α-Oxo-β-butyrolactam, N -containing pronucleophile in organocatalytic one-pot assembly of butyrolactam-fused indoloquinolizidines

Article abstract of DOI:10.1021/jo301192d

The ambident reactivity of α-oxo-β-butyrolactam has been explored in an organocatalytic one-pot Michael/Pictet-Spengler sequence. The synthetically interesting and medicinally important pentacyclic butyrolactam-fused indoloquinolizidines can be efficiently constructed in a highly stereocontrolled manner. Importantly, the chemistry described herein provides a general catalytic method for the enantioselective synthesis of butyrolactam-incorporated chemical entities.

Full text of DOI:10.1021/jo301192d

Note
pubs.acs.org/joc
α‑Oxo-γ-Butyrolactam, N‑Containing Pronucleophile in
Organocatalytic One-Pot Assembly of Butyrolactam-Fused
Indoloquinolizidines
Hai-Liang Zhu, Jun-Bing Ling, and Peng-Fei Xu*
State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou
730000, P. R. China
S
* Supporting Information
ABSTRACT: The ambident reactivity of α-oxo-γ-butyrolac-
tam has been explored in an organocatalytic one-pot Michael/
Pictet−Spengler sequence. The synthetically interesting and
medicinally important pentacyclic butyrolactam-fused indolo-
quinolizidines can be efficiently constructed in a highly
stereocontrolled manner. Importantly, the chemistry described
herein provides a general catalytic method for the enantioselective synthesis of butyrolactam-incorporated chemical entities.
characteristics, which enables various sequential or cascade
he development of new and efficient approaches to
Tfunctionalized molecules with structural complexity or transformations with suitable nucleophiles or electrophiles
leading to valuable synthetic intermediates with increased
complexity and diversity, such as α-/β-functionalized or ring-
fused butyrolactams.
biological importance continues to be a crucial, yet challenging,
target in modern organic synthesis.1 The identification of new
substrate with diverse reactivity is essential to achieve this goal.
Chiral butyrolactams is a common motif found in numerous
naturally occurring molecules and biologically active com-
pounds.2 Established strategies for catalytic asymmetric syn-
thesis of this important target were mostly limited to α,β-
unsaturated γ-butyrolactam and 2-siloxypyrrole-related trans-
formations.3 Hence, discovery of new and general catalytic
method for direct formation of chiral butyrolactam is still in
demand.
In the field of organocatalysis, compared to 1,3-dicarbonyl
compounds,4 there were only a handful of examples exploiting
1,2-dicarbonyl compounds (1,2-diketone, α-ketoester, and α-
ketoamide) as carbon-centered nucleophiles despite their
diverse reactivity and synthetic value.5 In hopes of developing
a straightforward approach to functionalized chiral butyrolac-
tams and related five-membered nitrogen-containing hetero-
cycles, we decided to explore the reactivity of α-ketobutyr-
olactam6 (Figure 1), which featured both the reaction pattern
of α-ketoamide and the synthetic value of butyrolactam-type N-
heterocycles. From the synthetic point of view, this cyclic α-
ketoamide combines both nucleophilic and electrophilic
Developing more effective strategies to generate molecule
libraries for biological screening is a challenging and significant
exploitation for organic chemists. This ambition could be
achieved through a facile modification of a single privileged
scaffold, such as transformation of functional groups or
substitution of ring patterns. Indoloquinolizidine7 constitutes
one key structural backbone of a large number of medicinally
interesting natural indole alkaloids such as normacusine,
reserpine, mitragynine, dihydroantirhine, and tangutorine
(Figure 2). The combination of butyrolactam and indoloqui-
nolizidine may introduce improved molecular diversity and
potential biological applications. However, to our knowledge,
butyrolactam-fused indoloquinolizidines have not been inves-
tigated. Over the past several years, the organocatalyzed one-
pot strategies8 have paved the way for the direct construction of
indoloquinolizidine scaffold from simple starting materials.9 In
connection with our interest in the facile and stereoselective
construction of functionalized chiral molecules by means of
organocatalysis, herein we present a organocatalytic one-pot
Michael/Pictet−Spengler sequence for the rapid construction
of pentacyclic butyrolac tam-fused indoloquinolizidine with
highly stereochemical control.
We envisaged that α-oxo-γ-butyrolactam 2 could be utilized
as readily available N-containing pronucleophile, and the
unprecedented butyrolactam-fused indoloquinolizidine could
be constructed by means of organocatalyzed three-component
coupling reaction of 2, α,β-unsaturated aldehyde 3, and
tryptamine. On the basis of the iminium ion activation
Figure 1. Development of new nucleophiles for the synthesis of chiral
butyrolactams and related N-heterocycles.
Received: June 22, 2012
Published: August 13, 2012
© 2012 American Chemical Society
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The Journal of Organic Chemistry
Note
Figure 2. Representative natural products incorporating the indoloquinolizidine scaffold.
Scheme 1. Proposed Sequential Michael Addition/Pictet−Spengler Cyclization to Butyrolactam-Fused Indoloquinolizidine
Scaffold
strategy,10 secondary amine catalyzed Michael addition of 2 to
3 would initiate the reaction sequence to deliver the chiral
hemiacetal A. Under the acidic conditions, the activated
hemiacetal A reacts with tryptamine to generate the iminium
ion B, which then undergoes a diastereoselective Pictet−
Spengler reaction11 to afford the anticipated butyrolactam-fused
indoloquinolizidine (Scheme 1).
utilizing CSA or TFA, but the yield was lower than that in the
case of benzoic acid. The results are summarized in Table 1.
The extension of this one-pot procedure to various substrates
was then investigated under the established conditions. The
results are summarized in Table 2. For α-oxo-γ-butyrolactam 2,
a wide range of α,β-unsaturated aldehydes with β-aryl groups,
either bearing electron-withdrawing or electron-donating
substitutions, could be efficiently utilized. With respect to aryl
substitution, ortho-, para-, and meta-substituents were all well
tolerated, leading to desired products with moderate to high
yields and high enantioselectivities. However, aldehydes bearing
electron-donating substituents on the phenyl ring delivered
lower diastereoselectivities. To our delight, for 2-furylacrolein,
the desired product was also obtained with 76% yield and low
diastereoselectivity (entry 16). The absolute configuration of
4o was determined to be (2R,13bR) according to the X-ray
crystal structure of compounds 4o and 5.13
To further illustrate the synthetic value of α-oxo-γ-
butyrolactam, o-aminobenzylamine was employed as a reaction
partner with two nucleophilic sites to trap the hemiacetal A in
this organocatalytic one-pot sequence. The interesting
heterocyclic architecture, butyrolactam-incorporated pyridoqui-
nazoline, can be efficiently generated in moderate yield and
with high enantioselectivity (Scheme 2). The absolute
configuration of 5 was determined to be (4R,5aR) by the X-
ray crystal structure of compound 5.13
With this speculation in mind, we began the investigation by
testing the model reaction between 2a and 3a in the presence
of diarylprolinol TMS ether12 1b. After complete formation of
the hemiacetal, benzoic acid and tryptamine were added. We
were pleased to find that further reaction proceeded smoothly
at room temperature to furnish the desired butyrolactam-fused
indoloquinolizidine with good yield and high stereoselectivity.
The successful implementation of one-pot transformation in
a cascade process requires the optimization of the first step to
make it compatible with the consecutive ones. In order to
simplify the reaction system of the first step, we switched the
ratio of 3a to 2a from 2:1 to 2:3. After an initial screening of
several solvents for this entire one-pot sequence performed at
room temperature, it was found that dichloromethane was the
most suitable one in terms of both diastereo- and
enantioselectivities. With the optimal solvent, various diary-
lprolinol-derived catalysts were screened briefly in the model
reaction. The enantioselectivities varied depending on the
organocatalysts used. As expected, the use of 1a and 1b gave
the same results only with a slightly different yield. For the
second step, the final desired product could also be obtained
With regard to the mechanism of this reaction sequence, we
assume that initially enal 3 is activated by catalyst 1a through
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Note
Table 1. Optimization of the One-Pot Reaction Conditions
a
b
c
d
entry
solvent
cat.
yield (%)
dr
e e (%)
1
2
toluene
THF
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
74
32
4:1
3:1
94
93
3
MeCN
EtOH
DCE
14
4
<10
81
5
4:1
4:1
4:1
4:1
4:1
94
95
6
DCM
DCM
DCM
DCM
DCM
87
7
85
−95
−94
−87
8
81
9
86
10
18
a
Unless otherwise noted, the reaction was carried out as follows: (step 1) 2 (0.3 mmol), 3 (0.2 mmol), 1 (0.04 mmol), PhCO2H (0.04 mmol); (step
b
c
1
2) tryptamine (0.24 mmol), PhCO2H (0.24 mmol) in dry CH2Cl2 (1.5 mL) at room temperature. Isolated yields. Determined by H NMR or
HPLC analysis. Determined by HPLC analysis of the main diastereomer.
d
Table 2. Scope of the Reaction
a
b
c
d
entry
R1, R2, R3
Ph, Bn, H
4
yield (%)
dr
ee (%)
1
2
4a
4b
4c
4d
4e
4f
87
74
71
75
81
72
79
69
83
76
62
62
53
60
84
76
4:1
4:1
95
96
96
96
95
95
96
93
95
97
93
93
93
93
95
90
o-MeOPh, Bn, H
p-MeOPh, Bn, H
p-MePh, Bn, H
p-BrPh, Bn, H
m-ClPh, Bn, H
p-ClPh, Bn, H
p-FPh, Bn, H
3
4:1
4
3:1
5
15:1
>20:1
17:1
8:1
6
7
4g
4h
4i
8
9
2,4-diChloroPh, Bn, H
p-CNPh, Bn, H
Ph, allyl, H
3:1
10
11
12
13
14
15
16
4j
8:1
4k
4l
>20:1
>20:1
>20:1
8:1
p-MePh, allyl, H
p-BrPh, allyl, H
p-CNPh, allyl, H
Ph, Bn, MeO
4m
4n
4o
4p
2:1
2-furyl, Bn, H
3:1
a
General conditions: (step 1) α-oxo-γ-butyrolactam (0.3 mmol), enal (0.2 mmol), 1a (0.04 mmol), PhCO2H (0.04 mmol) in CH2Cl2 (1.5 mL).
b
c
1
(step 2) Tryptamine (0.24 mmol), PhCO2H (0.24 mmol). Isolated yield after column chromatography. Determined by H NMR or HPLC.
d
Determined by the HPLC analysis of the major diastereomer.
the reactive iminium ion A. Because of the shielding effect of
catalyst 1a, subsequent stereoselective Re-facial Michael
addition by α-oxo-γ-butyrolactam 2 occurs and generates
intermediate B, which undergoes subsequent tautomerization
and hydrolysis to form C. The masked 1,5-dicarbonyl
compounds C could efficiently condense with tryptamine to
give rise to iminium ion D under acidic conditions, and
intermediate D performs diastereoseletive Pictet−Spengler
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The Journal of Organic Chemistry
Note
Scheme 2. Further Investigation of the Reaction Potential
Scheme 3. Plausible Catalytic Cycle of One-Pot Michael/Pictet−Spengler Sequence
spectra are reported in wavenumbers (cm−1). HRMS were performed
on FT-ICRMS mass instrument (ESI). Enantiomeric excess values
were determined by HPLC with employing a Daicel Chirapak AD-H,
OD-H, and AS-H and eluting with i-PrOH and n-hexane. Optical
rotation was measured on polarimeter with [α]D values reported in
degrees; concentration (c) is in g/100 mL. α-Oxo-γ-butyrolactam 2
were prepared according to the previously reported methods.14
General Procedure for the Synthesis of 4. To a solution of
compound 2 (0.3 mmol) and catalyst 1 (0.04 mmol) in CH2Cl2 (1.5
mL) were added enal 3 (0.2 mmol) and benzoic acid (0.04 mmol),
and the mixture was stirred at room temperature. The reaction was
monitored by TLC analysis. After full conversion of 3, tryptamine or
substituted tryptamine (0.24 mmol) and benzoic acid (0.24 mmol)
were added to the solution. After completion of the reaction, the
mixture was subjected directly to flash column chromatography
yielding the corresponding products.
cyclization to afford butyrolactam-fused indoloquinolizidine 4
owing to the steric hindrance of the R1 group (Scheme 3).
In conclusion, we have developed an organocatalytic one-pot
strategy for the stereoselective construction of synthetically
interesting and medicinally important pentacyclic butyrolactam-
fused indoloquinolizidines. Promoted by simple chiral secon-
dary amine and benzoic acid, the multicomponent coupling
reaction of α-oxo-γ-butyrolactam, α,β-unsaturated aldehyde,
and tryptamine proceeded efficiently with highly stereo-
chemical control. For the first time, α-oxo-γ-butyrolactam was
exploited as reactive pronucleophile to directly assemble chiral
butyrolactams. This chemistry provides a general catalytic
method for the enantioselective synthesis of butyrolactam-
incorporated chemical entities. The results presented here
potentially have an impact on new reaction design and scaffold
diversity synthesis of five-membered N-heterocyclic systems.
1
4a: 77.4 mg (87% yield); gray-white solid; mp 128−130 °C; H
NMR (400 MHz, CDCl3) δ = 8.21 (s, 1H), 7.46−7.41 (m, 1H), 7.39−
7.18 (m, 7H), 7.14−7.09(m, 4H), 7.08−7.03 (m, 2H), 4.76−4.68 (m,
2H), 4.47 (d, J = 6.8 Hz, 1H), 4.36 (d, J = 15.2 Hz, 1H), 3.58 (t, J =
5.6 Hz, 1H), 3.48−3.35 (m, 3H), 2.86−2.70 (m, 2H), 2.43−2.35 (m,
1H), 2.25−2.19 (m, 1H); 13C NMR (100 MHz, CDCl3) δ = 167.4,
143.6, 137.8, 137.3, 135.9, 132.7, 128.8, 128.6, 128.0, 127.9, 127.4,
127.3, 127.0, 123.6, 121.7, 119.6, 118.2, 110.8, 110.3, 51.4, 49.0, 46.4,
43.6, 37.8, 34.9, 21.3 ppm; IR (KBr) = 3287, 3027, 2840, 2357, 2049,
2024, 1664, 1493, 1452, 1402, 1360, 1253, 1225, 920, 744, 702, 571,
424 cm−1; HRMS (ESI) calcd for C30H27N3O [M + Na]+ 468.2046,
EXPERIMENTAL SECTION
■
General Remarks. Chemicals and solvents were either purchased
from commercial suppliers or purified by standards techniques.
Analytical thin-layer chromatography (TLC) was performed on silica
gel plates with F-254 indicator, and compounds were visualized by
irradiation with UV light. Flash chromatography was carried out
1
utilizing silica gel 200−300 mesh. H NMR and 13C NMR spectra
were recorded on 1H 400 MHz and 13C 100 MHz spectrometers. The
spectra were recorded in CDCl3 as solvents; 1H and 13C NMR
chemical shifts are reported in ppm relative to either the residual
solvent peak (13C) (δ = 77.00 ppm) or TMS (1H) (δ = 0 ppm) as an
internal standard. Data for 1H NMR are reported as follows: chemical
shift (δ ppm), multiplicity (s = singlet, d = doublet, t = triplet, m =
multiplet, dd = doublet), integration, coupling constant (Hz) and
assignment. Data for 13C NMR are reported as chemical shift. IR
found 468.2062; [α]20 = −31.1 (c 2.25, CH2Cl2, 95% ee. The
D
enantiomeric excess was determined by HPLC with an AD-H column.
(n-hexane/i-PrOH = 80:20), 1.0 mL/min; major enantiomer tR = 23.4
min, minor enantiomer tR = 33.0 min.
1
4b: 70.3 mg (74% yield); gray-white solid; mp 123−125 °C; H
NMR (400 MHz, CDCl3) δ = 7.72 (s, 1H), 7.49−7.43 (m, 1H), 7.29−
7.19 (m, 7H), 7.12−7.05 (m, 3H), 6.89−6.86 (m, 2H), 4.69 (d, J =
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The Journal of Organic Chemistry
Note
14.8 Hz, 1H), 4.64−4.59 (m, 1H), 4.50 (d, J = 14.8 Hz, 1H), 4.38−
4.35 (m, 1H), 4.06 (t, J = 4.8 Hz, 1H), 3.81 (s, 3H), 3.57 (d, J = 18.0
Hz, 1H), 3.51−3.43 (m, 2H), 2.91−2.79 (m, 2H), 2.23−2.20 (m, 2H);
13C NMR (100 MHz, CDCl3) δ = 167.5, 156.7, 138.3, 137.4, 135.9,
133.1, 131.5, 129.2, 128.6, 128.3, 127.9, 127.4, 127.3, 124.1, 121.5,
120.5, 119.3, 118.1, 110.7, 110.4, 109.9, 55.2, 51.2, 49.1, 46.3, 43.3,
32.7, 31.6, 21.5 ppm; IR (KBr) = 3277, 3028, 2910, 2837, 2049, 2023,
1664, 1490, 1454, 1401, 1288, 1243, 1113, 1095, 1028, 743, 702, 571,
437 cm−1; HRMS (ESI) calcd for C31H29N3O2 [M + H]+ 476.2333,
enantiomeric excess was determined by HPLC with an AD-H column.
(n-hexane/i-PrOH = 70:30), 1.0 mL/min; major enantiomer tR = 10.6
min, minor enantiomer tR = 17.7 min.
1
4g: 75.7 mg (79% yield); gray-white solid; mp 100−102 °C; H
NMR (400 MHz, CDCl3) δ = 8.09 (b, 1H), 7.49−7.43 (m, 1H),
7.28−7.22 (m, 6H), 7.16−7.14 (m, 2H), 7.12−7.06 (m, 3H), 4.81−
4.75(m, 1H), 4.69 (d, J = 15.2 Hz, 1H), 4.46 (d, J = 6.0 Hz, 1H), 4.41
(d, J = 15.2 Hz, 1H), 3.57 (t, J = 5.6 Hz, 1H), 3.48−3.35 (m, 3H),
2.88−2.73 (m, 2H), 2.41−2.34 (m, 1H), 2.22−2.17 (m, 1H); 13C
NMR (100 MHz, CDCl3) δ = 167.3, 141.9, 137.8, 137.1, 135.9, 133.4,
132.7, 132.5, 130.1, 129.3, 128.9, 128.6, 127.8, 127.4, 121.6, 119.5,
118.1, 110.9, 110.1, 51.5, 48.9, 46.3, 43.7, 37.2, 34.7, 21.2 ppm; IR
(KBr) = 3292, 3030, 2918, 2843, 2044, 2023, 1666, 1491, 1453, 1405,
found 476.2337; [α]20 = 20.0 (c 1.0, CH2Cl2, 96% ee. The
D
enantiomeric excess was determined by HPLC with an OD-H column
(n-hexane/i-PrOH = 80:20), 1.0 mL/min; major enantiomer tR = 30.5
min, minor enantiomer tR = 23.9 min.
1310, 1225, 1094, 1012, 833, 744, 701, 571 cm−1; HRMS (ESI) calcd
1
4c: 67.4 mg (71% yield); gray-white solid; mp 104−106 °C; H
+
for C30H26ClN3O [M + H] 480.1837, found 480.1830; [α]20
=
NMR (400 MHz, CDCl3) δ = 8.16 (s, 1H), 7.48−7.46 (m, 1H), 7.26−
7.20 (m, 4H), 7.15−7.03 (m, 6H), 6.81−6.79 (m, 2H), 4.75−4.66 (m,
2H), 4.47(d, J = 5.6 Hz, 1H), 4.38 (d, J = 15.2 Hz, 1H), 3.74 (s, 1H),
3.55 (t, J = 5.6 Hz, 1H), 3.49−3.36 (m, 3H), 2.85−2.71 (m, 2H),
2.39−2.33 (m, 1H), 2.22−2.16 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ = 167.5, 158.4, 137.4, 137.2, 135.9, 135.4, 132.9, 128.8,
128.5, 127.7, 127.3, 127.2, 124.7, 121.4, 119.3, 118.1, 114.1, 110.9,
109.8, 55.1, 51.6, 48.9, 46.2, 43.7, 36.8, 34.7, 21.2 ppm; IR (KBr) =
3286, 2913, 2838, 2021, 1665, 1510, 1454, 1249, 1176, 1033, 835, 741,
702, 568, 429 cm−1; HRMS (ESI) calcd for C26H24N3O2 [M + H]+
D
−65.0 (c 1.4, CH2Cl2, 96% ee). The enantiomeric excess was
determined by HPLC with an AD-H column (n-hexane/i-PrOH =
80:20), 1.0 mL/min; major enantiomer tR = 16.3 min, minor
enantiomer tR = 32.9 min.
4h: 63.9 mg (69% yield); gray-white solid; mp 96−98 °C; 1H NMR
(400 MHz, CDCl3) δ = 7.93 (b, 1H), 7.50−7.48 (m, 1H), 7.29−7.22
(m, 4H), 7.17−7.07 (m, 6H), 7.01−6.96 (m, 2H), 4.82−4.71 (m, 1H),
4.71 (d, J = 14.8 Hz, 1H), 4.48 (d, J = 6.0 Hz, 1H), 4.42 (d, J = 15.2
Hz, 1H), 3.60 (t, J = 5.6 Hz, 1H), 3.49−3.37 (m, 3H), 2.88−2.75 (m,
2H), 2.41−2.34 (m, 1H), 2.23−2.18 (m, 1H) ; 13C NMR (100 MHz,
CDCl3) δ = 167.3, 161.7 (d, J = 244.0 Hz), 139.1, 137.7, 137.2, 135.9,
132.5, 129.4, 128.6, 127.8, 127.4, 123.4, 121.7, 119.5, 118.2, 115.7,
115.5, 110.8, 110.2, 51.5, 48.9, 46.4, 43.6, 37.0, 34.9, 21.2 ppm; IR
(KBr) = 3669, 3311, 3031, 2912, 2842, 2049, 2023, 1661, 1508, 1453,
1401, 1225, 1157, 1109, 838, 741, 701, 651, 570, 429 cm−1; HRMS
(ESI) calcd for C30H26FN3O [M + H]+ 464.2133, found 464.2136;
476.2333, found 476.2321; [α]20 = −67.7 (c 0.9, CH2Cl2, 96% ee).
D
The enantiomeric excess was determined by HPLC with an AD-H
column (n-hexane/i-PrOH = 65:35), 1.0 mL/min; major enantiomer
tR = 10.2 min, minor enantiomer tR = 22.8 min.
4d: 68.8 mg (75% yield); gray-white solid; mp 94−96 °C; 1H NMR
(400 MHz, CDCl3) δ = 7.91 (b, 1H), 7.48 (d, J = 7.2 Hz, 1H), 7.29−
7.19 (m, 4H), 7.18−7.14 (m, 2H), 7.13−7.03 (m, 4H), 7.07−7.03 (m,
2H), 4.75−4.69 (m, 2H), 4.47 (d, J = 5.6 Hz, 1H), 4.41 (d, J = 15.2
Hz, 1H), 3.58 (t, J = 5.6 Hz, 1H), 3.53−3.38 (m, 3H), 2.88−2.75 (m,
2H), 2.37−2.31 (m, 4H), 2.23−2.17 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ = 167.5, 140.5, 137.6, 137.3, 136.6, 135.9, 132.8, 129.4,
128.6, 127.8, 127.4, 127.3, 124.3, 121.6, 119.4, 118.1, 110.8, 110.1,
110.0, 51.5, 49.0, 46.4, 43.7, 37.4, 34.9, 21.3, 20.9 ppm; IR (KBr) =
3302, 3029, 2921, 2845, 2022, 1657, 1513, 1452, 1399, 1317, 1224,
1103, 817, 739, 701, 569, 434 cm−1; HRMS (ESI) calcd for
[α]20 = −30.3 (c 1.45, CH2Cl2, 93% ee). The enantiomeric excess
D
was determined by HPLC with an AD-H column (n-hexane/i-PrOH =
70:30), 1.0 mL/min; major enantiomer tR = 9.2 min, minor
enantiomer tR = 15.8 min.
1
4i: 85.1 mg (83% yield); gray-white solid; mp 122−124 °C; H
NMR (400 MHz, CDCl3) δ = 7.88 (b, 1H), 7.50−7.41 (m, 2H),
7.29−7.18 (m, 7H), 7.12−7.06 (m, 3H), 4.76−4.70 (m, 2H), 4.48 (d, J
= 14.8 Hz, 1H), 4.33 (d, J = 8.8 Hz, 1H), 4.13−4.07 (m, 1H), 3.58−
3.42 (m, 3H), 2.92−2.78 (m, 2H), 2.34−2.27(m, 1H), 2.19(d, J = 13.6
Hz, 1H) ; 13C NMR (100 MHz, CDCl3) δ = 167.1, 139.4, 139.1,
137.1, 135.9, 134.1, 133.3, 132.2, 130.7, 129.7, 128.7, 128.0, 127.5,
127.3, 127.2, 121.7, 120.6, 119.5, 118.2, 110.8, 110.1, 50.8, 48.8, 46.4,
43.1, 34.5, 32.9, 21.5 ppm; IR (KBr) = 3607, 3302, 3059, 2919, 2843,
2049, 2024, 1668, 1557, 1494, 1465, 1404, 1309, 1225, 1201, 1102,
C31H29N3O [M + H]+ 460.2383, found 460.2387; [α]20 = 43.3 (c
D
1.2, CH2Cl2, 96% ee). The enantiomeric excess was determined by
HPLC with an AS-H column. (n-hexane/i-PrOH = 85:15), 1.0 mL/
min; major enantiomer tR = 27.0 min, minor enantiomer tR = 18.8 min.
1
4e: 84.7 mg (81% yield); gray-white solid; mp 134−136 °C; H
NMR (400 MHz, CDCl3) δ = 8.24 (b, 1H), 7.48−7.38 (m, 3H),
7.28−7.21 (m, 4H), 7.15−7.05(m, 4H), 7.05−7.01 (m, 2H), 4.81−
4.76 (m, 1H), 4.70(d, J = 15.2 Hz, 1H), 4.45−4.37 (m, 2H), 3.55 (t, J
= 5.6 Hz, 1H), 3.47−3.33 (m, 3H), 2.86−2.71 (m, 2H), 2.41−2.34 (m,
1H), 2.22−2.16 (m, 1H); 13C NMR (100 MHz, CDCl3) δ = 167.3,
142.4, 137.8, 137.1, 135.9, 132.5, 131.8, 129.6, 128.6, 127.8, 127.4,
127.2, 123.0, 121.6, 120.7, 119.5, 118.2, 110.9, 110.0, 51.5, 48.8, 46.3,
43.6, 37.2, 34.6, 21.2 ppm; IR (KBr): = 3265, 3058, 2910, 2842, 2049,
2022, 1661, 1553, 1487, 1458, 1402, 1262, 1223, 1071, 1009, 924, 827,
1048, 869, 820, 737, 571, 434 cm−1; HRMS (ESI) calcd for
+
C30H25Cl2N3O [M + H] 514.1447, found 514.1439; [α]20 = 4.6
D
(c 1.95, CH2Cl2, 95% ee). The enantiomeric excess was determined by
HPLC with an AD-H column (n-hexane/i-PrOH = 80:20), 1.0 mL/
min; major enantiomer tR = 25.1 min, minor enantiomer tR = 29.3 min.
1
4j: 71.4 mg (76% yield); gray-white solid; mp 140−142 °C; H
NMR (400 MHz, CDCl3) δ = 8.19 (b, 1H), 7.55−7.47 (m, 3H),
7.29−7.24 (m, 6H), 7.17−7.08 (m, 4H), 4.87−4.82 (m, 1H), 4.69 (d, J
= 14.8 Hz, 1H), 4.47−4.41 (m, 2H), 3.67 (t, J = 6.2 Hz, 1H), 3.43−
3.36 (m, 3H), 2.88−2.74 (m, 2H), 2.45−2.39 (m, 1H), 2.28−2.23 (m,
1H); 13C NMR (100 MHz, CDCl3) δ = 167.1, 149.1, 138.2, 137.0,
135.9, 132.5, 132.2, 128.8, 128.6, 127.8, 127.5, 127.2, 121.7, 121.1,
119.5, 118.4, 118.2, 110.9, 110.7, 110.1, 51.4, 48.7, 46.4, 43.5, 37.9,
34.5, 21.3 ppm; IR (KBr) = 3296, 2916, 2842, 2227, 2022, 1671, 1452,
1405, 1305, 1225, 1102, 841, 744, 701, 565, 433 cm−1; HRMS (ESI)
739, 568, 530, 438 cm−1; HRMS (ESI) calcd for C30H26BrN3O [M +
+
H] 524.1332, found 524.1333; [α]20 = −70.0 (c 2.4, CH2Cl2, 95%
D
ee). The enantiomeric excess was determined by HPLC with an AD-H
column (n-hexane/i-PrOH = 80:20), 1.0 mL/min; major enantiomer
tR = 16.5 min, minor enantiomer tR = 35.4 min.
1
4f: 68.9 mg (72% yield); gray-white solid; mp 116−118 °C; H
NMR (400 MHz, CDCl3) δ = 8.08 (b, 1H), 7.48−1.47 (m, 1H),
7.29−7.21 (m, 6H), 7.16−7.02 (m, 6H), 4.82−4.76 (m, 1H), 4.73 (d, J
= 15.2 Hz, 1H), 4.47 (d, J = 6.4 Hz, 1H), 4.40 (d, J = 15.2 Hz, 1H),
3.58 (t, J = 5.6 Hz, 1H), 3.51−3.35 (m, 3H), 2.87−2.72 (m, 2H),
2.35−2.42 (m, 1H), 2.24−2.18 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ = 167.3, 145.6, 137.9, 137.1, 135.9, 134.6, 132.5, 130.0,
128.6, 128.1, 127.7, 127.4, 127.2, 127.1, 126.1, 122.7, 121.7, 119.5,
118.2, 110.9, 110.1, 51.5, 48.9, 46.4, 43.6, 37.5, 34.6, 21.2 ppm; IR
(KBr) = 3306, 2913, 2031, 1662, 1453, 1317, 1225, 1112, 1062, 745,
699 cm−1; HRMS (ESI) calcd for C30H26ClN3O [M + H]+: 480.1837,
calcd for C31H26N4O [M + H+] 471.2179, found 471.2168; [α]20
=
D
−81.4 (c 1.4, CH2Cl2, 96% ee). The enantiomeric excess was
determined by HPLC with an AD-H column (n-hexane/i-PrOH =
70:30), 1.0 mL/min; major enantiomer tR = 13.7 min, minor
enantiomer tR = 28.4 min.
1
4k: 49.0 mg (62% yield); gray-white solid; mp 130−132 °C; H
NMR (400 MHz, CDCl3) δ = 7.90 (b, 1H), 7.48 (d, J = 7.6 Hz, 1H),
7.36−7.19 (m, 6H), 7.15−7.07 (m, 2H), 5.76−5.69 (m, 1H), 5.12−
5.06 (m, 2H), 4.75−4.71 (m, 1H), 4.50 (d, J = 5.6 Hz, 1H), 4.11−4.05
(m, 1H), 3.95−3.90 (m, 1H), 3.67 (t, J = 5.6 Hz, 1H), 3.58−3.52 (m,
found: 480.1826; [α]20 = −33.0 (c 1.0, CH2Cl2, 95% ee). The
D
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The Journal of Organic Chemistry
Note
2H), 3.41−3.35 (m, 1H), 2.83−2.76 (m, 2H), 2.43−2.24 (m, 2H); 13
C
95% ee). The enantiomeric excess was determined by HPLC with an
OD-H column (n-hexane/i-PrOH = 70:30), 1.0 mL/min; major
enantiomer tR = 28.5 min, minor enantiomer tR = 19.9 min
NMR (100 MHz, CDCl3) δ = 167.2, 143.5, 137.7, 135.8, 133.2, 132.7,
128.8, 128.1, 127.3, 127.0, 123.8, 121.6, 119.5, 118.2, 117.4, 110.8,
110.1, 51.5, 49.1, 45.1, 43.6, 37.8, 34.8, 21.2 ppm; IR (KBr) = 3273,
2926, 2845, 2022, 1661, 1456, 1400, 1315, 1223, 1144, 924, 744, 702,
567, 435 cm−1; HRMS (ESI) calcd for C26H25N3O [M + H]+
4p: 66.1 mg (76% yield); gray-white solid; mp 87−89 °C; 1H NMR
(400 MHz, CDCl3) δ = 8.03 (b, 1H), 7.50−7.48 (m, 1H), 7.32−7.19
(m, 7H), 7.13−7.08 (m, 2H), 6.27 (dd, J = 2.0, 2.8 Hz, 1H), 6.01 (d, J
= 2.8 Hz, 1H), 4.74−4.68 (m, 2H), 4.49−4.43 (m, 2H), 3.70 (t, J = 5.2
Hz, 1H), 3.66−3.52 (m, 2H), 3.44−3.37 (m, 1H), 2.85−2.75 (m, 2H),
2.42−2.37 (m, 1H), 2.28−2.21 (m, 1H) ; 13C NMR (100 MHz,
CDCl3) δ = 167.3, 155.9, 141.8, 137.4, 137.3, 135.9, 132.6, 130.1,
128.7, 128.4, 127.9, 127.4, 127.3, 121.7, 119.5, 118.2, 110.9, 110.3,
106.2, 51.8, 49.2, 46.4, 43.4, 31.6, 31.1, 21.3 ppm; IR (KBr) = 3319,
2930, 2829, 2049, 2023, 1668, 1644, 1452, 1316, 1226, 1139, 1008,
741, 725, 598, 557, 429 cm−1; HRMS (ESI) calcd for C28H25N3O2 [M
+ H+] 436.2020, found 436.2022; [α]20D = −44.5 (c 1.1, CH2Cl2, 90%
ee). The enantiomeric excess was determined by HPLC with an OD-H
column. (n-hexane/i-PrOH = 80:20), 1.0 mL/min; major enantiomer
tR = 22.2 min, minor enantiomer tR = 16.8 min.
396.2070, found 396.2075; [α]20 = −25.7 (c 1.05, CH2Cl2, 93%
D
ee). The enantiomeric excess was determined by HPLC with an OD-H
column (n-hexane/i-PrOH = 80:20), 1.0 mL/min; major enantiomer
tR = 29.2 min, minor enantiomer tR = 15.4 min.
1
4l: 50.7 mg (62% yield); gray-white solid; mp 105−107 °C; H
NMR (400 MHz, CDCl3) δ = 7.91 (s, 1H), 7.49−7.47 (m, 1H), 7.29−
7.24 (m, 1H), 7.16−7.08 (m, 6H), 5.77−5.67 (m, 1H), 5.11−5.05 (m,
2H), 4.72−4.67 (m, 1H), 4.49 (d, J = 6.0 Hz, 1H), 4.07 (dd, J = 6.0,
15.2 Hz, 1H), 3.92 (dd, J = 6.0, 15.2 Hz, 1H), 3.62 (t, J = 5.6 Hz, 1H),
3.58−3.46 (m, 2H), 3.41−3.37 (m, 1H), 2.82−2.76 (m, 2H), 2.37−
2.34 (m, 4H), 2.25−2.20(m, 1H); 13C NMR (100 MHz, CDCl3) δ =
167.3, 140.5, 137.7, 136.6, 135.8, 133.3, 132.9, 129.4, 127.9, 127.3,
124.3, 121.6, 119.4, 118.1, 117.4, 110.8, 110.1, 51.5, 49.1, 45.1, 43.6,
37.3, 34.8, 21.2, 20.9 ppm; IR (KBr) = 3399, 3282, 2918, 2844, 2045,
2023, 1664, 1511, 1457, 1402, 1308, 1223, 1171, 1065, 992, 930, 818,
741, 670, 566, 528, 434 cm−1; HRMS (ESI) calcd for C27H27N3O [M
+ H]+ 410.2227, found 410.2225; [α]20D = −53.7 (c 0.8, CH2Cl2, 93%
ee). The enantiomeric excess was determined by HPLC with an AD-H
column. (n-hexane/i-PrOH = 80:20), 1.0 mL/min; major enantiomer
tR = 11.34 min, minor enantiomer tR = 9.6 min.
Experimental Procedure for the Synthesis of 5. To a solution
of compound 2 (0.3 mmol) and catalyst 1a (0.04 mmol) in
dichloromethane (1.5 mL) were added enal 3 (0.2 mmol) and
PhCO2H (0.04 mmol), and the mixture was stirring at room
temperature. The reaction was monitored by TLC analysis. After full
conversion of 3, 2-(aminomethyl)aniline (0.24 mmol) and BzOH
(0.24 mmol) were added to the solution. After completion of the
reaction, the mixture was subjected directly to flash column
chromatography yielding the corresponding products.
1
4m: 50.1 mg (53% yield); gray-white solid; mp 126−128 °C; H
5: 74.1 mg (84% yield); gray-white solid; mp 98−100 °C; 1H NMR
(400 MHz, CDCl3) δ = 7.27−7.14 (m, 7H), 7.04−6.99 (m, 3H),
6.75−6.69 (m, 1H), 6.54 (d, J = 8.4 Hz, 1H), 5.97 (d, J = 16.8 Hz,
1H), 4.66−4.64 (m, 1H), 4.60 (d, J = 14.8 Hz, 1H), 4.42 (d, J = 15.2
Hz, 1H), 4.30 (d, J = 16.4 Hz, 1H), 3.87−3.79 (m, 2H), 3.38 (d, J =
2.4 Hz, 2H), 2.26−2.20 (m, 1H), 2.15−2.08 (m, 1H); 13C NMR (100
MHz, CDCl3) δ = 166.9, 144.8, 142.6, 137.1, 135.8, 134.6, 130.0,
128.6, 128.1, 127.9, 127.4, 127.2, 127.1, 126.9, 126.0, 121.8, 121.1,
118.8, 115.1, 64.4, 48.4, 46.4, 46.3, 36.6, 36.3 ppm; IR (KBr) = 3431,
2922, 2854, 1673, 1495, 1296, 1228, 750, 701, 584, 403 cm−1; HRMS
(ESI) calcd for C27H24ClN3O [M + H]+ 442.1681, found 442.1670;
NMR (400 MHz, CDCl3) δ = 8.07 (b, 1H), 7.49−7.45 (m, 3H), 7.29
(d, J = 7.6 Hz, 1H), 7.24−7.07 (m, 4H), 5.74−5.66 (m, 1H), 5.12−
5.06 (m, 2H), 4.78−7.74 (m, 1H), 4.48 (d, J = 6.0 Hz, 1H), 4.05 (dd, J
= 6.0, 15.6 Hz, 1H), 3.92 (dd, J = 6.0, 15.6 Hz, 1H), 3.63 (t, J = 5.6
Hz, 1H), 3.51 (s, 2H), 3.38−3.33 (m, 1H), 2.82−2.72(m, 2H), 2.44−
2.37 (m, 1H), 2.25−2.20 (m, 1H); 13C NMR (100 MHz, CDCl3) δ =
167.1, 142.5, 137.9, 135.9, 133.1, 132.5, 131.9, 129.7, 127.2, 122.8,
121.6, 120.8, 119.5, 118.2, 117.6, 110.9, 110.1, 51.5, 48.9, 45.1, 43.6,
37.3, 34.7, 21.2 ppm; IR (KBr): = 3601, 3277, 2910, 2841, 2359, 2047,
2023, 1661, 1486, 1458, 1403, 1313, 1224, 1070, 1008, 922, 828, 741,
569, 438 cm−1; HRMS (ESI) calcd for C26H24BrN3O [M + H]
+
[α]20 = −146.5 (c 0.43, CH2Cl2, 98% ee). The enantiomeric excess
474.1176, found 474.1173; [α]20 = −66.0 (c 1.0, CH2Cl2, 93% ee).
D
D
was determined by HPLC with an OD-H column (n-hexane: i-PrOH
= 70:30), 1.0 mL/min; major enantiomer tR = 31.5 min, minor
enantiomer tR = 41.6 min.
The enantiomeric excess was determined by HPLC with an AS-H
column (n-hexane/i-PrOH = 70:30), 1.0 mL/min; major enantiomer
tR = 11.9 min, minor enantiomer tR = 6.7 min.
1
4n: 50.4 mg (60% yield); gray-white solid; mp 136−138 °C; H
NMR (400 MHz, CDCl3) δ = 7.92 (b, 1H), 7.64−7.48 (m, 3H),
7.36−7.25 (m, 3H), 7.17−7.08 (m, 2H), 5.78−5.69 (m, 1H), 5.14−
5.08(m, 2H), 4.89−4.83 (m, 1H), 4.48 (d, J = 6.0 Hz, 1H), 4.08 (dd, J
= 6.0, 15.6 Hz, 1H), 3.94(dd, J = 6.0, 15.2 Hz, 1H), 3.75 (t, J = 5.2 Hz,
1H), 3.51 (s, 2H), 3.39−3.33 (m, 1H), 2.88−2.74 (m, 2H), 2.47−2.40
(m, 1H), 2.30−2.24 (m, 1H); 13C NMR (100 MHz, CDCl3) δ =
166.7, 149.2, 138.4, 135.9, 133.1, 132.6, 132.1, 128.9, 127.2, 121.9,
120.6, 119.6, 118.5, 118.3, 117.7, 111.0, 110.8, 110.4, 51.4, 48.7, 45.1,
43.5, 38.0, 34.7, 21.3 ppm; IR (KBr) = 3582, 3272, 3058, 2841, 2229,
2046, 2018, 1660, 1459, 1404, 1309, 1224, 929, 841, 740, 569 cm−1;
HRMS (ESI) calcd for C27H24N4O [M + H]+ 421.2023, found
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details, spectra data for the products, and X-ray
crystallographic data (CIF file of 4o: CCDC 873633, CIF file of
5: CCDC 881242). This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: xupf@lzu.edu.cn.
■
421.2017; [α]20 = −110.6 (c 0.75, CH2Cl2, 93% ee). The
D
enantiomeric excess was determined by HPLC with an AS-H column
(n-hexane/i-PrOH = 60:40), 1.0 mL/min; major enantiomer tR = 21.2
min, minor enantiomer tR = 9.5 min.
Notes
The authors declare no competing financial interest.
1
4o: 79.8 mg (84% yield); gray-white solid; mp 138−140 °C; H
ACKNOWLEDGMENTS
NMR (400 MHz, CDCl3) δ = 7.85 (b, 1H), 7.29−7.22 (m, 6H),
7.18−7.14 (m, 5H), 6.94 (d, J = 2.4 Hz, 1H), 6.77(dd, J = 2.4, 8.8 Hz,
1H), 4.78−4.70 (m, 2H), 4.47 (d, J = 6.0 Hz, 1H), 4.41 (d, J = 15.2
Hz, 1H), 3.84 (s, 3H), 3.61 (t, J = 5.6 Hz, 1H), 3.52−3.37 (m, 3H),
2.82−2.71 (m, 2H), 2.39−2.33 (m, 1H), 2.24−2.19 (m, 1H); 13C
NMR (100 MHz, CDCl3) δ = 167.4, 154.1, 143.5, 137.7, 137.3, 133.7,
130.9, 128.8, 128.6, 128.3, 128.0, 127.9, 127.7, 127.4, 126.9, 123.9,
111.6, 109.9, 100.3, 55.9, 51.6, 49.0, 46.4, 43.7, 37.8, 34.8, 21.3 ppm;
IR (KBr) = 3308, 2942, 2047, 2024, 1659, 1456, 1320, 1214, 1148,
1066, 802, 704, 629, 570 cm−1; HRMS (ESI) calcd for C31H29N3O2
■
We are grateful for the NSFC (21032005, 20972058,
21172097), the National Basic Research Program of China
(No. 2010CB833203), and the “111” program from MOE of P.
R. China.
REFERENCES
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D
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The Journal of Organic Chemistry
Note
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