, 2H), 7.38−7.28 (m,
6H), 7.27−7.22 (m, 1H), 6.20 (d, J = 7.6 Hz, 1H), 5.95 (d, J = 7.7
Hz, 1H), 1.42 (s, 9H).
■
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ASSOCIATED CONTENT
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Analytical data (1H and 13C NMR spectra, MS) for all
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AUTHOR INFORMATION
■
Corresponding Author
Yumiko Suzuki − Department of Materials and Life Sciences,
Faculty of Science and Technology, Sophia University, Tokyo
102-8554, Japan; orcid.org/0000-0002-8226-5867;
Email: yumiko_suzuki@sophia.ac.jp
Authors
Justin S. Lamb − Department of Materials and Life Sciences,
Faculty of Science and Technology, Sophia University, Tokyo
102-8554, Japan
10233
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Article
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