Enantioselective Mannich Reaction Employing 1,3,5-Triaryl-1,3,5-triazinanes Catalyzed by Chiral-at-Metal Rhodium Complexes

Article abstract of DOI:10.1002/ejoc.201700463

Chiral-at-metal Rh^III complexes catalyze the efficient enantioselective Mannich reaction of 2-acyl imidazoles with 1,3,5-triazinanes, affording the corresponding adducts in 81–99 % yield with up to >99 % enantioselectivity. This protocol performs with 0.1 mol-% of Rh^III complex on gram scale without any loss in enantioselectivity.

Full text of DOI:10.1002/ejoc.201700463

A Journal of
Accepted Article
Title: Highly Enantioselective Mannich Reaction Employing 1,3,5-
Triaryl-1,3,5-Triazinanes Catalyzed by Chiral-at-Metal Rhodium
Complexes
Authors: Jun Gong, Shi-Wu Li, Saira Qurban, and QIANG KANG
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700463
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10.1002/ejoc.201700463
European Journal of Organic Chemistry
FULL PAPER
Highly Enantioselective Mannich Reaction Employing 1,3,5-
Triaryl-1,3,5-Triazinanes Catalyzed by Chiral-at-Metal Rhodium
Complexes
Jun Gong,[a,b] Shi-Wu Li,[a,b] Saira Qurban,[a,b] and Qiang Kang*[a]
Abstract: Chiral-at-metal Rh(III) complexes catalyzed highly efficient
enantioselective Mannich reaction of 2-acyl imidazoles with 1,3,5-
triazinanes is developed, affording the corresponding adducts in 81-
99% yields with up to >99% enantioselectivities. This protocol
performs with 0.1 mol % of Rh(III) complex on gram scale without
loss in enantioselectivity.
Inspired by these works and as a continuation of our interest in
chiral-at-metal Lewis acid catalysts,[9-12] herein we report an
asymmetric Mannich reaction of 2-acyl imidazoles with 1,3,5-
triazinanes catalyzed by chiral-at-metal rhodium complexes,
delivering the corresponding β-amino derivatives in high yields
with good to excellent enantioselectivities (Scheme 1b).
Introduction
The Mannich reaction is an efficient method for the preparation
of β-amino carbonyl compounds and therefore a very important
carbon-carbon bond-formation reaction.[1] Specifically, the
asymmetric Mannich reaction[2] has received considerable
attention since the Kobayashi group reported the first catalytic
enantioselective Mannich-type reactions of aldimines with
silylenolates using
a
novel chiral zirconium catalyst.[3] In
Scheme 1. Previous asymmetric report and our work involving
utilization of 1,3,5-triaryl-1,3,5-triazinanes.
complement to one-pot three-component reaction, preformed
imines were extensively employed in the asymmetric Mannich
reaction.[4] However, such preformed Mannich reagents have
some defects such as low activity and instability despite its
important synthetic value.
Results and Discussion
As the promising and stable surrogates for aryl imines, 1,3,5-
triaryl-1,3,5-triazinanes, which are readily prepared through the
condensation of paraformaldehyde with aromatic amines,[5] have
been utilized as effective reagents in organic synthesis. For
We started our studies on this topic by investigating the reaction
of 2-acyl imidazole 1a with the 1,3,5-triphenyl-1,3,5-triazinane 2a
in the presence of chiral-at-metal rhodium complex Δ-Rh1 (2
mol%) developed by the Meggers group.[11a] The reaction
performed smoothly to afford the desired product 3aa in good
yield (80%), but with poor enantioselectivity (-32% ee) (Table 1,
entry 1). Replacing the methyl substituent of the imidazole
moiety with phenyl (1b) and o-tolyl (1c) improved the
enantioselectivity to 83% and 93%, respectively (entries 2-3).
Then we attempted to modify the catalyst by introducing 3,5-
dimethyl phenyl ring at the two R’ sites shown in Table 1. To our
example,
Krische
and
co-workers
reported
the
hydroaminomethylation of allenes and 1,3-dienes with 1,3,5-
triazinanes in ruthenium-catalyzed processes.[6] The Sun group
developed a series of gold-catalyzed [4+1]/[4+3], [2+2+2] and
[3+2+2]-cycloadditions employing 1,3,5-triazinanes.[7] However,
the application of 1,3,5-triazinanes in asymmetric synthesis is
quite limited. Only recently, the Feng group realized the first
asymmetric Mannich reaction using 1,3,5-triazinanes as the
Mannich reagents catalyzed by chiral N,N’-dioxide-metal
complexes, and optically active β-amino compounds with all-
carbon quaternary stereocenters were obtained (Scheme 1a).[8]
delight, Λ-Rh2 provided
a further increase in yield and
enantioselectivity (95% yield, 95% ee, entry 4). Replacing the
solvent CH2Cl2 with 1,2-dichlorethane (DCE) or CHCl3 provided
slightly reduced yields and enantioselectivities (entries 5-6),
while other tested solvents such as toluene and THF did not
provide satisfactory results (entries 7-8). Remarkably, reducing
the catalyst loading to 1 mol% still afforded the product 3ca in
95% yield with 95% ee (entry 9). Control experiment in the
absence of catalyst fail to provide any product, thereby
demonstrating that this reaction crucially depends on the chiral-
at-metal rhodium complexes (entry 10).
[a]
J. Gong, S.-W. Li, S. Qurban, Prof. Dr. Q. Kang
Key Laboratory of Coal to Ethylene Glycol and Its Related
Technology, Fujian Institute of Research on the Structure of Matter,
Chinese Academy of Sciences
155 Yangqiao Road West, Fuzhou, 350002, China
E-mail:kangq@fjirsm.ac.cn
http://www.fjirsm.cas.cn/research/R1/kangqianggroup/
J. Gong, S.-W. Li, S. Qurban
[b]
University of Chinese Academy of Sciences
Beijing, 100049, China
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/ejoc.201700463
European Journal of Organic Chemistry
FULL PAPER
(81-99% yield, 94-96% ee; 3na-3pa). Moreover, substrates with
aliphatic methyl, ethyl, allyl and benzyl groups in α-position to
the carbonyl group were also suitable substrates for the reaction,
offering products in good yields with good to excellent ee (81-
99% yields, 87-95% ee; 3qa-3ta).
Table 1. Initial experiments and optimization of the reaction conditions.[a]
Entry
R
Catalyst
Solvent
Time [h]
Yield
[%][b]
ee
[%][c]
1
Me
Δ-Rh1
Λ-Rh1
Λ-Rh1
Λ-Rh2
Λ-Rh2
Λ-Rh2
Λ-Rh2
Λ-Rh2
Λ-Rh2
none
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DCE
24
16
16
16
12
12
12
12
16
16
80
81
87
95
93
94
85
83
95
0
-32
83
93
95
94
93
84
83
95
n.d.
2
Ph
3
oTol
oTol
oTol
oTol
oTol
oTol
oTol
oTol
4
5
6
CHCl3
toluene
THF
7
8
9[d]
10
CH2Cl2
CH2Cl2
[a] Reaction conditions: 1a (0.20 mmol), 2a (0.08 mmol) and catalyst (0.004
mmol, 2.0 mol%) in solvent (0.4 mL) at 25 oC under argon. [b] Isolated yield.
[c] Determined by HPLC analysis using chiral stationary phase, n.d.= not
determined. [d] 1.0 mol% of catalyst was used.
Scheme 2. Substrate scope of 2-acyl imidazoles. Reaction conditions: 1
(0.20 mmol), 2a (0.08 mmol) and Λ-Rh2 (0.002 mmol, 1.0 mol%) in CH2Cl2
(0.4 mL) at 25 oC under argon atmosphere. All isolated yields were based on
substrate 1. ee values were determined by HPLC analysis using chiral
stationary phase. [a] 2.0 mol% of Λ-Rh2 was used. [b] The reaction was
conducted at 50 oC in 1,2-dichlorethane under argon atmosphere.
With the optimized reaction conditions in hand, we next
investigated the scope of 2-acyl imidazoles in this reaction
(Scheme 2). Electron-donating methyl group or methoxy group
on the phenyl ring had little influence on both the yields and
enantioselectivities (92-97% yields, 95-98% ee; 3da-3fa).
Substrates equipped with electron-withdrawing groups such as
halogen atoms, trifluoromethyl group or nitro group on the
phenyl ring were also tolerable, affording the corresponding
products with good yields and enantioselectivities, although the
ee values of 3ka and 3ma were diminished (87-99% yields, 73-
94% ee; 3ga-3ma). Ring-condensed 1n and heteroaromatic1o
or 1p were all well converted in good yields with excellent ee
Next, 1,3,5-triaryl-1,3,5-triazinanes derived from substituted
aromatic amines were investigated. As it shown in Scheme 3,
alkyl substituted 1,3,5-triazinanes 2b and 2c performed
smoothly under the optimized reaction conditions to give the
products in high yields with good ee (93% yield, 92-94% ee;
3cb-3cc). Notably, the 4-methoxyl substituted 1,3,5-triazinane
2d showed a slight decrease in yield and enantioselectivity
compared with 2-methoxyl substituted 1,3,5-triazinane 2e (89-
98% yields, 86-93% ee; 3cd-3ce). Furthermore, 1,3,5-
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10.1002/ejoc.201700463
European Journal of Organic Chemistry
FULL PAPER
triazinanes equipped with electron-withdrawing halogen groups
were tolerable, affording corresponding products in high yields
with excellent enantioselectivities (95-98% yields, 95->99% ee;
3cf-3ci).
On the basis of previous related investigations,[11a,11b,14]
a
putative mechanism is proposed as shown in Figure 1. The acyl
imidazole substrate can be activated by coordinating to the
rhodium catalyst in
a bidentate fashion, thus forming a
nucleophilic enolate complex after deprotonation. The Si-face of
coordinated substrate is effectively shielded by one of the tert-
butyl groups. The highly selective approach of the in situ
generated N-aryl formaldimine toward the Re-face of
coordinated substrate leads to the desired product with S
configuration, which is consistent with the observed absolute
configuration of 3ba determined by a single-crystal X-ray
analysis (for details, see the Supporting Information).[13]
Figure 1. Proposed mechanism and the X-ray structure of 3ba with thermal
ellipsoids shown at the 35% probability level.
Scheme 3. Substrate scope of 1,3,5-triaryl-1,3,5-triazinanes. Reaction
conditions: 1c (0.20 mmol), 2a-2i (0.08 mmol) and Λ-Rh2 (0.002 mmol,
1.0 mol%) in CH2Cl2 (0.4 mL) at 25 oC under argon atmosphere. All
isolated yields were based on substrate 1c. ee values were determined
by HPLC analysis using chiral stationary phase.
Conclusions
In conclusion, we have developed a highly enantioselective
Mannich reaction of 2-acyl imidazoles with 1,3,5-triaryl-1,3,5-
triazinanes as N-aryl formaldimine precursors. In the presence
of chiral-at-metal rhodium complexes (0.1-2.0 mol%), a variety
of optically active β-amino derivatives were obtained in high
yields (up to 99%) with good to excellent enantioselectivities (up
to >99% ee). Further studies focused on asymmetric reactions
catalyzed by chiral-at-metal rhodium complexes are underway in
our laboratory.
Experimental Section
General Procedure: A dried 25 mL Schlenk tube was charged with 2-
acyl imidazole 1 (0.20 mmol, 1.0 equiv), 1,3,5-triaryl-1,3,5-triazinane 2
(0.08 mmol, 0.4 equiv) and chiral catalysts Δ-Rh1, Λ-Rh1, or Λ-Rh2 (1.0-
2.0 mol%). The tube was purged with argon and anhydrous CH2Cl2 or
1,2-dichloroethane (0.4 mL) was added via syringe. The reaction mixture
was stirred at 25 C (CH2Cl2 as solvent) or 50 C (1,2-dichloroethane as
solvent) for the indicated time (monitored by TLC) under argon
atmosphere. Afterwards, the mixture was subjected to a silica gel flash
chromatography (petroleum ether/ EtOAc = 20:1 to 10:1) to afford chiral
products. The ee values were determined by chiral HPLC
chromatography using a Daicel Chiralpak IC column (250 x 4.6 mm).
Scheme 4. Gram-scale reaction and product transformation.
o
o
It is noteworthy that a gram-scale reaction with 1c (1.1 g) was
also conducted at a lower catalyst loading (0.1 mol%), and the
product 3ca was obtained in 95% yield without loss in
enantioselectivity (95% ee), which highlights the synthetic
potential of current methodology (Scheme 4a). On the other
hand, the product 3ca could be converted into optically active N-
protected β-amino methyl ester 5a and 5b by protection with
NsCl or TsCl followed by the removal of imidazole moieties,
albeit with a little loss in enantiomeric excess (Scheme 4b).
(R)-1-(1-methyl-1H-imidazol-2-yl)-2-phenyl-3-(phenylamino)propan-
1-one (3aa): light yellow oil (49.0 mg, yield: 80%). Enantiomeric excess
was determined by HPLC analysis using a Chiralpak IC column, ee =
32% (HPLC: Chiralpak column IC, λ = 254 nm, n-hexane/i-PrOH = 95:5,
flow rate: 0.5 mL/min, 40 oC, tr(minor) = 27.47 min, tr(major) = 28.37 min).
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10.1002/ejoc.201700463
European Journal of Organic Chemistry
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[α]D25 = +6.0o (c 0.5, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.46 (d, J =
7.1 Hz, 2H), 7.33 (t, J = 7.2 Hz, 2H), 7.27-7.23 (m, 1H), 7.16-7.12 (m, 3H),
6.97 (s, 1H), 6.70-6.66 (m, 1H), 6.62 (d, J = 1.0 Hz, 1H), 6.60 (d, J = 0.9
Hz, 1H), 5.48 (dd, J = 6.4 Hz, 8.5 Hz, 1H), 3.98 (dd, J = 8.5 Hz, 12.7 Hz,
1H), 3.94 (s, 3H), 3.52 (dd, J = 6.4 Hz, 12.7 Hz, 1H). 13C NMR (100 MHz,
CDCl3): δ = 191.25, 147.78, 142.88, 137.18, 129.52, 129.26, 128.83,
128.76, 127.56, 127.47, 117.56, 113.04, 52.51, 46.64, 36.27. IR (KBr): ν
(cm-1) 3054, 3026, 2954, 1670, 1602, 1507, 1402, 1317, 1289, 1257, 749,
694. HRMS (ESI, m/z) calcd for C19H19N3NaO [M+Na]+: 328.1420, found:
328.1427.
1401, 1317, 1261, 910, 764, 749, 692. HRMS (ESI, m/z) calcd for
C26H25N3NaO [M+Na]+: 418.1890, found: 418.1885.
(S)-3-(phenylamino)-2-(m-tolyl)-1-(1-(o-tolyl)-1H-imidazol-2-
yl)propan-1-one (3ea): yellow oil (75.7 mg, yield: 96%). Enantiomeric
excess was determined by HPLC analysis using a Chiralpak IC column,
ee = 95% (HPLC: Chiralpak column IC, λ = 254 nm, n-hexane/i-PrOH =
95:5, flow rate: 1.0 mL/min, 40 oC, tr(major) = 4.49 min, tr(minor) = 5.19
min). [α]D25 = -50.6o (c 0.5, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.40-
7.12 (m, 9H), 7.07-7.05 (m, 1H), 7.01 (d, J = 2.3 Hz, 1H), 6.93 (d, J = 7.7
Hz, 0.5H), 6.68 (t, J = 7.2 Hz, 1H), 6.58 (d, J = 8.3 Hz, 2H), 5.42-5.39 (m,
1H), 3.83 (s, 2H), 3.45-3.43 (m, 1H), 2.31 (d, J = 2.8 Hz, 3H), 1.99 (s,
1.4H), 1.67 (s, 1.5H) (Contained the rotamer). 13C NMR (100 MHz,
CDCl3): δ = 189.93, 189.88, 147.73, 143.32, 143.27, 138.55, 138.49,
137.89, 137.85, 136.90, 136.80, 134.63, 134.41, 130.79, 130.75, 130.27,
130.22, 129.35, 129.29, 129.20, 129.15, 128.75, 128.73, 128.31, 128.27,
126.67, 126.61, 126.49, 126.21, 125.83, 117.47, 117.42, 112.95, 52.76,
52.71, 46.57, 46.15, 21.47, 17.32, 16.76 (Contained the rotamer). IR
(KBr): ν (cm-1) 3420, 3053, 2924, 2864, 1681, 1602, 1503, 1460, 1403,
1304, 1265, 763, 744, 701. HRMS (ESI, m/z) calcd for C26H25N3NaO
[M+Na]+: 418.1890, found: 418.1891.
(S)-2-phenyl-1-(1-phenyl-1H-imidazol-2-yl)-3-(phenylamino)propan-1-
one (3ba): yellow solid (60.0 mg, yield: 81%). Enantiomeric excess was
determined by HPLC analysis using a Chiralpak IC column, ee = 83%
(HPLC: Chiralpak column IC, λ = 254 nm, n-hexane/i-PrOH = 90:10, flow
rate: 1.0 mL/min, 40 oC, tr(major) = 8.18 min, tr(minor) = 11.34 min). 3ba
can be recrystallized from a mixed solvent (n-hexane/i-PrOH = 4:1). After
recrystallization, enantiomeric excess of 3ba was determined by HPLC
analysis using a Chiralpak IC column, ee = 95% (HPLC: Chiralpak
column IC, λ = 254 nm, n-hexane/i-PrOH = 90:10, flow rate: 1.0 mL/min,
o
40 C, tr(major) = 8.65 min, tr(minor) = 11.70 min). [α]D20 = -55.5o (c 0.5,
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.45-7.41 (m, 5H), 7.33 (t, J =
7.3 Hz, 2H), 7.28-7.24 (m, 1H), 7.22 (s, 1H), 7.17-7.11 (m, 5H), 6.68 (t, J
= 7.2 Hz, 1H), 6.59 (d, J = 7.8 Hz, 2H), 5.48 (t, J = 7.9 Hz, 1H), 3.92-3.87
(m, 2H), 3.47 (dd, J = 6.2 Hz, 13.0 Hz, 1H). 13C NMR (100 MHz, CDCl3):
δ = 189.84, 147.73, 142.80, 138.30, 137.07, 130.06, 129.33, 129.08,
128.97, 128.86, 128.82, 127.56, 127.43, 125.78, 117.53, 113.02, 52.93,
46.45. IR (KBr): ν (cm-1) 3053, 3027, 2923, 2853, 1683, 1601, 1505,
1491, 1454, 1444, 1399, 1312, 1259, 909, 761, 749, 692. HRMS (ESI,
m/z) calcd for C24H21N3NaO [M+Na]+: 390.1577, found: 390.1574.
(S)-2-(4-methoxyphenyl)-3-(phenylamino)-1-(1-(o-tolyl)-1H-imidazol-
2-yl)propan-1-one (3fa): yellow oil (80.0 mg, yield: 97%). Enantiomeric
excess was determined by HPLC analysis using a Chiralpak IC column,
ee = 98% (HPLC: Chiralpak column IC, λ = 254 nm, n-hexane/i-PrOH =
95:5, flow rate: 1.0 mL/min, 40 oC, tr(major) = 13.42 min, tr(minor) = 17.61
min). [α]D25 = -92.5o (c 0.5, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.39-
7.22 (m, 6H), 7.17-7.12 (m, 2.5H), 7.02 (s, 1H), 6.93 (d, J = 7.8 Hz, 0.5H),
6.84 (dd, J = 2.6 Hz, 8.7 Hz, 2H), 6.67 (t, J = 7.2 Hz, 1H), 6.58 (d, J = 8.0
Hz, 2H), 5.42-5.38 (m, 1H), 3.81 (br, 2H), 3.77 (s, 3H), 3.45-3.42 (m, 1H),
1.99 (s, 1.4H), 1.65 (s, 1.5H) (Contained the rotamer). 13C NMR (100
MHz, CDCl3): δ = 190.04, 189.98, 158.95, 147.77, 143.24, 137.89,
137.85, 134.59, 134.42, 130.78, 130.74, 130.22, 130.18, 129.85, 129.29,
129.18, 129.13, 128.94, 128.88, 126.66, 126.62, 126.42, 126.20, 117.47,
117.43, 114.29, 114.25, 112.97, 55.26, 51.85, 46.47, 46.05, 17.31, 16.81
(Contained the rotamer). IR (KBr): ν (cm-1) 3392, 3051, 2952, 2924, 2855,
1681, 1602, 1509, 1461, 1401, 1249, 763, 747. HRMS (ESI, m/z) calcd
for C26H25N3NaO2 [M+Na]+: 434.1839, found: 434.1837.
(S)-2-phenyl-3-(phenylamino)-1-(1-(o-tolyl)-1H-imidazol-2-yl)propan-
1-one (3ca): light yellow oil (72.5 mg, yield: 95%). Enantiomeric excess
was determined by HPLC analysis using a Chiralpak IC column, ee =
95% (HPLC: Chiralpak column IC, λ = 254 nm, n-hexane/i-PrOH = 95:5,
o
flow rate: 1.0 mL/min, 40 C, tr(major) = 8.99 min, tr(minor) = 12.57 min).
25
1
[α]D = -59.5o (c 0.5, CHCl3). H NMR (400 MHz, CDCl3): δ = 7.41-7.21
(m, 9H), 7.16-7.12 (m, 2.5H), 7.01 (d, J = 1.4 Hz, 1H), 6.93 (d, J = 7.8 Hz,
0.5H), 6.67 (t, J = 7.2 Hz, 1H), 6.58 (d, J = 8.1 Hz, 2H), 5.46 (t, J = 7.2 Hz,
1H), 3.91-3.83 (m, 2H), 3.48-3.42 (m, 1H), 1.98 (s, 1.4H), 1.63 (s, 1.6H)
(Contained the rotamer). 13C NMR (100 MHz, CDCl3): δ = 189.82, 189.78,
147.68, 143.23, 137.83, 136.98, 136.94, 134.59, 134.41, 130.79, 130.74,
130.26, 130.23, 129.29, 129.19, 129.15, 128.88, 128.85, 128.75, 127.48,
126.72, 126.66, 126.63, 126.44, 126.19, 117.51, 117.46, 112.95, 52.77,
46.53, 46.07, 17.30, 16.74 (Contained the rotamer). IR (KBr): ν (cm-1)
3308, 3056, 3025, 2952, 1680, 1602, 1504, 1454, 1402, 909, 747, 693.
HRMS (ESI, m/z) calcd for C25H23N3NaO [M+Na]+: 404.1733, found:
404.1729.
(S)-2-(4-fluorophenyl)-3-(phenylamino)-1-(1-(o-tolyl)-1H-imidazol-2-
yl)propan-1-one (3ga): colorless oil (69.2 mg, yield: 87%). Enantiomeric
excess was determined by HPLC analysis using a Chiralpak IC column,
ee = 94% (HPLC: Chiralpak column IC, λ = 254 nm, n-hexane/i-PrOH =
95:5, flow rate: 1.0 mL/min, 40 oC, tr(major) = 6.72 min, tr(minor) = 9.16
min). [α]D25 = -52.9o (c 0.5, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.40-
7.23 (m, 6H), 7.16-7.13 (m, 2.5H), 7.04 (dd, J = 0.8 Hz, 3.2 Hz, 1H),
7.02-6.94 (m, 2.5H), 6.70-6.67 (m, 1H), 6.58 (d, J = 8.3 Hz, 2H), 5.48-
5.44 (m, 1H), 3.82 (br, 2H), 3.44-3.42 (m, 1H), 1.98 (s, 1.4H), 1.65 (s,
1.5H) (Contained the rotamer). 13C NMR (100 MHz, CDCl3): δ = 189.69,
189.63, 163.41, 160.97, 147.56, 143.07, 137.76, 134.56, 134.32, 132.74,
132.71, 132.66, 132.63, 130.81, 130.76, 130.39, 130.31, 129.31, 129.25,
129.21, 126.89, 126.70, 126.66, 126.40, 126.14, 117.63, 117.58, 115.84,
115.82, 115.63, 115.61, 112.95, 51.84, 46.58, 46.12, 17.26, 16.76
(Contained the rotamer). 19F NMR (376 MHz, CDCl3): δ = -114.97 and -
115.01. IR (KBr): ν (cm-1) 3410, 3110, 3052, 3025, 2961, 2926, 2858,
1681, 1602, 1507, 1461, 1401, 1317, 1305, 1264, 1224,1159, 910, 764,
749, 692. HRMS (ESI, m/z) calcd for C25H23N3FO [M+H]+: 400.1820,
found: 400.1820.
(S)-3-(phenylamino)-2-(p-tolyl)-1-(1-(o-tolyl)-1H-imidazol-2-yl)propan-
1-one (3da): colorless oil (72.5 mg, yield: 92%). Enantiomeric excess
was determined by HPLC analysis using a Chiralpak IC column, ee =
97% (HPLC: Chiralpak column IC, λ = 254 nm, n-hexane/i-PrOH = 95:5,
o
flow rate: 1.0 mL/min, 40 C, tr(major) = 9.80 min, tr(minor) = 13.04 min).
25
[α]D = -77.4o (c 0.5, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.40-7.22
(m, 6.5H), 7.16-7.11 (m, 4H), 7.01 (s, 1H), 6.93 (d, J = 7.7 Hz, 0.5H),
6.67 (t, J = 7.2 Hz, 1H), 6.58 (d, J = 7.9 Hz, 2H), 5.41 (s, 1H), 3.87-3.83
(m, 2H), 3.44-3.42 (m, 1H), 2.31 (s, 3H), 1.99 (s, 1.4H), 1.66 (s, 1.6H)
(Contained the rotamer). 13C NMR (100 MHz, CDCl3): δ = 189.96, 189.92,
147.74, 143.24, 137.89, 137.85, 137.16, 137.13, 134.59, 134.45, 133.93,
133.87, 130.78, 130.73, 130.23, 130.19, 129.61, 129.57, 129.28, 129.17,
129.13, 128.61, 128.59, 126.65, 126.44, 126.20, 117.46, 117.41, 112.96,
52.37, 46.49, 46.12, 21.13, 17. 31, 16.83 (Contained the rotamer). IR
(KBr): ν (cm-1) 3397, 3051, 3024, 2922, 2861, 1681, 1602, 1503, 1461,
(S)-2-(4-chlorophenyl)-3-(phenylamino)-1-(1-(o-tolyl)-1H-imidazol-2-
yl)propan-1-one (3ha): light yellow oil (83.0 mg, yield: 99%).
Enantiomeric excess was determined by HPLC analysis using
a
Chiralpak IC column, ee = 92% (HPLC: Chiralpak column IC, λ = 254 nm,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700463
European Journal of Organic Chemistry
FULL PAPER
n-hexane/i-PrOH = 95:5, flow rate: 1.0 mL/min, 40 oC, tr(major) = 6.66
134.44, 134.42, 130.84, 130.75, 130.59, 130.53, 130.09, 129.28, 129.22,
128.91, 128.85, 128.59, 127.06, 126.97, 126.83, 126.68, 126.66, 126.63,
126.22, 117.44, 117.40, 112.81, 49.54, 49.52, 45.88, 45.78, 17.29, 17.07
(Contained the rotamer). IR (KBr): ν (cm-1) 3397, 3059, 3028, 2919, 2863,
1681, 1614, 1521,1492, 1453, 1402, 1317, 1303, 1256, 944, 910, 808,
762, 699. HRMS (ESI, m/z) calcd for C25H22ClN3NaO [M+Na]+: 438.1344,
found: 438.1342.
25
min, tr(minor) = 8.65 min). [α]D = -95.5o (c 0.5, CHCl3). 1H NMR (400
MHz, CDCl3): δ = 7.41-7.23 (m, 8H), 7.17-7.13 (m, 2.5H), 7.04 (d, J = 1.6
Hz, 1H), 6.95 (d, J = 7.7 Hz, 0.5H), 6.69 (t, J = 7.2 Hz, 1H), 6.57 (d, J =
7.6 Hz, 2H), 5.48-5.44 (m, 1H), 3.88-3.82 (m, 2H), 3.45-3.41 (m, 1H),
1.98 (s, 1.4H), 1.67 (s, 1.6H) (Contained the rotamer). 13C NMR (100
MHz, CDCl3): δ = 189.41, 189.36, 147.51, 143.02, 137.74, 137.72,
135.58, 135.46, 134.56, 134.35, 133.40, 130.83, 130.79, 130.39, 130.36,
130.14, 129.34, 129.28, 129.24, 129.03, 129.01, 126.97, 126.72, 126.69,
126.40, 126.16, 117.68, 117.64, 112.97, 52.04, 52.01, 46.46, 46.08,
17.28, 16.86 (Contained the rotamer). IR (KBr): ν (cm-1) 3336, 3109,
3053, 3025, 2955, 2924, 2858, 1681, 1602, 1503, 1491, 1461, 1400,
1304, 1259, 1090, 1015, 910, 767, 749, 692. HRMS (ESI, m/z) calcd for
C25H22ClN3NaO [M+Na]+: 438.1344, found: 438.1346.
(S)-3-(phenylamino)-1-(1-(o-tolyl)-1H-imidazol-2-yl)-2-(4-
(trifluoromethyl)phenyl)propan-1-one (3la): colorless oil (83.2 mg,
yield: 93%). Enantiomeric excess was determined by HPLC analysis
using a Chiralpak IC column, ee = 92% (HPLC: Chiralpak column IC, λ =
254 nm, n-hexane/i-PrOH = 95:5, flow rate: 1.0 mL/min, 40 oC, tr(major) =
25
5.11 min, tr(minor) = 6.17 min). [α]D = -60.3o (c 0.5, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 7.58-7.51 (m, 4H), 7.41-7.24 (m, 4H), 7.17-7.14
(m, 2.5H), 7.06 (dd, J = 0.8 Hz, 3.1 Hz, 1H), 6.97 (d, J = 7.7 Hz, 0.5H),
6.70 (ddd, J = 0.9 Hz, 7.3 Hz, 1H), 6.58 (dd, J = 1.0 Hz, 7.6 Hz, 2H),
5.58-5.54 (m, 1H), 3.93-3.83 (m, 2H), 3.49-3.45 (m, 1H), 1.98 (s, 1.4H),
1.68 (s, 1.5H) (Contained the rotamer). 13C NMR (100 MHz, CDCl3): δ =
189.05, 189.00, 147.37, 147.36, 142.96, 141.18, 141.04, 137.66, 134.53,
134.31, 130.84, 130.80, 130.49, 130.46, 129.36, 129.32, 129.29, 129.14,
129.12, 127.12, 126.74, 126.72, 126.39, 126.14, 125.77, 125.75, 125.71,
117.78, 117.74, 112.95, 52.53, 52.46, 46.55, 46.18, 17.23, 16.82
(Contained the rotamer). 19F NMR (376 MHz, CDCl3): δ = -62.53 and -
62.54. IR (KBr): ν (cm-1) 3308, 3107, 3056, 3025, 2927, 1682, 1603,
1504, 1403, 1325, 1166, 1123, 1068, 1019, 910, 764, 750. HRMS (ESI,
m/z) calcd for C26H23F3N3O [M+H]+: 450.1788, found: 450.1785.
(S)-2-(4-bromophenyl)-3-(phenylamino)-1-(1-(o-tolyl)-1H-imidazol-2-
yl)propan-1-one (3ia): light yellow oil (80.2 mg, yield: 87%).
Enantiomeric excess was determined by HPLC analysis using
a
Chiralpak IC column, ee = 93% (HPLC: Chiralpak column IC, λ = 254 nm,
n-hexane/i-PrOH = 95:5, flow rate: 1.0 mL/min, 40 oC, tr(major) = 6.75
25
min, tr(minor) = 8.79 min). [α]D = -93.3o (c 0.5, CHCl3). 1H NMR (400
MHz, CDCl3): δ = 7.43 (d, J = 8.4 Hz, 2H), 7.41-7.23 (m, 6H), 7.17-7.13
(m, 2.5H), 7.04 (d, J = 1.3 Hz, 1H), 6.95 (d, J = 7.7 Hz, 0.5H), 6.69 (t, J =
7.2 Hz, 1H), 6.57 (d, J = 7.4 Hz, 2H), 5.44 (br, 1H), 3.88-3.81 (m, 2H),
3.45-3.41 (m, 1H), 1.98 (s, 1.4H), 1.68 (s, 1.6H) (Contained the rotamer).
13C NMR (100 MHz, CDCl3): δ = 189.31, 189.26, 147.47, 142.99, 137.73,
136.11, 135.98, 134.55, 134.35, 131.97, 131.95, 130.82, 130.78, 130.50,
130.48, 130.39, 130.36, 129.34, 129.28, 129.24, 126.97, 126.71, 126.69,
126.39, 126.15, 121,56, 117.68, 117.64, 112.96, 52.10, 52.07, 46.39,
46.03, 17.27, 16.87 (Contained the rotamer). IR (KBr): ν (cm-1) 3412,
3051, 3025, 2959, 2925, 2858, 1680, 1602, 1503, 1487, 1461, 1400,
1304, 1260, 1073, 1011, 944, 910, 766, 749, 692. HRMS (ESI, m/z)
calcd for C25H22BrN3NaO [M+Na]+: 482.0838, found: 482.0838.
(S)-2-(4-nitrophenyl)-3-(phenylamino)-1-(1-(o-tolyl)-1H-imidazol-2-
yl)propan-1-one (3ma): brown oil (79.3 mg, yield: 93%). Enantiomeric
excess was determined by HPLC analysis using a Chiralpak IC column,
ee = 76% (HPLC: Chiralpak column IC, λ = 254 nm, n-hexane/i-PrOH =
90:10, flow rate: 1.0 mL/min, 40 oC, tr(major) = 12.61 min, tr(minor) =
18.54 min). [α]D25 = -87.3o (c 0.5, CHCl3). 1H NMR (400 MHz, CDCl3): δ =
8.15 (dd, J = 1.8 Hz, 8.5 Hz, 2H), 7.58 (t, J = 7.7 Hz, 2H), 7.41-7.24 (m,
4H), 7.17-7.13 (m, 2.5H), 7.07 (d, J = 3.0 Hz, 1H), 6.97 (d, J = 7.8 Hz,
0.5H), 6.70 (t, J = 7.3 Hz, 1H), 6.58 (dd, J = 2.7 Hz, 7.7 Hz, 2H), 5.66-
5.61 (m, 1H), 3.95-3.89 (m, 2H), 3.52-3.47 (m, 1H), 1.97 (s, 1.5H), 1.69
(s, 1.5H) (Contained the rotamer). 13C NMR (100 MHz, CDCl3): δ =
188.43, 188.37, 147.28, 147.20, 147.18, 144.70, 144.52, 142.82, 142.79,
137.54, 134.51, 134.23, 130.90, 130.84, 130.64, 130.61, 129.73, 129.71,
129.40, 127.37, 126.80, 126.77, 126.37, 126.10, 123.96, 117.95, 117.90,
112.96, 52.59, 52.51, 46.53, 46.21, 17.21, 16.91 (Contained the rotamer).
IR (KBr): ν (cm-1) 3052, 3023, 2917, 2850, 1680, 1602, 1518, 1399, 1345,
1316, 1304, 909, 762, 749, 693. HRMS (ESI, m/z) calcd for
C25H22N4NaO3 [M+Na]+: 449.1584, found: 449.1586.
(S)-2-(3-chlorophenyl)-3-(phenylamino)-1-(1-(o-tolyl)-1H-imidazol-2-
yl)propan-1-one (3ja): light yellow oil (77.0 mg, yield: 93%).
Enantiomeric excess was determined by HPLC analysis using
a
Chiralpak IC column, ee = 90% (HPLC: Chiralpak column IC, λ = 254 nm,
n-hexane/i-PrOH = 95:5, flow rate: 1.0 mL/min, 40 oC, tr(major) = 7.15
25
min, tr(minor) = 8.89 min). [α]D = -64.4o (c 0.5, CHCl3). 1H NMR (400
MHz, CDCl3): δ = 7.41-7.37 (m, 2H), 7.34-7.21 (m, 6H), 7.17-7.13 (m,
2.5H), 7.05 (d, J = 4.4 Hz, 1H), 6.97 (d, J = 7.6 Hz, 0.5H), 6.69 (t, J = 7.3
Hz, 1H), 6.58 (d, J = 8.3 Hz, 2H), 5.48-5.43 (m, 1H), 3.84 (s, 2H), 3.45-
3.42 (m, 1H), 1.97 (s, 1.4H), 1.69 (s, 1.5H) (Contained the rotamer). 13C
NMR (100 MHz, CDCl3): δ = 189.23, 189.15, 147.46, 143.08, 143.02,
139.07, 138.94, 137.70, 137.69, 134.60, 134.55, 134.36, 130.82, 130.43,
130.39, 130.06, 129.34, 129.29, 129.25, 128.78, 128.72, 127.72, 127.07,
127.00, 126.71, 126.43, 126.20, 117.69, 117.64, 112..96, 112.95, 52.36,
52.28, 46.55, 46.12, 17.25, 16.77 (Contained the rotamer). IR (KBr): ν
(cm-1) 3308, 3051, 3022, 2927, 2862, 1681, 1602, 1503, 1400, 1317,
1303, 1258, 911, 763, 749, 692. HRMS (ESI, m/z) calcd for C25H23ClN3O
[M+H]+: 416.1524, found: 416.1521.
(S)-2-(naphthalen-2-yl)-3-(phenylamino)-1-(1-(o-tolyl)-1H-imidazol-2-
yl)propan-1-one (3na): light yellow oil (86.0 mg, yield: 99%).
Enantiomeric excess was determined by HPLC analysis using
a
Chiralpak IC column, ee = 96% (HPLC: Chiralpak column IC, λ = 254 nm,
n-hexane/i-PrOH = 95:5, flow rate: 1.0 mL/min, 40 oC, tr(major) = 10.53
min, tr(minor) = 13.51 min). [α]D25 = -142.5o (c 0.5, CHCl3). 1H NMR (400
MHz, CDCl3): δ = 7.85 (d, J = 7.2 Hz, 1H), 7.80 (d, J = 7.8 Hz, 3H), 7.54
(t, J = 7.8 Hz, 1H), 7.48-7.43 (m, 2H), 7.41-7.13 (m, 7H), 7.01 (s, 1H),
6.90 (d, J = 7.8 Hz, 0.5H), 6.69 (t, J = 7.3 Hz, 1H), 6.60 (d, J = 7.1 Hz,
2H), 5.63 (t, J = 7.3 Hz, 1H), 3.96 (br, 1H), 3.85 (s, 1H), 3.56 (br, 1H),
2.02 (s, 1.4H), 1.61 (s, 1.5H) (Contained the rotamer). 13C NMR (100
MHz, CDCl3): δ = 189.72, 189.68, 147.69, 147.67, 143.26, 143.20,
137.86, 137.79, 134.64, 134.55, 134.42, 134.40, 133.57, 132.73, 130.80,
130.77, 130.33, 130.27, 129.33, 129.24, 129.19, 128.64, 128.62, 127.92,
127.80, 127.68, 126.78, 126.74, 126.69, 126.64, 126.61, 126.46, 126.22,
126.01, 117.57, 117.53, 113.01, 52.87, 46.44, 46.14, 17.35, 16.83
(Contained the rotamer). IR (KBr): ν (cm-1) 3050, 2924, 2854, 1681, 1601,
(S)-2-(2-chlorophenyl)-3-(phenylamino)-1-(1-(o-tolyl)-1H-imidazol-2-
yl)propan-1-one (3ka): light yellow oil (81.2 mg, yield: 98%).
Enantiomeric excess was determined by HPLC analysis using
a
Chiralpak IC column, ee = 73% (HPLC: Chiralpak column IC, λ = 254 nm,
n-hexane/i-PrOH = 95:5, flow rate: 1.0 mL/min, 40 oC, tr(major) = 7.97
25
min, tr(minor) = 11.05 min). [α]D = -55.6o (c 0.5, CHCl3). 1H NMR (400
MHz, CDCl3): δ = 7.43-7.23 (m, 6H), 7.20-7.12 (m, 4.5H), 7.04-7.03 (m,
1.5H), 6.67 (t, J = 7.3 Hz, 1H), 6.63 (d, J = 8.0 Hz, 2H), 5.95-5.90 (m, 1H),
4.10 (s, 1H), 3.81-3.73 (m, 1H), 3.51-3.47 (m, 1H), 1.97 (s, 1.5H), 1.83 (s,
1.5H) (Contained the rotamer). 13C NMR (100 MHz, CDCl3): δ = 189.74,
189.65, 147.63, 143.28, 143.24, 137.83, 135.34, 135.28, 134.74, 134.48,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700463
European Journal of Organic Chemistry
FULL PAPER
1504, 1454, 1403, 763, 747, 692. HRMS (ESI, m/z) calcd for
4H), 7.15-7.08 (m, 3.5H), 7.02 (d, J = 7.4 Hz, 0.5H), 6.66 (t, J = 7.3 Hz,
1H), 6.54 (d, J = 8.5 Hz, 2H), 4.16-4.08 (m, 1H), 4.02 (s, 1H), 3.45-3.40
(m, 1H), 3.30 (dd, J = 4.7 Hz, 12.1 Hz, 1H), 1.97 (s, 1.5H), 1.91-1.79 (m,
C29H25N3NaO [M+Na]+: 454.1890, found: 454.1886.
2.5H), 1.69-1.62 (m, 1H), 0.96-0.91 (m, 3H) (Contained the rotamer). 13
C
(S)-2-(1-methyl-1H-indol-3-yl)-3-(phenylamino)-1-(1-(o-tolyl)-1H-
imidazol-2-yl)propan-1-one (3oa): pale yellow solid (76.2 mg, yield:
88%). Enantiomeric excess was determined by HPLC analysis using a
Chiralpak IC column, ee = 94% (HPLC: Chiralpak column IC, λ = 254 nm,
n-hexane/i-PrOH = 95:5, flow rate: 1.0 mL/min, 40 oC, tr(major) =
NMR (100 MHz, CDCl3): δ = 193.82, 193.66, 148.17, 143.91, 143.80,
137.96, 134.68, 134.22, 130.79, 130.67, 129.99, 129.18, 129.17, 129.13,
129.11, 126.74, 126.67, 126.60, 126.47, 126.17, 117.18, 117.14, 112.70,
48.36, 48.16, 45.72, 45.55, 23.08, 23.04, 17.15, 17.06, 11.97, 11.91
(Contained the rotamer). IR (KBr): ν (cm-1) 3392, 3109, 3052, 3025, 2964,
2930, 2875, 1680, 1603, 1503, 1460, 1320, 1302, 1265, 1149, 948, 763,
748, 692. HRMS (ESI, m/z) calcd for C21H24N3O [M+H]+: 334.1914,
found: 334.1911.
25
11.97min, tr(minor) = 13.99 min). [α]D = -80.0o (c 0.5, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 7.75 (d, J = 8.0 Hz, 1H), 7.38-7.07 (m, 11H), 7.01
(d, J = 0.8 Hz, 1H), 6.86 (d, J = 7.8 Hz, 0.5H), 6.67 (t, J = 7.3 Hz, 1H),
6.58 (d, J = 7.2 Hz, 2H), 5.76 (t, J = 7.2 Hz, 1H), 3.94-3.88 (m, 2H), 3.73
(s, 3H), 3.60-3.54 (m, 1H), 1.99 (s, 1.5H), 1.58 (s, 1.5H) (Contained the
rotamer). 13C NMR (100 MHz, CDCl3): δ = 190.40, 190.29, 147.98,
143.45, 137.96, 137.91, 136.96, 136.93, 134.63, 134.48, 130.73, 130.67,
130.10, 130.04, 129.24, 129.10, 129.06, 128.12, 127.24, 126.65, 126.61,
126.59, 126.52, 126.33, 121.80, 119.76, 119.30, 117.33, 117.28, 112.96,
109.88, 109.76, 109.30, 109.26, 46.24, 46.03, 44.31, 44.26, 32.86, 17.32,
16.78 (Contained the rotamer). IR (KBr): ν (cm-1) 3392, 3109, 3051, 2929,
1681, 1602, 1504, 1462, 1403, 1329, 909, 742, 692. HRMS (ESI, m/z)
calcd for C28H27N4O [M+H]+: 435.2179, found: 435.2175.
(S)-2-((phenylamino)methyl)-1-(1-(o-tolyl)-1H-imidazol-2-yl)pent-4-
en-1-one (3sa): colorless oil (56.0 mg, yield: 81%). Enantiomeric excess
was determined by HPLC analysis using a Chiralpak IC column, ee =
87% (HPLC: Chiralpak column IC, λ = 254 nm, n-hexane/i-PrOH = 95:5,
flow rate: 1.0 mL/min, 40 oC, tr(major) = 7.04 min, tr(minor) = 8.09 min).
[α]D25 = +85.0o (c 0.5, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.39-7.23
(m, 4H), 7.14-7.08 (m, 3.5H), 7.02 (d, J = 7.7 Hz, 0.5H), 6.66 (t, J = 7.3
Hz, 1H), 6.54 (dd, J = 1.5 Hz, 8.4 Hz, 2H), 5.86-5.74 (m, 1H), 5.08-5.03
(m, 1H), 5.00 (d, J = 10.2 Hz, 1H), 4.33-4.25 (m, 1H), 4.04 (s, 1H), 3.46-
3.41 (m, 1H), 3.34-3.31 (m, 1H), 2.62-2.52 (m, 1H), 2.39-2.32 (m, 1H),
1.94 (s, 1.5H), 1.87 (s, 1.4H) (Contained the rotamer). 13C NMR (100
MHz, CDCl3): δ = 192.95, 192.77, 148.04, 143.61, 143.53, 137.88,
135.34, 135.25, 134.62, 134.31, 130.78, 130.68, 130.07, 130.05, 129.18,
129.14, 126.82, 126.65, 126.59, 126.43, 126.26, 117.25, 117.21, 117.13,
112.74, 46.27, 46.12, 45.49, 45.44, 34.17, 34.14, 17.20, 17.09
(Contained the rotamer). IR (KBr): ν (cm-1) 3410, 3108, 3053, 3025, 2979,
1679, 1603, 1506, 1405, 1302, 1260, 1149, 910, 763, 749. HRMS (ESI,
m/z) calcd for C22H24N3O [M+H]+: 346.1914, found: 346.1913.
(S)-3-(phenylamino)-2-(thiophen-3-yl)-1-(1-(o-tolyl)-1H-imidazol-2-
yl)propan-1-one (3pa): yellow oil (62.6 mg, yield: 81%). Enantiomeric
excess was determined by HPLC analysis using a Chiralpak IC column,
ee = 94% (HPLC: Chiralpak column IC, λ = 254 nm, n-hexane/i-PrOH =
95:5, flow rate: 1.0 mL/min, 40 oC, tr(major) = 8.93 min, tr(minor) = 11.98
min). [α]D25 = -40.3o (c 0.5, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.39-
7.25 (m, 6H), 7.16-7.13 (m, 3.5H), 7.06 (d, J = 3.5 Hz, 1H), 6.98 (d, J =
7.7 Hz, 0.5H), 6.68 (t, J = 7.3 Hz, 1H), 6.58 (d, J = 8.0 Hz, 2H), 5.63 (s,
1H), 3.85 (s, 2H), 3.51-3.44 (m, 1H), 1.97 (s, 1.5H), 1.67 (s, 1.5H)
(Contained the rotamer). 13C NMR (100 MHz, CDCl3): δ = 189.47, 189.37,
147.65, 143.15, 137.77, 137.01, 136.98, 134.56, 134.37, 130.79, 130.76,
130.24, 129.29, 129.21, 129.16, 127.73, 127.69, 126.91, 126.88, 126.66,
126.37, 126.20, 125.89, 123.21, 123.14, 117.57, 117.52, 112.98, 48.10,
48.05, 46.50, 45.92, 17.23, 16.68 (Contained the rotamer). IR (KBr): ν
(cm-1) 3392, 3108, 3051, 2952, 1681, 1602, 1503, 1402, 1317, 1303, 909,
764, 750, 692. HRMS (ESI, m/z) calcd for C23H21N3NaOS [M+Na]+:
410.1298, found: 410.1294.
(S)-2-benzyl-3-(phenylamino)-1-(1-(o-tolyl)-1H-imidazol-2-yl)propan-
1-one (3ta): colorless oil (74.6 mg, yield: 94%). Enantiomeric excess was
determined by HPLC analysis using a Chiralpak IC column, ee = 94%
(HPLC: Chiralpak column IC, λ = 254 nm, n-hexane/i-PrOH = 95:5, flow
o
25
rate: 1.0 mL/min, 40 C, tr(major) = 7.69 min, tr(minor) = 8.30 min). [α]D
= +42.1o (c 0.5, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.39-7.14 (m,
9H), 7.10 (t, J = 7.8 Hz, 2H), 7.05 (dd, J = 0.8 Hz, 7.2 Hz, 1H), 6.98 (dd, J
= 7.0 Hz, 15.0 Hz, 1H), 6.66-6.63 (m, 1H), 6.47 (d, J = 7.7 Hz, 2H), 4.57-
4.46 (m, 1H), 4.11 (s, 1H), 3.45-3.41 (m, 1H), 3.31-3.28 (m, 1H), 3.18-
3.12 (m, 1H), 2.84 (dd, J = 7.6 Hz, 13.8 Hz, 1H), 1.86 (s, 1.4H), 1.73 (s,
1.5H) (Contained the rotamer). 13C NMR (100 MHz, CDCl3): δ = 192.95,
192.66, 148.06, 148.02, 143.66, 143.59, 139.19, 139.10, 137.83, 137.81,
134.62, 134.38, 130.76, 130.65, 130.10, 130.08, 129.22, 129.18, 129.16,
128.42, 126.78, 126.76, 126.61, 126.56, 126.40, 126.35, 126.32, 117.23,
117.20, 112.74, 48.42, 48.34, 45.58, 45.46, 35.75, 35.64, 17.10, 16.86
(Contained the rotamer). IR (KBr): ν (cm-1) 3308, 3056, 3025, 2922, 2856,
1679, 1602, 1503, 1454, 1405, 1302, 940, 910, 763, 747, 693. HRMS
(ESI, m/z) calcd for C26H26N3O [M+H]+: 396.2070, found: 396.2067.
(S)-2-methyl-3-(phenylamino)-1-(1-(o-tolyl)-1H-imidazol-2-yl)propan-
1-one (3qa): colorless oil (62.2 mg, yield: 97%). Enantiomeric excess
was determined by HPLC analysis using a Chiralpak IC column, ee =
92% (HPLC: Chiralpak column IC, λ = 254 nm, n-hexane/i-PrOH = 95:5,
flow rate: 1.0 mL/min, 40 oC, tr(major) = 7.71 min, tr(minor) = 8.94 min).
[α]D25 = +118.9o (c 0.5, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.39-7.24
(m, 4.5H), 7.13 (t, J = 7.7 Hz, 2H), 7.09 (d, J = 4.3 Hz, 1H), 7.02 (d, J =
7.8 Hz, 0.5H), 6.66 (t, J = 7.3 Hz, 1H), 6.56 (d, J = 6.6 Hz, 2H), 4.27-4.19
(m, 1H), 4.05 (s, 1H), 3.45-3.43 (m, 1H), 3.28-3.24 (m, 1H), 1.97 (s,
1.5H), 1.87 (s, 1.4H), 1.25 (t, J = 6.6 Hz, 3H) (Contained the rotamer).
13C NMR (100 MHz, CDCl3): δ = 193.86, 193.79, 148.06, 143.25, 143.20,
137.97, 137.92, 134.61, 134.27, 130.81, 130.71, 130.02, 129.99, 129.21,
129.15, 129.11, 126.70, 126.66, 126.62, 126.40, 126.17, 117.22, 117.18,
112.73, 47.28, 46.97, 41.56, 41.34, 17.17, 17.08, 15.22, 15.05
(Contained the rotamer). IR (KBr): ν (cm-1) 3392, 3050, 2967, 2933, 1680,
1603, 1504, 1460, 1405, 1302, 953, 912, 763, 748, 692. HRMS (ESI,
m/z) calcd for C20H22N3O [M+H]+: 320.1757, found: 320.1760.
(S)-2-phenyl-1-(1-(o-tolyl)-1H-imidazol-2-yl)-3-(p-tolylamino)propan-
1-one (3cb): light yellow oil (73.8 mg, yield: 93%). Enantiomeric excess
was determined by HPLC analysis using a Chiralpak IC column, ee =
94% (HPLC: Chiralpak column IC, λ = 254 nm, n-hexane/i-PrOH = 95:5,
flow rate: 1.0 mL/min, 40 oC, tr(major) = 11.11 min, tr(minor) = 15.37 min).
25
[α]D = -43.3o (c 0.5, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.40-7.22
(m, 9H), 7.16 (d, J = 7.5 Hz, 0.5H), 7.02 (d, J = 1.7 Hz, 1H), 6.96-6.92 (m,
2.5H), 6.51 (d, J = 7.8 Hz, 2H), 5.45 (t, J = 6.9 Hz, 1H), 3.88-3.81 (m, 1H),
3.68 (br, 1H), 3.46-3.40 (m, 1H), 2.22 (s, 3H), 1.99 (s, 1.4H), 1.63 (s,
1.6H) (Contained the rotamer). 13C NMR (100 MHz, CDCl3): δ = 189.92,
189.87, 145.42, 143.26, 137.86, 137.07, 137.03, 134.60, 134.42, 130.79,
130.74, 130.25, 130.21, 129.79, 129.18, 129.14, 128.86, 128.83, 128.78,
127.45, 126.69, 126.65, 126.63, 126.45, 126.19, 113.22, 52.78, 52.75,
(S)-2-((phenylamino)methyl)-1-(1-(o-tolyl)-1H-imidazol-2-yl)butan-1-
one (3ra): colorless oil (65.8 mg, yield: 99%). Enantiomeric excess was
determined by HPLC analysis using a Chiralpak IC column, ee = 95%
(HPLC: Chiralpak column IC, λ = 254 nm, n-hexane/i-PrOH = 95:5, flow
rate: 1.0 mL/min, 40 C, tr(major) = 6.36 min, tr(minor) = 7.48 min). [α]D
= +85.5o (c 0.5, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.39-7.23 (m,
o
25
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700463
European Journal of Organic Chemistry
FULL PAPER
46.99, 46.52, 20.44, 17.32, 16.75 (Contained the rotamer). IR (KBr): ν
(cm-1) 3397, 3059, 3028, 2919, 2863, 1681, 1614, 1521, 1492, 1453,
1402, 1317, 1303, 1256, 944, 910, 808, 762, 699. HRMS (ESI, m/z)
calcd for C26H25N3NaO [M+Na]+: 418.1890, found: 418.1896.
(S)-3-((4-fluorophenyl)amino)-2-phenyl-1-(1-(o-tolyl)-1H-imidazol-2-
yl)propan-1-one (3cf): colorless oil (78.3 mg, yield: 98%). Enantiomeric
excess was determined by HPLC analysis using a Chiralpak IC column,
ee = 95% (HPLC: Chiralpak column IC, λ = 254 nm, n-hexane/i-PrOH =
95:5, flow rate: 1.0 mL/min, 40 oC, tr(major) = 7.99 min, tr(minor) = 10.57
min). [α]D25 = -65.6o (c 0.5, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.40-
7.16 (m, 9.5H), 7.03 (dd, J = 0.8 Hz, 2.2 Hz, 1H), 6.93 (d, J = 8.0 Hz,
0.5H), 6.85 (t, J = 8.5 Hz, 2H), 6.53-6.49 (m, 2H), 5.46-5.42 (m, 1H),
3.87-3.80 (m, 1H), 3.71 (s, 1H), 3.44-3.39 (m, 1H), 1.99 (s, 1.3H), 1.62 (s,
1.7H) (Contained the rotamer). 13C NMR (100 MHz, CDCl3): δ = 189.77,
189.72, 157.04, 154.71, 144.04, 144.03, 143.22, 137.81, 137.77, 136.88,
136.83, 134.55, 134.41, 130.79, 130.77, 130.29, 130.25, 129.23, 129.18,
128.91, 128.88, 128.76, 127.55, 126.82, 126.66, 126.41, 126.19, 115.80,
115.58, 113.92, 113.85, 52.70, 52.68, 47.26, 46.80, 17.29, 16.72
(Contained the rotamer). 19F NMR (376 MHz, CDCl3): δ = -127.98 and -
128.03. IR (KBr): ν (cm-1) 3392, 3056, 3031, 2927, 1681, 1510, 1453,
1402, 1303, 1221, 909, 821, 762, 699. HRMS (ESI, m/z) calcd for
C25H22FN3NaO [M+Na]+: 422.1639, found: 422.1640.
(S)-3-((4-(tert-butyl)phenyl)amino)-2-phenyl-1-(1-(o-tolyl)-1H-
imidazol-2-yl)propan-1-one (3cc): light yellow oil (81.7 mg, yield: 93%).
Enantiomeric excess was determined by HPLC analysis using
a
Chiralpak IC column, ee = 92% (HPLC: Chiralpak column IC, λ = 254 nm,
n-hexane/i-PrOH = 95:5, flow rate: 1.0 mL/min, 40 oC, tr(major) = 10.21
25
min, tr(minor) = 13.82 min). [α]D = -43.9o (c 0.5, CHCl3). 1H NMR (400
MHz, CDCl3): δ = 7.41-7.21 (m, 9H), 7.18-7.15 (m, 2.5H), 7.02 (dd, J =
0.8 Hz, 3.0 Hz, 1H), 6.93 (d, J = 7.2 Hz, 0.5H), 6.54 (dd, J = 1.3 Hz, 8.5
Hz, 2H), 5.44 (t, J = 7.2 Hz, 1H), 3.89-3.82 (m, 1H), 3.73 (br, 1H), 3.47-
3.41 (m, 1H), 1.99 (s, 1.4H), 1.64 (s, 1.6H), 1.26 (s, 9H) (Contained the
rotamer). 13C NMR (100 MHz, CDCl3): δ = 189.87, 189.84, 145.35,
145.33, 143.25, 140.23, 140.17, 137.87, 137.84, 137.08, 137.05, 134.61,
134.42, 130.79, 130.74, 130.23, 130.19, 129.18, 129.14, 128.87, 128.83,
128.77, 127.45, 126.69, 126.66, 126.63, 126.45, 126.19, 126.07, 112.70,
112.67, 52.93, 52.89, 46.78, 46.32, 33.87, 31.60, 17.35, 16.76
(Contained the rotamer). IR (KBr): ν (cm-1) 3308, 3056, 3028, 2960, 2902,
2866, 1681, 1614, 1519, 1492, 1454, 1403, 1303, 1261, 909, 821, 762,
699. HRMS (ESI, m/z) calcd for C29H31N3NaO [M+Na]+: 460.2359, found:
460.2356.
(S)-3-((4-chlorophenyl)amino)-2-phenyl-1-(1-(o-tolyl)-1H-imidazol-2-
yl)propan-1-one (3cg): colorless oil (80.0 mg, yield: 96%). Enantiomeric
excess was determined by HPLC analysis using a Chiralpak IC column,
ee = 97% (HPLC: Chiralpak column IC, λ = 254 nm, n-hexane/i-PrOH =
95:5, flow rate: 1.0 mL/min, 40 oC, tr(major) = 7.33 min, tr(minor) = 8.89
min). [α]D25 = -47.2o (c 0.5, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.39-
7.19 (m, 9H), 7.16 (d, J = 7.7 Hz, 0.5H), 7.08 (d, J = 8.2 Hz, 2H), 7.03 (d,
J = 1.4 Hz,1H), 6.93 (d, J = 8.0 Hz, 0.5H), 6.50 (dd, J = 1.6 Hz, 8.6 Hz,
2H), 5.44 (t, J = 7.9 Hz, 1H), 3.85 (s, 2H), 3.43 (s, 1H), 1.98 (s, 1.3H),
1.62 (s, 1.6H) (Contained the rotamer). 13C NMR (100 MHz, CDCl3): δ =
189.65, 189.62, 146.24, 143.18, 137.77, 137.74, 136.76, 136.71, 134.53,
134.40, 130.79, 130.77, 130.33, 130.28, 129.24, 129.19, 129.10, 128.92,
128.90, 128.73, 127.58, 126.84, 126.66, 126.40, 126.18, 122.01, 121.96,
114.04, 52.59, 46.60, 46.14, 17.28, 16.72 (Contained the rotamer). IR
(KBr): ν (cm-1) 3309, 3057, 3029, 2955, 2925, 2854, 1681, 1599, 1501,
1454, 1403, 1315, 1258, 1088, 944, 909, 816, 762, 740, 699. HRMS (ESI,
m/z) calcd for C25H22ClN3NaO [M+Na]+: 438.1344, found: 438.1338.
(S)-3-((4-methoxyphenyl)amino)-2-phenyl-1-(1-(o-tolyl)-1H-imidazol-
2-yl)propan-1-one (3cd): light yellow oil (72.9 mg, yield: 89%).
Enantiomeric excess was determined by HPLC analysis using
a
Chiralpak IC column, ee = 86% (HPLC: Chiralpak column IC, λ = 254 nm,
n-hexane/i-PrOH = 95:5, flow rate: 1.0 mL/min, 40 oC, tr(major) = 21.77
25
min, tr(minor) = 30.75 min). [α]D = -31.3o (c 0.5, CHCl3). 1H NMR (400
MHz, CDCl3): δ = 7.38-7.26 (m, 9H), 7.17 (d, J = 7.6 Hz, 0.5H), 7.02 (s,
1H), 6.93 (d, J = 7.5 Hz, 0.5H), 6.75 (d, J = 8.3 Hz, 2H), 6.55 (d, J = 8.3
Hz, 2H), 5.45-5.43 (m, 1H), 3.86-3.79 (m, 1H), 3.74 (s, 3H), 3.54 (br, 1H),
3.43-3.40 (m, 1H), 1.99 (s, 1.4H), 1.63 (s, 1.6H) (Contained the rotamer).
13C NMR (100 MHz, CDCl3): δ = 189.92, 189.87, 152.20, 143.26, 141.90,
137.85, 137.82, 137.05, 136.99, 134.59, 134.41, 130.78, 130.74, 130.23,
130.19, 129.18, 129.14, 128.85, 128.82, 128.78, 127.45, 126.72, 126.64,
126.62, 126.43, 126.18, 114.92, 114.46, 55.82, 52.81, 52.76, 47.67,
47.21, 17.31, 16.74 (Contained the rotamer). IR (KBr): ν (cm-1) 3362,
3056, 3028, 2929, 2831, 1681, 1513, 1453, 1401, 1236, 1035, 909, 819,
762, 699. HRMS (ESI, m/z) calcd for C26H25N3NaO2 [M+Na]+: 434.1839,
found: 434.1834.
(S)-3-((4-bromophenyl)amino)-2-phenyl-1-(1-(o-tolyl)-1H-imidazol-2-
yl)propan-1-one (3ch): colorless oil (87.5 mg, yield: 95%). Enantiomeric
excess was determined by HPLC analysis using a Chiralpak IC column,
ee = 95% (HPLC: Chiralpak column IC, λ = 254 nm, n-hexane/i-PrOH =
95:5, flow rate: 1.0 mL/min, 40 oC, tr(major) = 7.49 min, tr(minor) = 8.96
min). [α]D25 = -30.1o (c 0.5, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.39-
7.20 (m, 11H), 7.15 (d, J = 7.6 Hz, 0.5H), 7.03 (d, J = 1.4 Hz, 1H), 6.92 (d,
J = 7.9 Hz, 0.5H), 6.45 (dd, J = 1.8 Hz, 8.6 Hz, 2H), 5.44 (t, J = 7.4 Hz,
1H), 3.87-3.80 (m, 2H), 3.43-3.40 (m, 1H), 1.98 (s, 1.3H), 1.62 (s, 1.7H)
(Contained the rotamer). 13C NMR (100 MHz, CDCl3): δ = 189.62, 189.59,
146.65, 143.16, 137.76, 137.73, 136.73, 136.68, 134.52, 134.39, 131.96,
130.80, 130.77, 130.33, 130.29, 129.24, 129.19, 128.93, 128.90, 128.72,
127.59, 126.85, 126.67, 126.39, 126.18, 114.53, 109.05, 108.99, 52.54,
46.47, 46.02, 17.28, 16.72 (Contained the rotamer). IR (KBr): ν (cm-1)
3308, 3029, 2955, 2924, 2854, 1681, 1594, 1493, 1454, 1402, 1313,
1258, 909, 813, 762, 699. HRMS (ESI, m/z) calcd for C25H22BrN3NaO
[M+Na]+: 482.0838, found: 482.0841.
(S)-3-((2-methoxyphenyl)amino)-2-phenyl-1-(1-(o-tolyl)-1H-imidazol-
2-yl)propan-1-one (3ce): colorless oil (81.0 mg, yield: 98%).
Enantiomeric excess was determined by HPLC analysis using
a
Chiralpak IC column, ee = 93% (HPLC: Chiralpak column IC, λ = 254 nm,
n-hexane/i-PrOH = 95:5, flow rate: 1.0 mL/min, 40 oC, tr(major) = 11.81
25
min, tr(minor) = 16.87 min). [α]D = -67.3o (c 0.5, CHCl3). 1H NMR (400
MHz, CDCl3): δ = 7.41-7.21 (m, 9H), 7.16 (d, J = 7.6 Hz, 0.5H), 7.01 (s,
1H), 6.95 (d, J = 7.8 Hz, 0.5H), 6.89-6.84 (m, 1H), 6.72-6.70 (m, 2H),
6.66-6.61 (m, 1H), 5.52-5.46 (m, 1H), 4.41 (s, 1H), 3.97-3.89 (m, 1H),
3.72 (d, J = 1.8 Hz, 3H), 3.48-3.43 (m, 1H), 1.97 (s, 1.4H), 1.64 (s, 1.6H)
(Contained the rotamer). 13C NMR (100 MHz, CDCl3): δ = 189.87, 189.80,
146.89, 146.86, 143.33, 137.90, 137.77, 137.71, 137.18, 137.14, 134.68,
134.42, 130.77, 130.73, 130.21, 129.16, 129.11, 128.82, 128.79, 128.74,
128.73, 127.39, 126.63, 126.61, 126.49, 126.19, 121.42, 116.54, 116.48,
110.07, 109.96, 109.63, 109.58, 55.40, 55.36, 52.86, 52.78, 46.34, 45.98,
17.16, 16.78 (Contained the rotamer). IR (KBr): ν (cm-1) 3064, 2952,
1681, 1601, 1514, 1454, 1403, 1249, 1221, 1028, 909, 762, 739, 699.
HRMS (ESI, m/z) calcd for C26H25N3NaO2 [M+Na]+: 434.1839, found:
434.1833.
(S)-3-((2-bromophenyl)amino)-2-phenyl-1-(1-(o-tolyl)-1H-imidazol-2-
yl)propan-1-one (3ci): colorless oil (90.5 mg, yield: 98%). Enantiomeric
excess was determined by HPLC analysis using a Chiralpak IC column,
ee = 99.4% (HPLC: Chiralpak column IC, λ = 254 nm, n-hexane/i-PrOH =
98:2, flow rate: 1.0 mL/min, 40 oC, tr(major) = 5.85 min, tr(minor) = 6.43
min). [α]D25 = -54.8o (c 0.5, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.41-
7.23 (m, 10H), 7.18-7.16 (m, 1.5H), 7.04 (s, 1H), 6.97(d, J = 7.7 Hz,
0.5H), 6.74-6.71 (m, 1H), 6.54 (t, J = 7.5 Hz, 1H), 5.52-5.46 (m, 1H),
4.52-4.45 (m, 1H), 3.97-3.90 (m, 1H), 3.53-3.43 (m, 1H), 1.98 (s, 1.5H),
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10.1002/ejoc.201700463
European Journal of Organic Chemistry
FULL PAPER
1.68 (s, 1.4H) (Contained the rotamer). 13C NMR (100 MHz, CDCl3): δ =
189.50, 144.49, 144.44, 143.21, 137.82, 136.73, 134.78, 134.38, 132.46,
130.79, 130.73, 130.36, 129.22, 129.18, 128.94, 128.92, 128.67, 128.60,
127.60, 126.85, 126.70, 126.60, 126.52, 126.14, 117.89, 117.87, 111.46,
111.31, 109.88, 109.78, 52.38, 46.42, 46.13, 17.37, 16.84 (Contained the
rotamer). IR (KBr): ν (cm-1) 3402, 3060, 3029, 2926, 2858, 1681, 1597,
1502, 1454, 1403, 1317, 1019, 909, 762, 740, 699. HRMS (ESI, m/z)
calcd for C25H22BrN3NaO [M+Na]+: 482.0838, found: 482.0839.
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Acknowledgements
We thank Prof. Daqiang Yuan (Fujian Institute of Research on
the Structure of Matter, Chinese Academy of Sciences) for his
kind help in an X-ray analysis. This work was supported by the
Strategic Priority Research Program of the Chinese Academy of
Sciences, Grant No. XDB20000000 and 100 Talents
Programme of the Chinese Academy of Sciences.
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Keywords: Asymmetric catalysis • Chiral-at-metal complexes •
Mannich reaction • 1,3,5-Triaryl-1,3,5-triazinanes •
Enantioselectivity
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10.1002/ejoc.201700463
European Journal of Organic Chemistry
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Key Topic*
Jun Gong, Shi-Wu Li, Saira Qurban, and
Qiang Kang*
Page No. – Page No.
Title
Highly efficient enantioselective Mannich reaction of 2-acyl imidazoles with 1,3,5-
triazinanes catalysed by Chiral-at-metal Rh(III) complexes is developed, affording
the corresponding adducts in good yields with excellent enantioselectivities.
*Chiral-at-metal rhodium complex for highly efficient enantioselective Mannich reaction.
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