Catalytic Asymmetric [3+3] Cycloaddition of Azomethine Ylides with C3-Substituted 2-Indolylmethanols

Article abstract of DOI:10.1002/adsc.201700203

The first catalytic asymmetric [3+3] cycloaddition of azomethine ylides with C3-substituted 2-indolylmethanols has been established, leading to diastereo- and enantioselective construction of a tetrahydropyrimido[1,6-a]indole framework (up to 91% yield, >

Full text of DOI:10.1002/adsc.201700203

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DOI: 10.1002/adsc.201700203
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Catalytic Asymmetric [3+3] Cycloaddition of Azomethine Ylides
with C3-Substituted 2-Indolylmethanols
a
a
a
a
a
Xiao-Xue Sun, Can Li, Ying-Ying He, Zi-Qi Zhu, Guang-Jian Mei, and
a,
Feng Shi *
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School of Chemistry & Material Science, Jiangsu Normal University, Xuzhou, 221116, People’s Republic of China
E-mail: fshi@jsnu.edu.cn
Received: February 17, 2017; Revised: April 27, 2017; Published online: && &&, 0000
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.201700203
membered heterocyclic skeletons, such as pyrrolidine
Abstract: The first catalytic asymmetric [3+3]
[
1–3]
or 2,5-dihydropyrrole.
In contrast, the enantioselec-
cycloaddition of azomethine ylides with C3-substi-
tuted 2-indolylmethanols has been established,
leading to diastereo- and enantioselective construc-
tion of a tetrahydropyrimido[1,6-a]indole frame-
work (up to 91% yield, >95:5 dr, 98:2 er). This
reaction also represents a new type of catalytic
enantioselective [3+3] cycloaddition using azome-
thine ylides.
tive [3+3] cycloaddition of azomethine ylides using
three-atom unconventional dipolarophiles has been
[4–5]
only sporadically reported in the literature (eq. 2).
Nevertheless, this transformation is an efficient means
of creating chiral, six-membered heterocyclic scaffolds.
Until recently, a limited number of examples of
catalytic asymmetric [3+3] cycloaddition of azome-
[
4–5]
thine ylides have been provided (Scheme 2).
Using
chiral metal catalysis, the enantioselective cross-[3+3]
Keywords: azomethine ylide; chiral phosphoric
acid; enantioselectivity; [3+3] cycloaddition; organ-
ic catalysis
cycloaddition of azomethine ylides with other 1,3-
[4a–c]
dipoles was realized by Wang and Guo (eq. 3–4).
The Deng group has recently reported tandem [3+3]
cycloaddition of azomethine ylide and 2-indolylnitro-
[
4d]
ethylenes (eq. 5).
Employing an organocatalytic
strategy, the Gong group and our group have
developed asymmetric [3+3] cycloaddition of azome-
Introduction
[
5a–c]
thine ylides with 3-indolylmethanols (eq. 6).
Very
Catalytic asymmetric 1,3-dipolar cycloaddition of azo- recently, we demonstrated the use of C3-unsubstituted
methine ylide is one of the most powerful methods for 2-indolylmethanols as 3C building blocks to carry out
constructing enantioenriched heterocyclic frameworks an enantioselective and regioselective [3+3] cyclo-
[
5d]
and the technique has been well-developed over the addition with azomethine ylide (eq. 7). In spite of
[
1–6]
past two decades.
As illustrated in Scheme 1, most this recent progress, the catalytic asymmetric [3+3]
enantioselective transformations of azomethine ylides cycloaddition of azomethine ylides remains under-
have utilized electronically poor alkenes or alkynes as
dipolarophiles to perform [3+2] cycloaddition reaction
(eq. 1). This results in the construction of chiral, five-
Scheme 1. Profile of catalytic asymmetric cycloadditions of
Scheme 2. Limited examples of catalytic asymmetric [3+3]
azomethine ylides.
cycloaddition of azomethine ylides.
Adv. Synth. Catal. 2017, 359, 1–12
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developed. Thus, the development of new enantiose- and enantioselective tetrahydropyrimido[1,6-a]indole
lective [3+3] cycloadditions of azomethine ylides framework.
using other three-atom dipolarophiles is highly de-
sired.
C3-substituted 2-indolylmethanols can act as NCC
(Nitrogen-Carbon-Carbon) building blocks in cyclo-
[
7]
addition reactions (Scheme 3). Using this class of
reactants with electron-rich alkenes (vinylindoles and
enamides), the Schneider group demonstrated [3+2]
cycloadditions with excellent enantioselectivities
1
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1
1
1
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5
[7]
(eq. 8). However, this class of NCC building block
has never been employed in [3+3] cycloadditions
with 1,3-dipoles, nor in analogous catalytic asymmetric
syntheses (eq. 9). There are three inherent challenges
in this type of transformation. The first is the self-
cyclodimerization of 1,3-dipoles, which will compete
with the [3+3] cycloaddition of 1,3-dipoles and C3-
substituted 2-indolylmethanols. The second is the
relatively weak nucleophilicity of the indole N-H in
tandem cycloaddition. The third is the tendency for
racemization at the aminal chiral center contained in
the [3+3] cycloaddition products. So, it has become
Scheme 4. Design of catalytic asymmetric [3+3] cycloaddi-
tion reactions of azomethine ylides with C3-substituted 2-
indolylmethanols.
Herein, we report the first catalytic asymmetric
an urgent task to explore the unknown chemistry and [3+3] cycloaddition of azomethine ylides with C3-
settle the great challenges in catalytic asymmetric [3+ substituted 2-indolylmethanols, resulting in the dia-
3] cycloadditions of C3-substituted 2-indolylmethanols stereo- and enantioselective construction of a tetrahy-
with 1,3-dipoles.
dropyrimido[1,6-a]indole framework (up to 91% yield,
>95:5 dr, 98:2 er). This reaction is not only the first
catalytic asymmetric [3+3] cycloaddition of C3-sub-
stituted 2-indolylmethanols, but also represents a new
type of catalytic enantioselective [3+3] cycloaddition
reaction using azomethine ylides.
Results and Discussion
As shown in Table 1, a model three-component
reaction of C3-substituted 2-indolylmethanol 1a, p-
nitrobenzaldehyde 2a, and amino-ester 3 was em-
ployed to test our hypothesized synthesis. Initially, in
the presence of CPA 5a, the designed [3+3] cyclo-
addition occurred, affording the desired product 4aa,
Scheme 3. Profile of C3-substituted 2-indolylmethanol-in- albeit with a moderate yield of 45% and a low
volved catalytic asymmetric cycloadditions.
enantioselectivity of 65:35 er (entry 1). A series of
BINOL-derived CPAs, 5b–5g, were then screened
through the same reaction (entries 2–7), revealing that
To address these challenges and develop new CPA 5e, which bears two 3,3’-(9-phenanthrenyl)
enantioselective [3+3] cycloaddition reactions with groups, delivered the highest enantioselectivity of
azomethine ylides, we designed a chiral phosphoric 84:16 er (entry 5). To further improve enantioselectiv-
[8]
acid (CPA) -catalyzed asymmetric [3+3] cycloaddi- ity while keeping the 3,3’-(9-phenanthrenyl) groups
tion of azomethine ylides with C3-substituted 2- unchanged, H -BINOL-derived CPA 6a and phos-
8
indolylmethanols (Scheme 4). In this design, the vinyl- phoramide 7a were also evaluated as catalysts (entries
iminium ion, derived from 2-indolylmethanol and the 8–9). Catalyst 6a facilitated an enantioselectivity of
azomethine ylide, generated in situ from a reaction 95:5 er with a moderate yield of 54% (entry 8).
between the aldehyde and amino-ester, is activated by
Therefore, different solvents (entries 8 and 10–13)
CPA anion via hydrogen-bonding and/or ion pair were evaluated in the presence of the optimal catalyst
interactions. This facilitates the stereoselective tandem 6a. Toluene was the most effective solvent for
[3+3] cycloaddition of azomethine ylide with C3- controlling enantioselectivity (entries 10–13 vs. 8) and
substituted 2-indolylmethanol, resulting in a diastereo- was therefore chosen as the most suitable solvent for
Adv. Synth. Catal. 2017, 359, 1–12
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Table 1. Screening of catalysts and optimization of reaction sieves (MS) (entries 8 and 15–16) revealed that 3 ꢁ
[a]
conditions
MS was the best additive, absorbing water generated
from the reaction and modulating both enantioselec-
tivity and yield (entry 8 vs. 14).
Reaction temperature was also evaluated for its
effect on enantioselectivity (entries 17–20). However,
no improvements were observed upon lowering or
elevating the reaction temperature (entries 17–20 vs.
8). Altering the reagent ratio (entries 21–25), however,
had a strong effect. A yield of 64% and an enantiose-
lectivity of 95:5 er were observed at 1a:2a:3=2:1.2:1
(entry 23 vs. 8). Lowering the catalyst load to 5 mol%
still afforded product 4aa while maintaining both yield
and enantioselectivity (entry 26 vs. 23). The above set
of optimal conditions was therefore used in subse-
quent experiments. It should be noted that only one
diastereomer of 4aa was observed during condition
optimization, and the yield of product 4aa could
hardly be improved due to the self-cyclodimerization
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5
5
o
[b]
[c]
entry Cat. solvent
T ( C) yield (%)
er
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
5a
5b
5c
5d
5e
5f
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
acetone
EtOAc
DCE
50
50
50
50
50
50
50
50
50
50
50
50
45
33
34
38
20
trace
16
54
47
65:35
78:22
65:35
77:23
84:16
–
75:25
95:5
57:43
–
[
9]
of azomethine ylide.
5g
6a
7a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
With this set of optimal conditions, we then
investigated the substrate scope of catalytic asymmet-
ric [3+3] cycloaddition. First, the applicability of C3-
substituted 2-indolylmethanols 1 was evaluated by
reactions with p-nitrobenzaldehyde 2a and amino-
ester 3. As shown in Table 2, this reaction was indeed
0
1
2
3
4
5
6
7
8
trace
23
67
92:8
78:22
–
1,4-dioxane 50
trace
17
45
54
22
[d]
[e]
[f]
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
50
50
50
0
92:8
95:5
93:7
90:10
95:5
86:14
67:33
95:5
95:5
95:5
93:7
92:8
95:5
Table 2. Applicability of C3-substituted 2-indolylmethanols
[a]
1 in catalytic asymmetric [3+3] cycloadditions
25
70
90
50
50
50
50
50
50
31
59
60
54
51
64
63
66
19
20
21
[
[
[
[
[
[
g]
h]
i]
2
2
2
2
2
2
3
4
5
6
j]
1
[c]
[d]
entry 4
R/R (1)
yield
(%)
dr
er
k]
i,l]
[b]
64
1
2
3
4
5
6
7
8
4aa Ph/Me (1a)
65
>95:5 95:5
>95:5 95:5
>95:5 93:7
>95:5 98:2
>95:5 98:2
>95:5 94:6
>95:5 93:7
>95:5 95:5
[
a]
Unless otherwise indicated, the reaction was carried out at
the 0.1 mmol scale in the presence of 10 mol% 5–7 for 15 h
in a solvent (2 mL) with 3 ꢁ MS (100 mg), and at a molar
ratio of 1a:2a:3=1:1.2:1.1.
Isolated yield and only one diastereomer was observed.
The er value was determined by HPLC.
In the absence of additives.
4ba 2-MeC H /Me (1b) 77
6
4
4ca 3-MeC H /Me (1c) 49
6
4
4da 4-MeC H /Me (1d) 60
6
4
4ea 4-MeOC H /Me (1e) 61
[
[
[
[
b]
c]
d]
e]
6
4
4fa 4-FC H /Me (1f)
60
47
58
6
4
4ga 4-ClC H /Me (1g)
6
4
4ha 2-thiophenyl/Me
(1h)
In the presence of 4 ꢁ MS (100 mg).
In the presence of 5 ꢁ MS (100 mg).
[f]
9
4ia 4-MeOC
H (1i)
H
6
/4-ClC
4
57
77:23 98:2
[g]
[h]
6
The molar ratio of 1a:2a:3 was 1:2.4:2.2.
The molar ratio of 1a:2a:3 was 1:3.6:3.3.
The molar ratio of 1a:2a:3 was 2:1.2:1.
The molar ratio of 1a:2a:3 was 3:1.2:1.
The molar ratio of 1a:2a:3 was 4:1.2:1.
In the presence of 5 mol% 6a.
[e]
(91:9)
4
[
[
[
[
i]
[a]
Unless otherwise indicated, the reaction was carried out at
the 0.1 mmol scale and catalyzed by 5 mol% 6a in toluene
(2 mL) with 3 ꢁ MS (100 mg) for 15 h, and the molar ratio
of 1:2a:3 was 2:1.2:1.
Isolated yield.
The dr value was determined by H NMR.
j]
k]
l]
[
[
[
[
b]
c]
d]
e]
1
The er value was determined by HPLC.
The er value of minor diastereomer.
these syntheses. Running the reactions in the absence
of additives (entry 14) or in the presence of molecular
Adv. Synth. Catal. 2017, 359, 1–12
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applicable to a series of C3-substituted 2-indolylme- aliphatic aldehydes, such as cyclohexanecarbaldehyde
thanols 1 bearing different R/R groups, which partici- 2k and 2-phenylacetaldehyde 2l, which often failed to
1
pated in [3+3] cycloadditions to give the products 4 in participate in 1,3-dipolar cycloadditions of azomethine
[
5a–b,9–10]
generally high enantioselectivities (93:7 to 98:2 er) and ylides,
were amenable to [3+3] cycloaddition
excellent diastereoselectivities (most >95:5 dr). In (entries 11–12). Although yields were unsatisfying and
general, both electronically rich (entries 2–5) and the degree of enantioselectivity only moderate, the
electronically poor (entries 6–7) phenyl groups served inclusion of aliphatic aldehydes 2k–2l in catalytic
as suitable R substituents. The position of the sub- asymmetric [3+3] cycloadditions greatly enhanced
stituents may have exerted some effect on enantiose- the applicability of the reaction.
lectivity, as evidenced by the para-methyl-substituted
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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5
substrate 1d delivering a higher enantioselectivity
[a]
Table 3. Substrate scope of aldehydes 2.
than its ortho- or meta-substituted counterparts 1b–1c
(entry 4. vs 2–3). The electronic nature of the
substituents also had some influence on enantioselec-
tivity, since para-methyl or para-methoxy-substituted
substrates 1d–1e yielded higher enantioselectivity than
para-fluoro or para-chloro-substituted analogues 1f–1g
(entries 4–5 vs. 6–7). Notably, a 2-thiophenyl group as
[
c]
[d]
a heteroaromatic substituent was also a suitable R entry 4
group of substrate 1h, which successfully took part in
the [3+3] cycloaddition to generate product 4ha in an
1
R (2)
1a 4-NO C H
4
yield
(%)
dr
er
[b]
1
2
3
4
5
6
7
8
9
4aa
65
>95:5 95:5
>95:5 92:8
>95:5 92:8
>95:5 92:8
2
6
acceptable yield of 58%, a high enantioselectivity of
95:5 er and an excellent diastereoselectivity of
>95:5 dr (entry 8). In addition, the R group could be
changed from a methyl group to a para-chlorobenzyl
group, which also underwent [3+3] cycloaddition
(entry 9). Although the diastereoselectivity was not
very satisfying (77:23 dr), both of the diastereomers of
product 4ia were produced with good enantioselectiv-
ity (98:2 and 91:9 er).
(
2a)
4bb 1b 4-CNC H
4
63
57
53
91
1
6
(
2b)
4dc
4ed
1d 4-BrC H
6
4
4
4
(
2c)
1e 3-BrC H
6
(2d)
[
[
[
[
e]
g]
g]
g]
ent- 1e 2-BrC
4ee
4df
H
6
67:33 88:12 [
(98:2)
>95:5 92:8
f]
(2e)
1d 3-MeOC H 47
Second, the substrate scope of aldehydes 2 was
investigated. As listed in Table 3, entries 1–7, this
reaction was not only amenable to electronically poor
benzaldehydes 2a–2e (entries 1–5), but also to elec-
tronically rich benzaldehydes 2f–2g (entries 6–7),
which often display low reactivity and poor enantiose-
lective control in 1,3-dipolar cycloadditions of azome-
6
4
(
2f)
4eg
4eh
1e 2-MeC H
52
50
>95:5 87:13
>95:5 94:6
>95:5 89:11
6
4
(
2g)
1e 1-naphthyl
2h)
ent- 1e 3-thiophenyl 53
(
[h]
4
ei
(2i)
[9–10]
thine ylides.
The position of the substituents linked
[i,j]
10
1
4ej
1e styryl (2j)
1e cyclohexyl
(2k)
41
33
>95:5 80:20
>95:5 89:11
[i]
to the phenyl ring seemed to have some effect on both
the yield and stereoselectivity of the reaction. For
1
4ek
instance, ortho-bromobenzaldehyde 2e showed much 12
4bl
1b Bn (2l)
47
>95:5 82:18
higher reactivity than para- and meta-bromobenzalde-
hydes 2c–2d (entry 5 vs. 3–4), while the latter
demonstrated higher diastereo- and enantioselective
control of the reaction than the former (entries 3–4 vs.
5). 1-Naphthaldehyde 2h was also suitable for [3+3]
cycloaddition and resulted in a moderate yield of
50%, a good enantioselectivity of 94:6 er and an
excellent diastereoselectivity of >95:5 dr (entry 8).
Moreover, heteroaromatic aldehydes, as exemplified
by thiophene-3-carbaldehyde 2i, were also suitable
substrates, generating the corresponding product 4ei
in moderate yield and good enantioselectivity (entry
9). As listed in entry 10, cinnamaldehyde 2j, an
unsaturated aliphatic aldehyde, also took part in the
[3+3] cycloaddition with an acceptable yield and a
moderate enantioselectivity. It is worth noting that
[a ]
Unless otherwise indicated, the reaction was carried out at
the 0.1 mmol scale and catalyzed by 5 mol% 6a in toluene
2 mL) with 3 ꢁ MS (100 mg) for 15 h, and the molar ratio of
(
1
:2:3 was 2:1.2:1.
[
[
[
[
[
[
[
[
[
b]
Isolated yield.
c]
1
The dr value was determined by H NMR.
The er value was determined by HPLC.
Catalyzed by 5 mol% ent-6a.
d]
e]
f]
The er value of minor diastereomer.
The volume of toluene is 5 mL.
g]
h]
i]
Catalyzed by 5 mol% ent-6a in acetal acetate (14 mL).
Catalyzed by 5 mol% ent-5f.
The volume of toluene was 8 mL.
j]
Adv. Synth. Catal. 2017, 359, 1–12
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The relative and absolute configuration of product
4fa (99:1 er after recrystallization) was unambiguously scale synthesis of ent-4ea was carried out in 1 mmol
To show the utility of this reaction, a preparative
determined to be cis and (1S, 4R) by single crystal X- scale under standard conditions (Scheme 6). The
[
11]
ray diffraction analysis (Figure 1). The relative and resulting [3+3] cycloaddition generated the product
absolute configurations of other products 4 were ent-4ea in a moderate yield of 54%, while largely
assigned by analogy.
maintaining the high degree of stereoselectivity (>
95:5 dr, 97:3 er) observed in the small-scale reaction
(Table 2, entry 5).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
Figure 1. Single crystal structure of 4fa.
Scheme 6. Preparative scale synthesis of ent-4ea.
Based on the experimental results, we propose a
reaction pathway, shown in Scheme 5, to explain the
We also performed preliminary synthetic trans-
chemistry and stereochemistry of this [3+3] cyclo- formations of products 4 (Scheme 7). First, we per-
addition via stepwise tandem cyclization. In the formed a Krapcho decarboxylation of compound 4ba,
presence of CPA 6a, C3-substituted 2-indolylmetha- which gave the decarboxylative product 8 in a
nols 1 transformed into vinyliminium A via dehydra- moderate yield (eq. 10). However, due to the high
tion, and azomethine ylide B was generated in situ by reaction temperature of 1308C, product 8 was race-
the condensation of aldehydes 2 with amino-ester 3. mized. We next performed a Suzuki coupling of
The two intermediates were simultaneously activated compound 4dc with 4-chlorophenylboronic acid at a
by CPA 6a via hydrogen-bonding and ion pair lower temperature of 808C, which afforded the
interactions, which facilitated the enantioselective desired product 9 with a high yield of 98% and a
nucleophilic addition of azomethine ylide B to vinyl- retained enantioselectivity of 92:8 er.
iminium A to generate another intermediate C. This
intermediate C could be activated again by catalyst 6a
to perform an intramolecular aza-Mannich reaction,
leading to the formation of final products 4 with (1S,
4R)-configurations.
Scheme 7. Preliminary synthetic transformations.
Conclusions
We have established the first catalytic asymmetric [3+
3] cycloaddition of azomethine ylides with C3-sub-
stituted 2-indolylmethanols, which resulted in tetrahy-
Scheme 5. Suggested reaction pathway.
Adv. Synth. Catal. 2017, 359, 1–12
5
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
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UPDATES
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8
9
0
1
2
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dropyrimido[1,6-a]indole frameworks in high diaster- acetate=8/1; Reaction time=15 h; yield: 65% (34.4 mg);
20
yellowish solid, m.p 78–808C; [a]D = +122.8 (c 0.37,
eo- and enantioselectivities (up to 91% yield,
>95:5 dr, 98:2 er). This reaction was not only the first
catalytic asymmetric [3+3] cycloaddition of C3-sub-
stituted 2-indolylmethanols, but also represents a new
type of catalytic enantioselective [3+3] cycloaddition
of azomethine ylides. This approach has provided
valuable insight into the chemistry of, and resolved
several of the challenges associated with, catalytic
asymmetric [3+3] cycloadditions of C3-substituted 2-
indolylmethanols with 1,3-dipoles. In addition, this
1
Acetone); H NMR (400 MHz, CDCl ) d 8.37 (d, J=8.6 Hz,
2
3
H), 7.80 (d, J=8.6 Hz, 2H), 7.49 (t, J=6.8 Hz, 3H), 7.29 (d,
J=6.5 Hz, 2H), 7.25–7.21 (m, 1H), 7.06 (t, J=7.5 Hz, 1H),
.87 (t, J=7.7 Hz, 1H), 6.26 (d, J=8.3 Hz, 1H), 5.96 (d, J=
.6 Hz, 1H), 5.27 (s, 1H), 4.28 (q, J=7.1 Hz, 2H), 4.10–4.01
m, 1H), 4.00–3.91 (m, 1H), 3.09 (d, J=5.6 Hz, 1H), 2.15 (s,
H), 1.28 (t, J=7.1 Hz, 3H), 1.11 (t, J=7.1 Hz, 3H);
NMR (100 MHz, CDCl ) d 167.9, 166.9, 148.7, 146.2, 138.2,
34.6, 133.1, 130.1, 129.3, 128.9, 128.4, 127.6, 124.5, 121.1,
20.0, 118.6, 111.3, 109.1, 69.9, 69.4, 62.7, 62.5, 43.2, 14.2,
6
5
(
3
13
C
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
1
1
protocol also provides a useful means of enantioselec- 13.8, 7.9; IR (KBr): 3342, 2980, 2921, 2854, 1741, 1526, 1459,
-1
tively constructing tetrahydropyrimido[1,6-a]indole 1348, 1017, 856, 744, 702 cm ; ESI FTMS exact mass calcd
-
skeletons.
for (C30
26.1965; Diastereomeric ratio: >95:5, determined by
NMR; Enantiomeric ratio: 95:5, determined by HPLC
Daicel Chiralpak AD-H, hexane/ isopropanol=70/30, flow
rate 1.0 mL/min, T=308C, 254 nm): t =5.58 min (minor), t
H N O -H) requires m/z 526.1972, found m/z
29 3 6
1
5
H
Experimental Section
General
(
R
R
=
6.74 min (major).
1
13
H and C NMR spectra were measured at 400 and
00 MHz, respectively. The solvent used for NMR spectro-
(1S,4R)-Diethyl5-methyl-1-(4-nitrophenyl)-4-(o-tolyl)-1,2-di-
hydropyrimido[1,6-a]indole-3,3(4H)-dicarboxylate (4ba):
Preparative thin layer chromatography: petroleum ether/
1
scopy was CDCl , using tetramethylsilane as the internal
3
reference. HRMS (ESI) was determined by a HRMS/MS
instrument. Enantiomeric ratios (er) were determined by
chiral high-performance liquid chromatography (chiral
HPLC). The chiral columns used for the determination of
enantiomeric ratio by chiral HPLC were Chiralpak AD-H,
OD-H, AD-H and IA columns. Optical rotation values were
measured with instruments operating at l=589 nm, corre-
sponding to the sodium D line at the temperatures indicated.
The X-ray source used for the single crystal X-ray diffraction
analysis of compound 4fa was CuKa (l=1.54178), and the
thermal ellipsoid was drawn at the 30% probability level.
Analytical grade solvents for the preparative thin layer
chromatography were distilled before use. All starting
materials commercially available were used directly. Sub-
strates 1 were synthesized according to the literature
toluene/ethyl acetate=10:10:1; Reaction time=15 h; yield:
20
7
7% (41.7 mg); yellow solid; m.p. 43–458C; [a]D = +149.3
1
(c 0.66, Acetone); H NMR (400 MHz, CDCl ) d 8.39 (d, J=
3
8.5 Hz, 2H), 7.82 (d, J=8.5 Hz, 2H), 7.67 (d, J=7.5 Hz, 1H),
7.50 (d, J=7.9 Hz, 1H), 7.19 (d, J=7.2 Hz, 1H), 7.14 (d, J=
7.0 Hz, 1H), 7.09 (s, 1H), 7.08–7.03 (m, 1H), 6.87 (t, J=
7.7 Hz, 1H), 6.25 (d, J=8.3 Hz, 1H), 5.99 (d, J=5.7 Hz, 1H),
5.66 (s, 1H), 4.35–4.27 (m, 2H), 3.88–3.78 (m, 1H), 3.88–3.77
(
m, 1H), 3.20 (d, J=5.7 Hz, 1H), 2.68 (s, 3H), 2.12 (s, 3H),
13
1.32 (t, J=7.1 Hz, 3H), 1.01 (t, J=7.1 Hz, 3H); C NMR
(100 MHz, CDCl ) d 168.3, 167.0, 148.7, 146.1, 136.5, 135.8,
3
134.5, 134.1, 130.6, 130.0, 129.5, 128.9, 127.4, 126.3, 124.6,
120.9, 119.9, 118.5, 111.4, 108.8, 69.7, 69.2, 62.7, 62.4, 37.5,
2
0.2, 14.2, 13.6, 8.0; IR (KBr): 3358, 2971, 2923, 1735, 1524,
À1
[
7a]
1459, 1343, 1258, 1100, 1023, 858, 748 cm ; ESI FTMS exact
mass calcd for (C H N O -H) requires m/z 540.2129, found
m/z 540.2130; Diastereomeric ratio: >95:5, determined by H
method.
-
3
1
31
3
6
1
General Procedure for the Catalytic Asymmetric
Synthesis of Products 4
NMR; Enantiomeric ratio: 95:5, determined by HPLC
(Daicel Chiralpak OD-H, hexane/ isopropanol=80/20, flow
rate 1.0 mL/min, T=308C, 254 nm): t =5.47 min (minor), t
R
R
Toluene (0.5 mL) was added to the mixture of aldehydes 2
(0.12 mmol), 3ꢁ MS (100 mg), and the catalyst 6a
(0.005 mmol). Then, amino-ester 3 (0.1 mmol) and another
potion of toluene (0.5 mL) were sequentially added to the
reaction mixture, which was stirred at room temperature for
=
7.52 min (major).
(1S,4R)-Diethyl5-methyl-1-(4-nitrophenyl)-4-(m-tolyl)-1,2-
dihydropyrimido[1,6-a]indole-3,3(4H)-dicarboxylate (4ca):
Preparative thin layer chromatography: petroleum ether/
toluene/ethyl acetate=10:10:1; Reaction time=15 h; yield:
30 min. Next, C3-substituted 2-indolylmethanols
1
20
4
9% (26.5 mg); yellow solid; m.p. 45–478C; [a]D = +141.5
(
0.2 mmol) and another potion of toluene (1 mL) were
1
(c 0.42, Acetone); H NMR (400 MHz, CDCl ) d 8.37 (d, J=
sequentially added to the reaction mixture, which was stirred
at 508C for 15 h. After the completion of the reaction
indicated by TLC, the reaction mixture was filtered to
remove the molecular sieves. The resultant solution was
concentrated under the reduced pressure to give the residue,
which was purified through preparative thin layer chroma-
tography to afford pure products 4.
3
8.5 Hz, 2H), 7.83 (d, J=8.5 Hz, 2H), 7.53 (d, J=7.8 Hz, 1H),
7.30–7.26 (m, 2H), 7.17 (t, J=7.6 Hz, 1H), 7.11–7.03 (m, 2H),
6.89 (t, J=7.7 Hz, 1H), 6.31 (d, J=8.3 Hz, 1H), 6.00 (d, J=
6.3 Hz, 1H), 5.26 (s, 1H), 4.33–4.24 (m, 2H), 4.13–4.04 (m,
1H), 4.04–3.94 (m, 1H), 3.07 (d, J=6.3 Hz, 1H), 2.30 (s, 3H),
2.18 (s, 3H), 1.27 (t, J=7.0 Hz, 3H), 1.15 (t, J=7.1 Hz, 3H);
13
C NMR (100 MHz, CDCl ) d 167.9, 166.9, 148.7, 146.2,
3
(
1S,4R)-Diethyl5-methyl-1-(4-nitrophenyl)-4-phenyl-1,2-di-
1
1
6
38.0, 137.8, 134.7, 133.2, 130.2, 130.1, 128.9, 128.4, 128.3,
26.3, 124.5, 121.1, 120.0, 118.6, 111.3, 109.0, 69.9, 69.4, 62.6,
2.4, 43.2, 21.5, 14.2, 13.8, 7.9; IR (KBr): 3418, 2971, 2923,
hydropyrimido[1,6-a]indole-3,3(4H)-dicarboxylate (4aa):
Flash column chromatography eluent, petroleum ether/ethyl
Adv. Synth. Catal. 2017, 359, 1–12
6
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
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UPDATES
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4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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6
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6
7
1743, 1527, 1458, 1347, 1256, 1101, 1018, 856, 744 cm ; ESI
123.2 (c 0.47, Acetone); H NMR (400 MHz, CDCl ) d 8.37
3
-
FTMS exact mass calcd for (C H N O -H) requires m/z
40.2129, found m/z 540.2133; Diastereomeric ratio: >95:5,
determined by H NMR; Enantiomeric ratio: 93:7, deter-
mined by HPLC (Daicel Chiralpak OD-H, hexane/ isopropa-
nol=80/20, flow rate 1.0 mL/min, T=308C, 254 nm): t =
(d, J=8.5 Hz, 2H), 7.78 (d, J=8.5 Hz, 2H), 7.57–7.47 (m,
3H), 7.06 (t, J=7.5 Hz, 1H), 6.98 (t, J=8.5 Hz, 2H), 6.88 (t,
J=7.7 Hz, 1H), 6.26 (d, J=8.3 Hz, 1H), 5.96 (d, J=4.5 Hz,
1H), 5.27 (s, 1H), 4.28 (q, J=7.1 Hz, 2H), 4.14–4.04 (m, 1H),
4.03–3.94 (m, 1H), 3.13 (d, J=4.3 Hz, 1H), 2.16 (s, 3H), 1.27
(t, J=7.1 Hz, 3H), 1.14 (t, J=7.1 Hz, 3H); C NMR
100 MHz, CDCl ) d 167.9, 166.8, 162.1 (J=246.0 Hz), 148.7,
46.1, 134.6, 134.2, 134.2, 132.9, 131.0, 130.1 (J=8.0 Hz),
28.9, 124.6, 121.2, 120.1, 118.6, 115.2 (J=21.0 Hz), 111.3,
09.1, 69.8, 69.5, 62.7, 62.6, 42.4, 14.2, 13.8, 7.9; IR (KBr):
981, 2925, 1743, 1606, 1526, 1457, 1347, 1217, 1102, 1017,
833, 739 cm ; ESI FTMS exact mass calcd for (C H FN O -
H) requires m/z 544.1878, found m/z 544.1877; Diastereo-
meric ratio: >95:5, determined by H NMR; Enantiomeric
ratio: 94:6, determined by HPLC (Daicel Chiralpak AD-H,
hexane/ isopropanol=80/20, flow rate 1.0 mL/min, T=308C,
31 31
3
6
5
1
R
13
4
.91 min (minor), t =5.91 min (major).
R
(
3
(1S,4R)-Diethyl5-methyl-1-(4-nitrophenyl)-4-(p-tolyl)-1,2-di-
hydropyrimido[1,6-a]indole-3,3(4H)-dicarboxylate (4da):
Preparative thin layer chromatography: petroleum ether/
toluene/ethyl acetate=10:10:1; Reaction time=15 h; yield:
0% (32.6 mg); yellow solid; m.p. 41–438C; [a] = +162.1
1
1
1
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
2
D
0
6
(
À1
1
30 28
3
6
c 0.69, Acetone); H NMR (400 MHz, CDCl ) d 8.37 (d, J=
-
3
8
7
1
1
1
.6 Hz, 2H), 7.81 (d, J=8.5 Hz, 2H), 7.51 (d, J=7.8 Hz, 1H),
.36 (d, J=7.9 Hz, 2H), 7.13–7.04 (m, 3H), 6.88 (t, J=7.6 Hz,
H), 6.28 (d, J=8.3 Hz, 1H), 5.98 (d, J=6.0 Hz, 1H), 5.26 (s,
H), 4.35–4.24 (m, 2H), 4.15–4.05 (m, 1H), 4.05–3.93 (m,
H), 3.08 (d, J=5.9 Hz, 1H), 2.30 (s, 3H), 2.17 (s, 3H), 1.27
(t, J=7.1 Hz, 3H), 1.16 (t, J=7.1 Hz, 3H); C NMR
(100 MHz, CDCl ) d 167.9, 167.0, 148.7, 146.2, 137.3, 135.1,
134.7, 133.4, 130.2, 129.1, 129.1, 128.9, 124.5, 121.0, 120.0,
118.6, 111.3, 108.9, 69.9, 69.4, 62.6, 62.5, 42.9, 21.1, 14.2, 13.8,
.9; IR (KBr): 3434, 2975, 2924, 1743, 1525, 1457, 1347, 1257,
104, 1019, 824, 745 cm ; ESI FTMS exact mass calcd for
C H N O -H) requires m/z 540.2129, found m/z 540.2129;
Diastereomeric ratio: >95:5, determined by H NMR;
Enantiomeric ratio: 98:2, determined by HPLC (Daicel
Chiralpak OD-H, hexane/ isopropanol=80/20, flow rate
1
2
54 nm): t =5.97 min (minor), t =7.51 min (major).
R
R
1
3
(1S,4R)-Diethyl4-(4-chlorophenyl)-5-methyl-1-(4-nitrophen-
yl)-1,2-dihydropyrimido[1,6-a]indole-3,3(4H)-dicarboxylate
(4ga): Preparative thin layer chromatography: petroleum
ether/toluene/ethyl acetate=10:10:1; Reaction time=15 h;
3
2
0
7
1
(
yield: 47% (26.5 mg); yellow solid; m.p. 52–548C; [a]D = +
À1
1
114.9 (c 0.48, Acetone); H NMR (400 MHz, CDCl ) d 8.36
3
-
(d, J=8.5 Hz, 2H), 7.77 (d, J=8.5 Hz, 2H), 7.49 (t, J=
8.3 Hz, 3H), 7.26 (d, J=8.3 Hz, 2H), 7.06 (t, J=7.5 Hz, 1H),
6.87 (t, J=7.7 Hz, 1H), 6.25 (d, J=8.3 Hz, 1H), 5.95 (d, J=
4.4 Hz, 1H), 5.25 (s, 1H), 4.28 (q, J=7.1 Hz, 2H), 4.14–4.05
(m, 1H), 4.03–3.94 (m, 1H), 3.12 (d, J=4.4 Hz, 1H), 2.15 (s,
3H), 1.27 (t, J=7.1 Hz, 3H), 1.15 (t, J=7.1 Hz, 3H);
NMR (100 MHz, CDCl ) d 167.8, 166.8, 148.7, 146.1, 136.9,
34.7, 133.5, 132.6, 130.7, 130.1, 128.8, 128.5, 124.6, 121.3,
120.1, 118.7, 111.3, 109.3, 69.7, 69.5, 62.7, 62.6, 42.6, 14.2,
13.8, 8.0; IR (KBr): 2970, 2925, 1743, 1527, 1459, 1346, 1259,
1098, 1018, 824, 746, 668 cm ; ESI FTMS exact mass calcd
31
31
3
6
1
1
.0 mL/min, T=308C, 254 nm): t =4.90 min (minor), t
R
R
13
=
6.11 min (major).
C
3
(
1S,4R)-Diethyl4-(4-methoxyphenyl)-5-methyl-1-(4-nitro-
1
phenyl)-1,2-dihydropyrimido[1,6-a]indole-3,3(4H)-dicarbox-
ylate (4ea): Preparative thin layer chromatography: petro-
leum ether/toluene/ethyl acetate=10:10:1; Reaction time=
5 h; yield: 61% (33.9 mg); yellow solid; m.p. 58–608C;
a]D = +122.3 (c 0.71, Acetone); H NMR (400 MHz,
CDCl ) d 8.36 (d, J=8.5 Hz, 2H), 7.79 (d, J=8.6 Hz, 2H),
.50 (d, J=7.9 Hz, 1H), 7.40 (d, J=8.6 Hz, 2H), 7.06 (t, J=
.5 Hz, 1H), 6.87 (t, J=7.7 Hz, 1H), 6.81 (d, J=8.6 Hz, 2H),
6.27 (d, J=8.3 Hz, 1H), 5.96 (d, J=5.5 Hz, 1H), 5.23 (s, 1H),
4.28 (q, J=7.1 Hz, 2H), 4.14–4.05 (m, 1H), 4.03–3.93 (m,
1H), 3.76 (s, 3H), 3.09 (d, J=5.5 Hz, 1H), 2.16 (s, 3H), 1.27
(t, J=7.1 Hz, 3H), 1.16 (t, J=7.1 Hz, 3H); C NMR
100 MHz, CDCl ) d 168.0, 167.0, 159.0, 148.7, 146.2, 134.6,
À1
1
[
-
for (C30
H28ClN
O
6
-H) requires m/z 560.1583, found m/z
20
1
3
1
5
60.1575; Diastereomeric ratio: >95:5, determined by
NMR; Enantiomeric ratio: 93:7, determined by HPLC
Daicel Chiralpak AD-H, hexane/ isopropanol=70/30, flow
rate 1.0 mL/min, T=308C, 254 nm): t =5.98 min (minor), t
H
3
7
7
(
R
R
=
7.36 min (major).
(1S,4R)-Diethyl5-methyl-1-(4-nitrophenyl)-4-(thiophen-2-
yl)-1,2-dihydropyrimido[1,6-a]indole-3,3(4H)-dicarboxylate
(4ha): Preparative thin layer chromatography: petroleum
ether/toluene/ethyl acetate=10:10:1; Reaction time=15 h;
1
3
(
3
1
1
33.5, 130.4, 130.2, 128.9, 124.5, 121.0, 120.0, 118.6, 113.7,
11.3, 108.8, 70.0, 69.4, 62.6, 62.5, 55.2, 42.5, 14.2, 13.9, 7.9;
IR (KBr): 3422, 2978, 1743, 1610, 1521, 1458, 1347, 1251,
2
0
yield: 58% (31.0 mg); yellow solid; m.p. 64–668C; [a]D = +
1
105.1 (c 0.52, Acetone); H NMR (400 MHz, CDCl ) d 8.34
3
À1
1
(
104, 1029, 830, 743 cm ; ESI FTMS exact mass calcd for
(d, J=8.5 Hz, 2H), 7.84 (d, J=8.6 Hz, 2H), 7.50 (d, J=
7.9 Hz, 1H), 7.17 (d, J=5.3 Hz, 1H), 7.12 (d, J=3.3 Hz, 1H),
7.05 (t, J=7.5 Hz, 1H), 6.95–6.91 (m, 1H), 6.87 (t, J=7.7 Hz,
1H), 6.27 (d, J=8.3 Hz, 1H), 6.00 (d, J=4.7 Hz, 1H), 5.63 (s,
1H), 4.30–4.21 (m, 2H), 4.19–4.12 (m, 1H), 4.12–4.05 (m,
1H), 3.31 (d, J=4.6 Hz, 1H), 2.27 (s, 3H), 1.24 (t, J=7.1 Hz,
3H), 1.15 (t, J=7.1 Hz, 3H); C NMR (100 MHz, CDCl ) d
167.4, 166.6, 148.7, 146.3, 140.6, 134.7, 132.7, 130.0, 129.2,
126.6, 126.0, 125.7, 124.4, 121.4, 120.1, 118.7, 111.2, 109.2,
9.6, 62.7, 39.5, 14.1, 13.8, 7.9; IR (KBr): 3436, 2978, 2925,
744, 1527, 1459, 1346, 1231, 1103, 1018, 855, 739 cm ; ESI
FTMS exact mass calcd for (C H N O S-H) requires m/z
32.1537, found m/z 532.1526; Diastereomeric ratio: >95:5,
-
C H N O -H) requires m/z 556.2078, found m/z 556.2073;
31 31 3 7
1
Diastereomeric ratio: >95:5, determined by H NMR;
Enantiomeric ratio: 98:2, determined by HPLC (Daicel
Chiralpak AD-H, hexane/ isopropanol=80/20, flow rate
1
.0 mL/min, T=308C, 254 nm): t =11.47 min (major), t
R
R
13
=12.92 min (minor).
3
(
1S,4R)-Diethyl4-(4-fluorophenyl)-5-methyl-1-(4-nitrophen-
yl)-1,2-dihydropyrimido[1,6-a]indole-3,3(4H)-dicarboxylate
4fa): Preparative thin layer chromatography: petroleum
6
1
(
À1
ether/toluene/ethyl acetate=10:10:1; Reaction time=15 h;
-
20
2
8
27
3
6
yield: 60% (32.6 mg); yellow solid; m.p. 62–648C; [a]D = +
5
Adv. Synth. Catal. 2017, 359, 1–12
7
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

UPDATES
asc.wiley-vch.de
1
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
determined by H NMR; Enantiomeric ratio: 95:5, deter-
mined by HPLC (Daicel Chiralpak AD-H, hexane/ isopropa-
(1S,4R)-Diethyl1-(4-bromophenyl)-5-methyl-4-(p-tolyl)-1,2-
dihydropyrimido[1,6-a]indole-3,3(4H)-dicarboxylate (4dc):
Preparative thin layer chromatography: petroleum ether/
nol=80/20, flow rate 1.0 mL/min, T=308C, 254 nm): t =
.50 min (minor), t =10.12 min (major).
R
7
ethyl acetate=6/1; Reaction time=15 h; 2 yield: 57%
R
0
(
32.9 mg); yellow solid; m.p. 75–778C; [a]D = +131.1 (c
(
1S,4R)-Diethyl5-(4-chlorophenyl)-4-(4-methoxyphenyl)-1-
1
0
8
7
5
4
1
.64, Acetone); H NMR (400 MHz, CDCl ) d 7.64 (d, J=
3
(4-nitrophenyl)-1,2-dihydropyrimido[1,6-a]indole-3,3(4H)-di-
carboxylate (4ia): Preparative thin layer chromatography:
petroleum ether/ethyl acetate=4/1; Reaction time=15 h;
yield: 57% (37.4 mg) (inseparable diastereomers); yellow
solid; m.p. 83–858C; [a]D = +17.3 (c 0.50, Acetone);
NMR (400 MHz, CDCl ) d 8.40 (d, J=8.4 Hz, 2.6H), 7.88 (t,
.2 Hz, 2H), 7.53–7.46 (m, 3H), 7.34 (d, J=7.9 Hz, 2H), 7.10–
.02 (m, 3H), 6.88 (t, J=7.6 Hz, 1H), 6.37 (d, J=8.3 Hz, 1H),
.81 (d, J=6.1 Hz, 1H), 5.22 (s, 1H), 4.27 (q, J=7.1 Hz, 2H),
.13–4.03 (m, 1H), 4.02–3.91 (m, 1H), 3.03 (d, J=6.1 Hz,
H), 2.29 (s, 3H), 2.14 (s, 3H), 1.26 (t, J=7.1 Hz, 3H), 1.15 (t,
J=7.1 Hz, 3H); C NMR (100 MHz, CDCl ) d 168.1, 167.1,
2
0
1
H
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
3
13
3
J=7.5 Hz, 2.6H), 7.61 (d, J=8.0 Hz, 0.3H), 7.55 (d, J=
138.4, 137.1, 135.3, 134.8, 133.6, 132.4, 130.1, 129.5, 129.2,
129.0, 123.5, 120.8, 119.7, 118.3, 111.7, 108.5, 70.0, 69.7, 62.4,
7
7
7
6
2
3
.9 Hz, 1H), 7.40–7.30 (m, 3H), 7.28 (s, 0.9H), 7.24 (s, 1.9H),
.17 (d, J=8.2 Hz, 2H), 7.13–7.07 (m, 1.3H), 6.96 (t, J=
.7 Hz, 1.3H), 6.82–6.76 (m, 2.6H), 6.40 (d, J=8.3 Hz, 1.3H),
.13–6.02 (m, 1.3H), 5.25 (s, 0.3H), 5.18 (s, 1H), 4.31–4.16 (m,
.6H), 4.14–4.05 (m, 1.3H), 4.02–3.93 (m, 1.3H), 3.77 (s,
.9H), 3.09 (d, J=6.4 Hz, 1.3H), 1.22–1.16 (m, 3.9H), 1.13 (q,
62.3, 42.9, 21.1, 14.2, 13.8, 7.9; IR (KBr): 3366, 2976, 1743,
À1
1
458, 1256, 1207, 1103, 1061, 1014, 816, 742, 674 cm ; ESI
-
FTMS exact mass calcd for (C H BrN O -H) requires m/z
31 31
2
4
5
73.1383, found m/z 573.1366; Diastereomeric ratio: >95:5,
1
determined by H NMR; Enantiomeric ratio: 92:8, deter-
mined by HPLC (Daicel Chiralpak AD-H, hexane/ isopropa-
1
3
J=7.3 Hz, 3.9H); C NMR (100 MHz, CDCl ) d 167.6, 166.8,
3
166.7, 159.0, 158.9, 148.7, 145.9, 145.7, 134.9, 134.3, 134.1,
132.5, 132.3, 131.3, 131.1, 130.3, 129.8, 129.1, 128.9, 128.8,
128.6, 128.4, 126.5, 124.6, 121.9, 121.7, 121.1, 121.0, 119.6,
19.3, 115.1, 113.9, 113.8, 111.7, 111.6, 69.9, 69.8, 62.6, 62.6,
5.2, 42.8, 14.2, 13.9; IR (KBr): 3348, 2973, 1742, 1608, 1521,
456, 1348, 1246, 1097, 1030, 836, 742 cm ; ESI FTMS exact
mass calcd for (C H ClN O -H) requires m/z 652.1845,
found m/z 652.1838; Diastereomeric ratio: 77:23, determined
by H NMR; Enantiomeric ratio of major diastereomer: 98:2,
determined by HPLC (Daicel Chiralpak AD-H, hexane/
isopropanol=80/20, flow rate 1.0 mL/min, T=308C,
54 nm): tR =8.27 min (minor), tR =21.18 min (major);
Enantiomeric ratio of minor diastereomer: 91:9, determined
by HPLC (Daicel Chiralpak AD-H, hexane/ isopropanol=
80/20, flow rate 1.0 mL/min, T=308C, 254 nm): t =6.37min
nol=90/10, flow rate 1.0 mL/min, T=308C, 254 nm): t =
R
4
.93 min (minor), t =6.66 min (major).
R
1
5
1
(1S,4R)-Diethyl1-(3-bromophenyl)-4-(4-methoxyphenyl)-5-
methyl-1,2-dihydropyrimido[1,6-a]indole-3,3(4H)-dicarboxy-
late (4ed): Preparative thin layer chromatography: petroleum
ether/toluene/ethyl acetate=10:10:1; Reaction time=15 h;
À1
-
3
6
32
3
7
20
yield: 53% (31.1 mg); yellow oil; [a]D = +124.4 (c 0.59,
1
1
Acetone); H NMR (400 MHz, CDCl ) d 7.78 (s, 1H), 7.63
3
(d, J=8.0 Hz, 1H), 7.54 (d, J=7.7 Hz, 1H), 7.49 (d, J=
7.8 Hz, 1H), 7.41 (d, J=8.6 Hz, 2H), 7.37 (t, J=7.9 Hz, 1H),
7.05 (t, J=7.5 Hz, 1H), 6.88 (t, J=7.7 Hz, 1H), 6.81 (d, J=
8.6 Hz, 2H), 6.37 (d, J=8.3 Hz, 1H), 5.77 (d, J=5.6 Hz, 1H),
5.21 (s, 1H), 4.27 (q, J=7.1 Hz, 2H), 4.14–4.04 (m, 1H), 4.03–
3.93 (m, 1H), 3.76 (s, 3H), 3.07 (d, J=5.7 Hz, 1H), 2.15 (s,
2
R
1
3
(minor), t
=16.28 min (major).
3H), 1.27 (t, J=7.1 Hz, 3H), 1.16 (t, J=7.1 Hz, 3H);
NMR (100 MHz, CDCl ) d 168.2, 167.1, 158.9, 141.7, 134.9,
33.7, 132.7, 131.0, 130.8, 130.5, 130.4, 130.1, 126.4, 123.1,
C
R
3
(
1S,4R)-Diethyl1-(4-cyanophenyl)-5-methyl-4-(o-tolyl)-1,2-
1
1
5
1
dihydropyrimido[1,6-a]indole-3,3(4H)-dicarboxylate (4bb):
Preparative thin layer chromatography: petroleum ether/
toluene/ethyl acetate=10:10:1; Reaction time=15 h; yield:
63% (32.9 mg); yellow solid; m.p. 81–838C; [a] = +160.7
(c 0.52, Acetone); H NMR (400 MHz, CDCl ) d 7.82 (d, J=
20.9, 119.7, 118.3, 113.7, 111.7, 108.5, 70.0, 69.8, 62.5, 62.3,
5.2, 42.4, 14.2, 13.9, 7.9; IR (KBr): 3831, 3735, 3440, 1746,
À1
646, 1513, 1465, 1249, 1106, 676 cm ; ESI FTMS exact mass
2
D
0
-
calcd for (C H BrN O -H) requires m/z 589.1333, found
m/z 589.1323; Diastereomeric ratio: >95:5, determined by H
1
31 31
2
5
3
1
8.1 Hz, 2H), 7.74 (d, J=8.1 Hz, 2H), 7.63 (d, J=7.5 Hz, 1H),
7.47 (d, J=7.8 Hz, 1H), 7.17 (d, J=7.3 Hz, 1H), 7.12 (t, J=
NMR; Enantiomeric ratio: 92:8, determined by HPLC
(Daicel Chiralpak AD-H, hexane/ isopropanol=80/20, flow
7
6
5
1
2
.2 Hz, 1H), 7.08 (d, J=7.7 Hz, 1H), 7.03 (d, J=7.6 Hz, 1H),
.86 (t, J=7.7 Hz, 1H), 6.22 (d, J=8.3 Hz, 1H), 5.90 (d, J=
.7 Hz, 1H), 5.63 (s, 1H), 4.33–4.24 (m, 2H), 4.04–3.93 (m,
H), 3.85–3.72 (m, 1H), 3.16 (d, J=5.7 Hz, 1H), 2.66 (s, 3H),
.09 (s, 3H), 1.29 (t, J=7.1 Hz, 3H), 1.00 (t, J=7.1 Hz, 3H);
rate 1.0 mL/min, T=308C, 254 nm): t =4.45 min (major), t
R
R
=
5.75 min (minor).
(1R,4S)-Diethyl1-(2-bromophenyl)-4-(4-methoxyphenyl)-5-
methyl-1,2-dihydropyrimido[1,6-a]indole-3,3(4H)-dicarboxy-
late (ent-4ee): Preparative thin layer chromatography: petro-
leum ether/ethyl acetate=10/1; Reaction time=15 h; yield:
91% (53.5 mg) (inseparable diastereomers); yellow solid;
13
C NMR (100 MHz, CDCl ) d 168.3, 167.0, 144.3, 136.6,
3
1
1
6
1
35.7, 134.5, 134.1, 133.1, 130.5, 129.9, 129.5, 128.7, 127.4,
26.3, 120.9, 119.9, 118.4, 118.3, 113.6, 111.4, 108.7, 69.6, 69.5,
2.6, 62.4, 37.5, 20.2, 14.2, 13.5, 7.9; IR (KBr): 3439, 2980,
741, 1460, 1256, 1209, 1103, 1052, 842, 745, 675 cm ; ESI
FTMS exact mass calcd for (C H N O -H) requires m/z
20
1
m.p. 60–628C; [a]D =-57.7 (c 1.08, Acetone); H NMR
À1
(400 MHz, CDCl ) d 7.74 (d, J=7.6 Hz, 1H), 7.62 (d, J=
3
-
7.9 Hz, 0.5H), 7.53 (d, J=7.4 Hz, 1.5H), 7.49 (d, J=8.3 Hz,
3H), 7.40–7.30 (m, 2H), 7.23 (d, J=8.4 Hz, 1H), 7.11–7.02
(m, 2H), 7.02–6.96 (m, 1H), 6.93 (t, J=7.6 Hz, 0.5H), 6.87 (t,
J=7.7 Hz, 1H), 6.81 (d, J=8.4 Hz, 2H), 6.75 (t, J=8.1 Hz,
1.5H), 6.33 (d, J=4.1 Hz, 1H), 6.30 (d, J=8.3 Hz, 1H), 5.70
(d, J=7.7 Hz, 0.5H), 5.23 (s, 0.5H), 5.20 (s, 1H), 4.35–4.19
3
2
31
3
4
520.2231, found m/z 520.2234; Diastereomeric ratio: >95:5,
1
determined by H NMR; Enantiomeric ratio: 92:8, deter-
mined by HPLC (Daicel Chiralpak OD-H, hexane/ isopropa-
nol=90/10, flow rate 1.0 mL/min, T=308C, 254 nm): t =
.03 min (minor), t =7.79 min (major).
R
7
R
(m, 2H), 4.15–4.02 (m, 2H), 4.02–3.93 (m, 1H), 3.91–3.83 (m,
Adv. Synth. Catal. 2017, 359, 1–12
8
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

UPDATES
asc.wiley-vch.de
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2
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4
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6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
0.5H), 3.76 (s, 3H), 3.75 (s, 1.5H), 3.65–3.56 (m, 0.5H), 3.30
d, J=4.0 Hz, 1H), 2.85–2.72 (m, 0.5H), 2.17 (s, 3H), 2.13 (s,
.5H), 1.29 (t, J=7.1 Hz, 3H), 1.17 (t, J=6.8 Hz, 3H), 1.12
118.2, 114.4, 113.7, 112.0, 108.3, 70.0, 66.3, 62.4, 62.2, 55.2,
42.6, 18.8, 14.2, 13.9, 7.9; IR (KBr): 3371, 2979, 2926, 1742,
(
1
À1
1511, 1458, 1250, 1104, 1036, 830, 739, 672 cm ; ESI FTMS
1
3
-
(
d, J=7.1 Hz, 1.5H), 0.87 (t, J=7.1 Hz, 1.5H); C NMR
exact mass calcd for (C H N O -H) requires m/z 525.2384,
3
2
34
2
5
(
100 MHz, CDCl ) d 169.7, 168.5, 167.9, 167.3, 158.8, 158.7,
found m/z 525.2375; Diastereomeric ratio: >95:5, determined
3
1
1
1
1
1
6
1
1
36.5, 136.1, 134.6, 134.0, 133.9, 133.2, 132.9, 132.6, 131.5,
30.7, 130.6, 130.4, 130.3, 130.1, 130.0, 129.5, 129.3, 129.2,
28.7, 127.9, 126.3, 121.0, 120.7, 119.6, 119.6, 118.4, 118.3,
13.5, 113.4, 111.5, 110.4, 108.3, 107.6, 69.9, 66.8, 66.4, 65.6,
2.5, 62.2, 62.0, 61.6, 55.2, 55.1, 42.5, 41.1, 14.2, 13.9, 13.9,
3.4, 8.1, 8.0; IR (KBr): 3370, 2928, 1742, 1611, 1511, 1460,
by H NMR; Enantiomeric ratio: 87:13, determined by
HPLC (Daicel Chiralpak IA, hexane/ isopropanol=98/2,
flow rate 1.0 mL/min, T=308C, 254 nm): t =10.80 min
R
(minor), t =12.94 min (major).
R
(1S,4R)-Diethyl4-(4-methoxyphenyl)-5-methyl-1-(naphtha-
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
À1
len-1-yl)-1,2-dihydropyrimido[1,6-a]indole-3,3(4H)-dicarbox-
ylate (4eh): Preparative thin layer chromatography: petro-
leum ether/ethyl acetate=6/1; Reaction time=15 h; yield:
249, 1103, 1041, 832, 737, 675 cm ; ESI FTMS exact mass
-
calcd for (C H BrN O -H) requires m/z 589.1333, found
3
1
31
2
5
1
m/z 589.1330; Diastereomeric ratio: 67:33, determined by H
NMR; Enantiomeric ratio of major diastereomer: 88:12,
determined by HPLC (Daicel Chiralpak OD-H, hexane/
isopropanol=95/5, flow rate 1.0 mL/min, T=308C, 254 nm):
tR =5.93 min (minor), tR =8.17 min (major); Enantiomeric
ratio of minor diastereomer: 98:2, determined by HPLC
2
0
5
(
0% (28.2 mg); yellow solid; m.p. 70–728C; [a]D = +190.8
1
c 0.66, Acetone); H NMR (400 MHz, CDCl ) d 8.39 (d, J=
3
8.2 Hz, 1H), 7.99 (t, J=9.0 Hz, 2H), 7.70 (d, J=7.1 Hz, 1H),
7.66–7.56 (m, 2H), 7.52 (t, J=7.2 Hz, 2H), 7.41 (d, J=8.5 Hz,
2H), 7.04 (t, J=7.4 Hz, 1H), 6.84–6.73 (m, 4H), 6.30 (d, J=
8.3 Hz, 1H), 5.31 (s, 1H), 4.44–4.26 (m, 2H), 4.13–4.02 (m,
1H), 4.00–3.89 (m, 1H), 3.74 (s, 3H), 3.23 (d, J=7.2 Hz, 1H),
2.21 (s, 3H), 1.36 (t, J=7.1 Hz, 3H), 1.14 (t, J=7.1 Hz, 3H);
(
Daicel Chiralpak OD-H, hexane/ isopropanol=95/5, flow
rate 1.0 mL/min, T=308C, 254 nm): t =6.71min (minor), t
R
R
=
10.28 min (major).
13
C NMR (100 MHz, CDCl ) d 168.2, 167.0, 158.8, 135.0,
3
(
1S,4R)-Diethyl1-(3-methoxyphenyl)-5-methyl-4-(p-tolyl)-
134.2, 134.1, 134.0, 131.0, 130.5, 130.4, 130.1, 129.5, 129.0,
127.0, 126.1, 125.5, 125.2, 123.0, 120.5, 119.5, 118.2, 113.7,
112.4, 108.4, 70.0, 65.9, 62.5, 62.2, 55.2, 43.0, 14.2, 13.9, 7.9;
IR (KBr): 3439 2971, 1742, 1610, 1511, 1458, 1303, 1251,
1
(
,2-dihydropyrimido[1,6-a]indole-3,3(4H)-dicarboxylate
4df): Preparative thin layer chromatography: petroleum
ether/ethyl acetate=6/1; Reaction time=15 h; yield: 47%
2
0
À1
(
24.8 mg); yellow solid; m.p. 53–558C; [a]D = +138.9 (c
1208, 1039, 742, 674 cm ; ESI FTMS exact mass calcd for
1
-
0
7
.53, Acetone); H NMR (400 MHz, CDCl ) d 7.47 (d, J=
(C H N O -H) requires m/z 561.2384, found m/z 561.2377;
3
35 34
2
5
1
.8 Hz, 1H), 7.43–7.35 (m, 3H), 7.20 (d, J=7.7 Hz, 1H), 7.16
Diastereomeric ratio: >95:5, determined by H NMR;
Enantiomeric ratio: 94:6, determined by HPLC (Daicel
Chiralpak AD-H, hexane/ isopropanol=80/20, flow rate
1.0 mL/min, T=308C, 254 nm): t =4.14 min (major), t =
(
s, 1H), 7.07 (d, J=7.9 Hz, 2H), 7.05–7.00 (m, 2H), 6.85 (t,
J=7.7 Hz, 1H), 6.42 (d, J=8.3 Hz, 1H), 5.76 (d, J=6.0 Hz,
H), 5.21 (s, 1H), 4.26 (q, J=7.1 Hz, 2H), 4.12–4.02 (m, 1H),
1
R
R
4.00–3.91 (m, 1H), 3.83 (s, 3H), 3.09 (d, J=6.1 Hz, 1H), 2.28
(s, 3H), 2.14 (s, 3H), 1.26 (t, J=7.1 Hz, 3H), 1.13 (t, J=
6.43 min (minor).
1
3
(1R,4S)-Diethyl 4-(4-methoxyphenyl)-5-methyl-1-(thiophen-
7.1 Hz, 3H); C NMR (100 MHz, CDCl
160.2, 141.0, 137.0, 135.5, 135.1, 133.7, 130.2, 130.0, 129.2,
) d 168.3, 167.2,
3
3
-yl)-1,2-dihydropyrimido[1,6-a]indole-3,3(4H)-dicarboxy-
late (ent-4ei): Flash column chromatography eluent, petro-
leum ether/toluene/ethyl acetate=10:10:1; Reaction time=
1
7
2
6
28.9, 120.6, 120.0, 119.5, 118.1, 115.1, 113.2, 111.9, 108.2,
0.3, 70.0, 62.4, 62.2, 55.4, 42.9, 21.1, 14.2, 13.8, 7.9; IR (KBr):
926, 1741, 1601, 1458, 1257, 1207, 1153, 1102, 1043, 814, 744,
1
5 h; yield: 53% (27.6 mg); yellowish solid, m.p 53–558C;
2
0
1
À1
-
[a] =-158.8 (c 0.54, Acetone); H NMR (400 MHz, CDCl )
D
3
78 cm ; ESI FTMS exact mass calcd for (C H N O -H)
3
2
34
2
5
d 7.60 (s, 1H), 7.52 (d, J=7.8 Hz, 1H), 7.49–7.45 (m, 1H),
7.44–7.39 (m, 2H), 7.36 (d, J=4.9 Hz, 1H), 7.08 (t, J=7.4 Hz,
1H), 6.94 (t, J=7.7 Hz, 1H), 6.87–6.77 (m, 2H), 6.53 (d, J=
8.3 Hz, 1H), 6.02 (d, J=6.2 Hz, 1H), 5.24 (s, 1H), 4.35–4.24
requires m/z 525.2384, found m/z 525.2376; Diastereomeric
1
ratio: >95:5, determined by H NMR; Enantiomeric ratio:
9
2:8, determined by HPLC (Daicel Chiralpak AD-H,
hexane/ isopropanol=90/10, flow rate 1.0 mL/min, T=308C,
54 nm): t =4.93 min (minor), t =5.61 min (major).
(m, 2H), 4.18–4.08 (m, 1H), 4.07–3.96 (m, 1H), 3.78 (d, J=
2
R
R
1
.7 Hz, 3H), 3.15 (d, J=6.2 Hz, 1H), 2.17 (s, 3H), 1.28 (t, J=
13
(
1
(
1S,4R)-Diethyl4-(4-methoxyphenyl)-5-methyl-1-(o-tolyl)-
,2-dihydropyrimido[1,6-a]indole-3,3(4H)-dicarboxylate
4eg): Preparative thin layer chromatography: petroleum
7.1 Hz, 3H), 1.20 (t, J=7.1 Hz, 3H); C NMR (100 MHz,
CDCl ) d 168.3, 167.3, 158. 9, 141.2, 135.1, 133.7, 130.7, 130.5,
3
130.0, 127.3, 126.8, 124.8, 120.8, 119.6, 118.2, 113.7, 111.6,
108.0, 70.0, 65.9, 62.4, 62.3, 55.2, 42.5, 14.2, 14.0, 7.9; IR
(KBr): 2980, 1740, 1610, 1511, 1460, 1300, 1253, 1177, 1036,
ether/toluene/dichloromethane=1:1:1; Reaction time=15 h;
20
yield: 52% (27.5 mg); yellow solid; m.p. 73–758C; [a]D = +
1
À1
1
43.8 (c 0.59, Acetone); H NMR (400 MHz, CDCl ) d 7.60
833, 743, 662 cm ; ESI FTMS exact mass calcd for (C H N
3
29 30
2
-
(
8
d, J=7.6 Hz, 1H), 7.52 (d, J=7.8 Hz, 1H), 7.43 (d, J=
.4 Hz, 2H), 7.39 (d, J=6.2 Hz, 2H), 7.31 (d, J=5.9 Hz, 1H),
O S-Na) requires m/z 495.1977, found m/z 495.1974; Diaster-
eomeric ratio: >95:5, determined by H NMR; Enantiomeric
5
1
7.06 (t, J=7.4 Hz, 1H), 6.91–6.79 (m, 3H), 6.34 (d, J=8.2 Hz,
1H), 6.08 (d, J=7.1 Hz, 1H), 5.27 (s, 1H), 4.28 (q, J=6.9 Hz,
2H), 4.16–4.05 (m, 1H), 4.04–3.94 (m, 1H), 3.77 (s, 3H), 3.03
ratio: 89:11, determined by HPLC (Daicel Chiralpak AD-H,
hexane/ isopropanol=90/10, flow rate 1.0 mL/min, T=308C,
254 nm): t
=9.59 min (major), t
=10.27 min (minor).
R
R
(
7
d, J=7.1 Hz, 1H), 2.62 (s, 3H), 2.19 (s, 3H), 1.30 (t, J=
.1 Hz, 3H), 1.19 (t, J=7.1 Hz, 3H); C NMR (100 MHz,
1
3
(1S,4R)-Diethyl
4-(4-methoxyphenyl)-5-methyl-1-((E)-
styryl)-1,2-dihydropyrimido[1,6-a]indole-3,3(4H)-dicarboxy-
late (4ej): Flash column chromatography eluent, petroleum
CDCl ) d 168.4, 167.2, 158.8, 137.0, 136.2, 135.1, 134.3, 132.0,
3
131.1, 130.8, 130.4, 130.1, 129.0, 127.2, 126.9, 120.6, 119.5,
Adv. Synth. Catal. 2017, 359, 1–12
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6
7
ether/toluene/ethyl acetate=10:10:1; Reaction time=15 h;
yield: 41% (22.1 mg); yellowish solid, m.p 38–408C; [a]D =-
Enantiomeric ratio: 82:18, determined by HPLC (Daicel
Chiralpak AD-H, hexane/ isopropanol=80/20, flow rate
20
1
5
7
1
2
1
4
5
7
1
1
6.5 (c 0.40, Acetone); H NMR (400 MHz, CDCl ) d 7.57–
1.0 mL/min, T=308C, 254 nm): t =5.69 min (major), t =
3
R
R
.51 (m, 2H), 7.49 (d, J=7.1 Hz, 1H), 7.46 (d, J=8.0 Hz,
H), 7.43–7.37 (m, 2H), 7.37–7.32 (m, 1H), 7.30–7.26 (m,
H), 7.11–6.99 (m, 3H), 6.84–6.75 (m, 2H), 6.70–6.63 (m,
H), 5.65–5.53 (m, 1H), 5.15 (s, 1H), 4.30–4.18 (m, 2H), 4.16–
.06 (m, 1H), 4.06–3.95 (m, 1H), 3.75 (s, 3H), 3.00 (d, J=
.5 Hz, 1H), 2.09 (s, 3H), 1.22 (t, J=7.1 Hz, 3H), 1.18 (t, J=
.2 Hz, 3H); C NMR (100 MHz, CDCl ) d 168.3, 167.3,
58.8, 135.6, 135.4, 134.9, 132.7, 130.5, 129.8, 128.8, 128. 7,
28.7, 127.1, 120.7, 119.5, 118.3, 113.6, 111.4, 107.4, 69.6, 68.6,
6.53 min (minor).
Procedure for the Synthesis of Product 8
Under argon atmosphere, compound 4ba (0.05 mmol) and
lithium chloride (6 equiv.) were added to a dried tube. After
adding DMSO (2 mL) and water (0.5 mL) to the reaction
system, the reaction mixture was stirred at 1308C for 15 h.
After the completion of the reaction which was indicated by
TLC, the reaction mixture was subjected to preparative thin
layer chromatography on silicon gel to give pure product 8.
13
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
62.4, 62.3, 55.2, 42.5, 14.1, 13.9, 7.8; IR (KBr): 2980, 2915,
1741, 1611, 1511, 1460, 1250, 1177, 1108, 1035, 823, 744,
À1
-
695 cm ; ESI FTMS exact mass calcd for (C33
H N O -Na)
34 2 5
Ethyl 5-methyl-1-(4-nitrophenyl)-4-(o-tolyl)-1,2-dihydropyri-
mido[1,6-a]indole-3-carboxylate (8): Flash column chroma-
tography eluent, petroleum ether/ethyl acetate=6/1; Reac-
requires m/z 515.2570, found m/z 515.2567; Diastereomeric
1
ratio: >95:5, determined by H NMR; Enantiomeric ratio:
8
0:20, determined by HPLC (Daicel Chiralpak AD-H,
hexane/ isopropanol=95/5, flow rate 1.0 mL/min, T=308C,
54 nm): t =10.42 min (minor), t =13.10 min (major).
tion time=15 h; yield: 54% (12.5 mg); red solid, m.p 27–
1
2
7
98C; H NMR (400 MHz, CDCl ) d 8.48 (d, J=8.2 Hz, 2H),
2
3
R
R
.96 (s, 2H), 7.73 (d, J=8.1 Hz, 1H), 7.43–7.37 (m, 2H), 7.34
(1S,4R)-Diethyl 1-cyclohexyl-4-(4-methoxyphenyl)-5-methyl-
1,2-dihydropyrimido[1,6-a]indole-3,3(4H)-dicarboxylate
(d, J=7.6 Hz, 1H), 7.29 (d, J=7.4 Hz, 1H), 7.27 (s, 1H),
7.25–7.21 (m, 1H), 7.14–7.08 (m, 1H), 6.64 (d, J=8.7 Hz,
(
4ek): Flash column chromatography eluent, petroleum
1H), 4.07 (q, J=7.1 Hz, 2H), 2.22 (s, 3H), 1.76 (s, 3H), 0.95
ether/dichlormethane= 1/1; Reaction time=15 h; yield: 33%
13
(t, J=7.1 Hz, 3H); C NMR (100 MHz, CDCl ) d 165.7,
3
2
0
(
17.2 mg); yellowish solid, m.p 44–468C; [a]D =-195.9 (c
149.1, 147.6, 141.3, 137.1, 135.0, 132.1, 130.9, 130.0, 129.9,
129.6, 129.0, 128.7, 128.6, 125.7, 124.5, 124.1, 122.8, 119.4,
1
0
2
2
3
3
3
3
.39, Acetone); H NMR (400 MHz, CDCl ) d 7.54–7.43 (m,
3
H), 7.30–7.26 (m, 2H), 7.16–7.06 (m, 2H), 6.80–6.74 (m,
H), 5.09 (s, 1H), 5.01–4.91 (m, 1H), 4.21–4.07 (m, 3H), 4.05–
.93 (m, 1H), 3.76 (s, 3H), 2.95 (d, J=5.9 Hz, 1H), 2.03 (s,
H), 1.99–1.92 (m, 1H), 1.90–1.75 (m, 3H), 1.67–1.53 (m,
H), 1.52–1.39 (m, 2H), 1.35–1.27 (m, 2H), 1.21 (t, J=6.3 Hz,
1
1
14.7, 109.2, 61.2, 19.8, 13.6, 8.5; IR (KBr): 2965, 2918, 1721,
À1
523, 1446, 1380, 1346, 1263, 1151, 1018, 853, 802, 733 cm ;
-
ESI FTMS exact mass calcd for (C H N O -H) requires
2
8
25
3
4
m/z 466.1767, found m/z 466.1762; Enantiomeric ratio: 50:50,
determined by HPLC (Daicel Chiralpak AD-H, hexane/
isopropanol=90/10, flow rate 1.0 mL/min, T=308C,
1
3
H), 1.17 (t, J=6.3 Hz, 3H); C NMR (100 MHz, CDCl ) d
3
168.5, 167.8, 158.7, 134.3, 134.1, 130.8, 130.7, 130.1, 120.5,
119.1, 118.3, 113.4, 111.2, 107.6, 70.9, 69.3, 62.1, 62.1, 55.1,
43.0, 41.1, 29.2, 27.0, 26.5, 26.4, 25.0, 14.1, 13.9, 7.8; IR (KBr):
2
54 nm): t =29.46 min, t =34.39 min.
R R
3381, 2932, 2853, 1742, 1611, 1512, 1459, 1258, 1096, 1035,
Procedure for the Synthesis of Product 9
À1
8
26, 738 cm ; ESI FTMS exact mass calcd for (C H N O -
31 38
2
5
Under argon atmosphere, compound 4dc (0.06 mmol), 4-
chlorophenylboronic acid (1.5 equiv.), CsCO3 (2 equiv.),
-
H) requires m/z 517.2703, found m/z 517.2700; Diastereo-
meric ratio: >95:5, determined by H NMR; Enantiomeric
1
Pd(OAc) (0.05 equiv.) and butyl di-1-adamantylphosphine
2
ratio: 89:11, determined by HPLC (Daicel Chiralpak AD-H,
hexane/ isopropanol=90/10, flow rate 1.0 mL/min, T=308C,
(0.06 equiv.) were added to a dried tube. After adding DME
(4 mL) and water (1 mL) to the reaction system, the reaction
mixture was stirred at 808C for 13 h. After the completion of
the reaction which was indicated by TLC, the reaction
mixture was subjected to preparative thin layer chromatog-
raphy on silicon gel to give pure product 9.
2
54 nm): t =3.86 min (minor), t =4.49 min (major).
R
R
(1S,4R)-Diethyl1-benzyl-5-methyl-4-(o-tolyl)-1,2-dihydropyr-
imido[1,6-a]indole-3,3(4H)-dicarboxylate (4bl): Preparative
thin layer chromatography: petroleum ether/toluene/ethyl
acetate=10:10:1; Reaction time=15 h; yield: 47% (24.1 mg);
(1S,4R)-Diethyl 1-(4’-chloro-[1,1’-biphenyl]-4-yl)-5-methyl-4-
(p-tolyl)-1,2-dihydropyrimido[1,6-a]indole-3,3(4H)-dicarbox-
ylate (9): Flash column chromatography eluent, petroleum
2
D
0
yellow solid; m.p. 41–428C; [a] = +20.0 (c 0.42, Acetone);
1
H NMR (400 MHz, CDCl ) d 7.58–7.49 (m, 2H), 7.30–7.25
3
(
m, 3H), 7.23–7.19 (m, 1H), 7.17–7.09 (m, 5H), 7.09–7.02 (m,
ether/ethyl acetate=5/1; Reaction time=13 h; yield: 98%
2
5
H), 5.44–5.34 (m, 1H), 4.61 (d, J=6.0 Hz, 1H), 4.33 (d, J=
.9 Hz, 1H), 4.16–4.02 (m, 4H), 3.65 (t, J=5.6 Hz, 1H), 3.22
20
(
35.5 mg); yellowish solid, m.p 37–398C; [a]D = +75.2 (c
1
0
7
2
8
7
.67, Acetone); H NMR (400 MHz, CDCl ) d 7.68 (s, 4H),
3
(
4
t, J=6.9 Hz, 1H), 2.02 (s, 3H), 1.95 (s, 3H), 1.18 (t, J=
.9 Hz, 3H), 1.15 (t, J=4.9 Hz, 3H); C NMR (100 MHz,
.62–7.57 (m, 2H), 7.52–7.43 (m, 3H), 7.38 (d, J=8.1 Hz,
H), 7.11–7.00 (m, 3H), 6.91–6.81 (m, 1H), 6.45 (d, J=
.3 Hz, 1H), 5.87 (d, J=6.4 Hz, 1H), 5.24 (s, 1H), 4.29 (q, J=
.1 Hz, 2H), 4.15–4.03 (m, 1H), 4.02–3.89 (m, 1H), 3.09 (d,
1
3
CDCl ) d 168.7, 168.3, 141.2, 141.1, 139.7, 136.0, 133.9, 132.7,
3
130.4, 128.9, 127.6, 127.4, 127.3, 126.8, 126.5, 120.9, 119.4,
118.6, 110.3, 103.1, 65.4, 62.2, 62.0, 60.5, 47.1, 19.8, 14.0, 13.9,
J=6.4 Hz, 1H), 2.29 (s, 3H), 2.16 (s, 3H), 1.29 (d, J=7.1 Hz,
8
1
.3; IR (KBr): 3436, 2924, 2857, 1741, 1458, 1227, 1157, 1103,
13
3
1
1
H), 1.15 (t, J=7.1 Hz, 3H); C NMR (100 MHz, CDCl ) d
À1
3
027, 806, 745, 676 cm ; ESI FTMS exact mass calcd for (C
32
68.2, 167.2, 141.0, 138.9, 138.7, 137.0, 135.5, 135.0, 133.8,
33.7, 130.1, 129.2, 129.1, 129.0, 128.5, 128.4, 127.7, 120.6,
-
H N O -H) requires m/z 509.2435, found m/z 509.2437;
Diastereomeric ratio: >95:5, determined by H NMR;
34
2
4
1
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119.6, 118.3, 111.9, 108.3, 70.0, 70.0, 62.4, 62.3, 42.9, 21.1,
W.-J. Qin, F.-F. Tang, X. Yu, W.-P. Deng, ACS Catal.
2016, 6, 5685.
1
1
4.2, 13.8, 7.9; IR (KBr): 2980, 2919, 2858, 1741, 1459, 1299,
À1
257, 1207, 1094, 1017, 817, 741 cm ; ESI FTMS exact mass
[5] For organocatalytic asymmetric [3+3] cycloadditions of
azomethine ylide: a) J. Huang, S. Luo, L. Gong, Acta
Chim. Sin. 2013, 71, 879; b) F. Shi, R.-Y. Zhu, W. Dai,
C.-S. Wang, S.-J. Tu, Chem. Eur. J. 2014, 20, 2597; c) W.
Dai, H. Lu, X. Li, F. Shi, S.-J. Tu, Chem. Eur. J. 2014,
20, 11382; d) X.-X. Sun, H.-H. Zhang, G.-H. Li, Y.-Y.
He, F. Shi, Chem. Eur. J. 2016, 22, 17526.
6] For catalytic asymmetric [6+3] cycloadditions of azo-
methine ylide: a) M. Potowski, J. O. Bauer, C. Stroh-
mann, A. P. Antonchick, H. Waldmann, Angew. Chem.
Int. Ed. 2012, 51, 9512; b) Z.-L. He, H.-L. Teng, C.-J.
Wang, Angew. Chem. Int. Ed. 2013, 52, 2934; c) H.-L.
Teng, L. Yao, C.-J. Wang, J. Am. Chem. Soc. 2014, 136,
4075; d) Q.-H. Li, L. Wei, C.-J. Wang, J. Am. Chem. Soc.
2014, 136, 8685; e) Z.-L. He, F. K. Sheong, Q.-H. Li, Z.
Lin, C.-J. Wang, Org. Lett. 2015, 17, 1365.
-
calcd for (C H ClN O -H) requires m/z 605.2207, found
3
7
35
2
4
m/z 605.2204; Enantiomeric ratio: 92:8, determined by HPLC
Daicel Chiralpak AD-H, hexane/ isopropanol=90/10, flow
(
rate 1.0 mL/min, T=308C, 254 nm): t =7.67 min (minor),
R
tR =10.83 min (major).
[
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
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5
Acknowledgements
We are grateful for financial supports from NSFC (21372002
and 21232007), PAPD, Natural Science Foundation of
Jiangsu Province (BK20160003).
References
[7] a) K. Bera, C. Schneider, Chem. Eur. J. 2016, 22, 7074;
b) K. Bera, C. Schneider, Org. Lett. 2016, 18, 5660.
8] For some reviews: a) T. Akiyama, Chem. Rev. 2007, 107,
[
1] For some recent reviews: a) J. Adrio, J. C. Carretero,
Chem. Commun. 2011, 47, 6784; b) R. Narayan, M.
Potowski, Z.-J. Jia, A. P. Antonchick, H. Waldmann,
Acc. Chem. Res. 2014, 47, 1296; c) T. Hashimoto, K.
Maruoka, Chem. Rev. 2015, 115, 5366.
[
5
744; b) M. Terada, Chem. Commun. 2008, 35, 4097;
c) M. Terada, Synthesis 2010, 1929; d) J. Yu, F. Shi, L.-Z.
Gong, Acc. Chem. Res. 2011, 44, 1156; e) D. Parmar, E.
Sugiono, S. Raja, M. Rueping, Chem. Rev. 2014, 114,
[2] For early reports on metal-catalyzed asymmetric [3+2]
cycloadditions of azomethine ylide: a) J. M. Longmire,
B. Wang, X. Zhang, J. Am. Chem. Soc. 2002, 124, 13400;
b) A. S. Gothelf, K. V. Gothelf, R. G. Hazell, K. A.
Jørgensen, Angew. Chem. Int. Ed. 2002, 41, 4236.
9
1
047; f) H. Wu, Y.-P. He, F. Shi, Synthesis, 2015, 47,
990; For some recent prominent examples: g) W. Zhao,
Z. Wang, B. Chu, J. Sun, Angew. Chem. Int. Ed. 2015,
4, 1910; h) Z. B. Wang, F. J. Ai, Z. Wang, W. X. Zhao,
G. Y. Zhu, Z. Y. Lin, J. W. Sun, J. Am. Chem. Soc. 2015,
37, 383; For some representative examples in our
5
[
3] For early reports on organocatalytic asymmetric [3+2]
cycloadditions of azomethine ylide: a) J. L. Vicario, S.
Reboredo, D. Badꢂa, L. Carrillo, Angew. Chem. Int. Ed.
1
group: i) F. Shi, G.-J. Xing, R.-Y. Zhu, W. Tan, S. Tu,
Org. Lett. 2013, 15, 128; j) Y.-C. Zhang, J.-J. Zhao, F.
Jiang, S.-B. Sun, F. Shi, Angew. Chem. Int. Ed. 2014, 53,
13912.
2
007, 46, 5168; b) I. Ibrahem, R. Rios, J. Vesely, A.
Cordova, Tetrahedron Lett. 2007, 48, 6252; c) M.-X.
Xue, X.-M. Zhang, L.-Z. Gong, Synlett 2008, 691; d) Y.-
K. Liu, H. Liu, W. Du, L. Yue, Y.-C. Chen, Chem. Eur.
J. 2008, 14, 9873; e) X.-H. Chen, W.-Q. Zhang, L.-Z.
Gong, J. Am. Chem. Soc. 2008, 130, 5652.
[9] R.-Y. Zhu, C.-S. Wang, F. Jiang, F. Shi, S.-J. Tu,
Tetrahedron: Asymmetry 2014, 25, 617.
10] a) W.-J. Liu, X.-H. Chen, L.-Z. Gong, Org. Lett. 2008,
[4] For metal-catalyzed asymmetric [3+3] cycloadditions
of azomethine ylide: a) M.-C. Tong, X. Chen, H.-Y. Tao,
C.-J. Wang, Angew. Chem. Int. Ed. 2013, 52, 12377;
b) H. Guo, H. Liu, F.-L. Zhu, R. Na, H. Jiang, Y. Wu, L.
Zhang, Z. Li, H. Yu, B. Wang, Y. Xiao, X.-P. Hu, M.
Wang, Angew. Chem. Int. Ed. 2013, 52, 12641; c) C.
Yuan, H. Liu, Z. Gao, L. Zhou, Y. Feng, Y. Xiao, H.
Guo, Org. Lett. 2015, 17, 26; d) W.-L. Yang, C.-Y. Li,
[
1
0, 5357; b) F. Shi, G.-J. Xing, W. Tan, R.-Y. Zhu, S. Tu,
Org. Biomol. Chem. 2013, 11, 1482.
[11] CCDC 1524703 (4fa) contains the supplementary
crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_re-
quest/cif. See the Supporting Information for details.
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Catalytic Asymmetric [3+3] Cycloaddition of Azome-
thine Ylides with C3-Substituted 2-Indolylmethanols
Adv. Synth. Catal. 2017, 359, 1–12
X.-X. Sun, C. Li, Y.-Y. He, Z.-Q. Zhu, G.-J. Mei, F. Shi*
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